Episode #000 - The Roadmap to Solve Aging (Mark Hamalainen & Nathan Cheng, Co-Directors at Longevity Biotech Fellowship)

Welcome to the Longgevity Acceleration Podcast, where we talk to visionary thinkers in longevity about their mental models and road maps to solve aging. Wear your hosts, Nathan Chang and Mark Hamilton, co-directors of the Longgevity Biotech Fellowship. Hi, I'm Nathan Chang, and I'm Mark Hamilton. And this is the Longgevity Acceleration Podcast. So we started this podcast because we're building a technical road map to solve aging and we'll be interviewing experts in a wide range of fields in order to build that. And we wanted to share those conversations with you. There'll be long form, deep dives into the technicals on the research and technology necessary to solve aging entirely. We're not the only Longgevity Podcast, and we're definitely not the first. But the term "Longgevity" has come to mean so many different things that it can sort of mean almost anything. So what do we mean by solving aging? We're not talking about squaring the mortality curve. We're not talking about health span. We're not talking about supplements, diets, or drug repurposing. We're talking about developing advanced technologies to achieve unlimited length of healthy lifespan available to anybody who wants it. Our view is that no amount of aging is good and that the more healthy years science can give us the better, and that humanity should be prioritizing research and technology paths to solve aging. So what types of technology and research are we talking about? Things like whole body, genetic software updates, that means solving the gene delivery problem, growing nonsensual clones for replacement parts, whether it be organically, organs, or entire bodies, gradual brain replacement, reversible travel preservation, as well as tools that accelerate the rate of progress such as artificial intelligence and automation. To be clear, we're in favor of practicing things like health optimization, longevity optimization, and in the hearing now. Also near-term technologies like pharmacology. But ultimately, we think those sort of things can only buy us a small amount of extra time. They're not going to be the actual solutions for solving aging. And they shouldn't be the bulk of our efforts. Yeah, so now we should probably introduce ourselves a little bit. Why are you listening to us? I'll go ahead and start. Again, my name is Mark Himalayan. I got into longevity, interested in longevity in the '90s, actually, as a teenager reading, a particular science fiction series called The Mars Trilogy. It was a story about people terraforming Mars. It took place over 250 years, and some of the original main characters from the beginning of the story were still alive to see the completion of the project, and it was really inspiring to me. It was the world that I wanted to live in, and the characters in the book were role models for me. They were scientists and engineers, and they built the technology both to terraform Mars and to extend human lifespan. So I started studying gerontology, getting my hands on all the textbooks, journals available. At the time, I was pretty discouraging. The state of understanding of aging was quite primitive. It really wasn't clear whether this was something that would be feasible on any reasonable time scale. But I wasn't deterred. I decided it's not -- problem's not going to solve itself. People need to work on it. And academia and quickly ran into something that many of you would have heard of, which is the reproducibility crisis I spent two years trying to reproduce the results of a predecessor during my PhD, only to find that none of those results were reproducible. And after that experience, I realized that if this is the way we do research, we're definitely not going to solve this problem in my lifetime. I would call that sort of artisanal science. Hypothesis-driven manual for the purposes of generating publications. So I dropped out of my PhD and I moved to California and focused on startups to do technology development, to do research faster and more reliably. I was the first employee at Synthigo and the director of science there, which does genome engineering as a service, fully automated in the background. It was a service that allows researchers to make faster progress because they don't have to know how to do and optimize all of those methods. They can just get any cells they want with any modifications that they want. But I saw that there was a growing interest in longevity and yet the pace of progress was still extremely slow. When I got interested in the field, there were zero aging therapeutics, aging interventions. And 15 years later, when I was at Synthigo and getting ready to think about my next project, there were still zero aging therapies. And even today, there are still zero aging therapies. So I realized that we really need to grow this movement. It can't just be a niche. It needs to be a priority. And so I started on nonprofit that was called Less Death and ran an event called Longivity Summer Camp. The idea there was to reproduce and experience I had had early in my career, which was going to one of the early Synth conferences and meeting a bunch of people that were like-minded about wanting to do something about aging. And they became my friends, my coworkers, my collaborators, my co-founders. And I wanted to reproduce that experience for as many people as possible. And I invited Nathan Chang to it because Nathan was running another program, which was an online program called ODLB, that was having quite a bit of success. And so I wanted his help to make sure that my program was a success. And Nathan, maybe you should now tell the audience how you ended up in longevity and how you ended up working with me. Yeah, sure. So my story is a little bit convoluted and a little bit different. But yeah, I came into the longevity space sort of late in life. I started off doing it in physics, actually. And I didn't like biology when I was growing up in high school. I didn't even take biology as a specialization because I thought it was so boring. It was more interested in physics. And yeah, I was doing a PhD in physics at the University of Toronto. I got two years into my PhD and had this like very sudden existential crisis where I just had this epiphany that I was going to die and that this was a big problem. And not just myself, but everyone that I loved and so forth. And yeah, it was a real wake up call for me to think about like, what am I doing with my life? Well, like what is actually important to be working on? And it got to the point where I just couldn't handle this existential pressure, this sort of thing hanging over my head. And I had to do something. So I ended up quitting dropping out of my PhD. And a long time sort of passed in between my PhD and trying to figure out what I wanted to do. But shortly after I dropped out of my PhD, I remember stumbling across a YouTube video of Ray Kurzweil documentary. And in that documentary, he was trying to do all these sort of things to extend his lifespan. And that led me down like the rabbit hole to find other people like Aubrey Degre, obviously and that got me sort of introduced to this idea that we can actually do something about aging. But at that time, I didn't have a biology background at all. I knew nothing about biology. So I didn't think I could really have an impact on the space. So I was just basically waiting for hoping that other people would figure this out and just kind of like continue with my life. But fast forward a couple of years, it became just more and more interested in the space and trying to figure out what was going on. And I think it was around maybe 2019, 2018 around that time. I remember watching this YouTube video of Laura Deming, basically she was saying that the biggest bottleneck in the space in longevity was that there wasn't enough founders. And I guess something just like got me, I don't know, woke something up in my mind that I should actually get involved and do something about this problem. And if the lack of founders was the biggest problem, then maybe I should try and start a company. So I tried to learn as much biology on my own and in the process when it's learned as much about aging biology in the longevity industry. So I started a newsletter, the longevity market cap newsletter. And then that sort of just like following my curiosity about how to build companies in the space and just learning more about the industry. I ended up starting a podcast, the longevity biotech show and then building all these other resources like a job sport and industry database at longevity list. And yeah, essentially I was just building all these reeds. resources and sort of, you know, also doing sort of some community building around the podcast. And that sort of took off. And at some point I decided that I had this realization that maybe instead of just like starting my own one company in the space in longevity, maybe I could, you know, help hundreds of people start companies in the space or get involved in some sort of way. And that could be like a higher leverage way to push things forward. And then, you know, one thing linked to another. I got connected to Eric Tornberg at, he was one of the co-founders of Ondeck. And yeah, we ended up working together. I was hired there to, to, to, to build the longevity biotech fellowship at Ondeck, ODLB. And we did two cohorts there. Basically, you know, it was an online program trying to increase the number of people working on longevity by creating this community, connecting people together. And, um, yeah, so that was really cool. And did that for about a year and a half. Two cohorts, 200 plus people went through that program. And, yeah, and on the side, I, during that time, I also got involved in venture capital. So I co-founded a firm called HealthSpan Capital. And, yeah, we've been operational for two years, investing in early-stage longevity biotech companies. And so far, we've invested in roughly 28 companies now. So, yeah, so it's been really cool, um, getting involved in this space. Um, yeah. And then, I don't know, Mark, if you wanted to discuss, kind of like, talk about, uh, the merge, I guess. Yeah. So, Iran, longevity summer camp, which Nathan attended, and ODLB was not planning to continue and do another a third cohort. Um, they were, I think, refocus saying on more traditional, just tech rather than biotech. And Nathan got permission to spin ODLB out as a nonprofit. And I already had a nonprofit. So we just merged our efforts together. I think that was a big improvement for both communities because, uh, I had specialized in the in real life interactions and the sort of intensive, retreat style, um, onboarding. And Nathan's program was, uh, an online program, which was more persistent as a community, to support people in, in changing careers or accelerating careers or starting companies. We just decided to rent a venue without really much of a plan. And, but that forced us to come up with a plan and run a cohort. And that was LBF1 in January of 2022. And we've done two more cohorts since then, the most recent one in Sweden, uh, this past January. And yeah, what we're trying to do is help people enter this field and have the most impactful career they can, whether they're an entrepreneur, an engineer, a scientist, an investor. Uh, we have every type of person in our community. There's one thing I also wanted to add to that, which is, you know, just to really emphasize this idea of building a community of mission aligned people, people who actually share the same ultimate goal. And for us at LBF, this is solving aging completely. And, uh, you know, we're quite different from other, let's say longevity organizations and that's in that sense. Um, and, uh, if you're, and it's our superpower, I think, because if you're thinking about getting involved, you know, dedicating a large amount of your time, your career, your life to some sort of goal, you know, you're going to build a company or join a company or dedicate your career to something, you better make sure that the people that you're going to be working with also share that same goal, right? And as the only community of builders who are, you know, hyper aligned on this goal of solving aging completely, um, you know, that makes us stand out. And, uh, I think that's really important that we have this kind of community. And I guess one of the questions that we have to answer for people that come through our programs is what should they work on? So that's why we started building this technical roadmap. It was actually an interesting story behind the initiation of this project. We were attending some longevity conferences last year. And one of our members who was new to the Biotux space, uh, came to the conferences with us. And you, you maybe just kind of, if you've been in the space for a long time, you stopped noticing certain things. But, but he pointed out that while there was a lot of people giving, you know, incremental updates on their particular research topic or technology that they were working on, nobody presented an overview, a coherent plan of how do we get from where we are today to where we want to be this future where people don't have to age anymore. Um, it was all focused on just the next steps and people trying to fundraise for their particular projects. And so we were thinking, yeah, how should people decide what to work on? We had our opinions, um, but we also, we surveyed 400 professionals from the field on what the bottlenecks to progress are and what the solutions might be. So in doing research to start building this roadmap, we developed certain, uh, criteria for what would be included. And the main one is that, um, the research or technology path has to, in its mature form, have the potential to extend lifespan indefinitely. Um, there's a lot of people working on buying time with methods that we know intrinsically can't achieve that goal. Um, and it's good to buy time, but buy time for what? And so our, uh, we are focused on things that could solve aging entirely. And we came up with another criteria or categorization system, which is whether the strategy requires you to understand aging or not. So when you're talking about traditional farmer and biotech, that requires a certain level of understanding of aging. Uh, sometimes it can be just empirical, we're just doing screens and you don't necessarily all use understand the details, but that traditional approach, um, runs into limitations. Um, if we really wanted to have indefinite lifespans, we would need engineering control of biology. Uh, and so one of the, uh, categories that we came up with is advanced bioengineering. This is basically the principle that it doesn't violate any law of physics for an organism to have an indefinite lifespan. We already know that across nature, there's huge variability in lifespan. It's a malleable trait, uh, natural selection produces, uh, extreme longevity under certain conditions. We live as long as we do because of the equilibrium between extrinsic and intrinsic causes of death and that natural selection is only acting on things that happen before you would die of something else. And that equilibrium shifts over time, uh, due to the environment changing and the traits, uh, of species evolving. But if you had engineering control, you could instead of just waiting for evolution to extend lifespan, you could actually just understand how aging works by collecting a lot of data and building models and then develop tools to design, deliver and make edits to biology. And principle, this is possible. It doesn't mean that it's easy. And we'll dive a lot deeper into, uh, the difficulties and the challenges, uh, in future episodes, uh, with this approach. Um, but it turns out there's actually other approaches to, uh, solving aging that don't necessarily require you to understand aging entirely and I'll let Nathan cover those. Yeah. So just high level, um, the other two approaches in addition to bioengineering that we've identified as potential solutions to aging, um, are one, uh, replacement. So this would include whole body replacement and progressive brain replacement. And, uh, number two would be biostasis, which technically speaking is not an actual solution for aging. It's more of a stop gap solutions or an interim solution that puts biological aging or, or deterioration of your tissues and so forth, uh, on indefinite pause, uh, which would buy you enough time potentially to, to, uh, wait for technologies to be developed to solve aging completely or, um, your particular cause of death. So those are the two, um, other strategies that we identified in our roadmap. And this is, uh, one thing to also note is these are the strategies that we've identified today. We're leaving the door open, obviously, in the future when we anticipate that we'll be updating the LBF technical roadmap as time goes by to include promising new technologies and breakthroughs that could also potentially get us to indefinite lifespan. But given our current understanding of the field and where we stand today in terms of technology and science, these are the three main strategies that we are going with. So going into a little bit more detail about replacement first. So replacement is a strategy whereby you don't need to understand all the complex modifications and mechanisms of aging at the cellular and molecular levels. You just essentially replace old tissues, parts, organs, entire bodies with young, ideally genetically identical versions of your tissues, organs, body. It really takes two forms, two steps in our estimation and our roadmap. So one, as I mentioned before, is whole body replacement. And the second is progressive brain replacement and there are people working on both parts of the strategy. So maybe I'll just briefly talk about the first part, whole body replacement. So basically what you would do is create a clone of yourself, but a non-sentient clone. And there's a proof of concept that this could be done because in nature this already happens. It's a congenital birth defect condition called hydra and encephaly where a fetus is born without a neocortex or parts of the forebrain. And some of these fetuses, you know, when they're born, they're non-sentient, but if they're left on life support, their bodies can develop normally up until there's been cases where they can develop past 20, 30 years and it's essentially, yeah, a young body without the part of the brain that gives rise to consciousness. So it's non-sentient. Now so if we can do this by genetically modifying the embryos, it doesn't develop, you know, the conscious forming parts of the brain, then you could see how in theory this is somewhat elegant solution for bypassing all the complexity of aging that goes on in all your tissues, cells, organs in the body. And then what you would do is, you know, to get that body would be to do a head transplant. So that's another part of the strategy. And this also has a proof of concept in 1971, Robert White, pioneer in transplant all AG did these head transplant experiments in monkeys. And even though, you know, he was able to do these transplants on monkeys that were not genetically identical, they would still survive for a couple days as they still had, you know, they could restore certain function like the monkeys could chew and their eyes can move and so forth. But they died eventually because they were not genetically identical. There would be an immune response, but in the case of genetically identical clone, you wouldn't have this problem. So that sort of takes care of the aging situation in the body, but then what do you do for the brain? So there's a researcher by the name of Jean Habaret at Albert Einstein College of Medicine who is working on a strategy for replacement for the brain. And basically what you would do is you would progressively replace the brain in a gradual manner, sort of like in the shipathesis by engineering graphs of that resemble young neocortex and in graphed these, put them into the brain. And because the brain has a certain amount of plasticity, you know, functions in the brain can migrate to these new graphs. So that's sort of the strategy for progressive brain replacement and there are people working on it. Yeah. And just to be clear, we're not trying to sell opium here. There are major science challenges even within this replacement strategy that, that in principle, replacing old parts with young parts sounds great. But obviously you have to reconnect nerves. Your neural graphs have to form the right connections with the rest of the brain. You have to be able to produce all of the different cell types necessary to build those graphs. And you have to be able to grow these bodies in a way that is, that they are healthy. So we'll be diving much deeper into all of the technical objectives and challenges on future episodes. That's kind of the part of this podcast. So by a stasis, the core strategy here is to try to put biological deterioration on indefinite paws. So you would do this most likely with one of two strategies. One, either cryopreservation. So bringing tissues, bodies, organs down to cryogenic temperatures, like liquid nitrogen temperatures, minus 200 degrees Celsius around there. Or you could also do this through chemical fixation. So by cross-linking all the biomolecules and proteins in the body with an appropriate chemical fixative. Now this doesn't actually solve aging. As we've said before, it just puts biological time on paws for potentially almost indefinitely, let's say. And in that time, you would basically wait for humanity to develop the necessary technologies to solve aging. But also to figure out how to revive these preserved bodies and potentially repair some of the damage that has accumulated or has occurred in the process of the preservation or revival process. So this is also, by no means, a slam dunk. There's tons of technical risks and some scientific unknowns and so forth. But when faced with the alternatives to preservation of the body, most people today will either bury someone who has died or they will cremate them. So compared to those two, preservation seems like a more rational bet. There's actually been some pretty amazing breakthroughs in car preservation recently, despite a chronically low level of funding. People have used a technique called nanowormane, where that often facilitated the freezing and thine of a freezing to cryogenic temperatures and thine of arachidne, which was then transplanted back into the rat and functioned. And people have frozen nematode worms and then revived them and shown that they not only functioned but also retained memory from training that they had received before the freezing. And so those are obviously not humans. These are small examples. But the problem of cryo is actually a problem of scale up, which is different than trying to solve aging through bioengineering. Scale up is sort of an engineering problem versus bioengineering where you have a huge number of open science questions unknown. You don't even know how many unknowns there are. So that's why we think that cryo preservation and other forms of bioestases are very promising areas and will be an important pillar of the roadmap that we're building. Yeah. And another note is, you know, in terms of interest from the longevity space, there's definitely a trend, let's say, of people becoming more interested in working on bioestases and replacement as well. And replacement, that's for sure. So for instance, Laura Deming recently started a company and looking at cryo preservation raised $40 million. The company is called the rents bio. And Joe Pedro de Magalash, also really well-known researcher, professor in aging biology. Because at the end of the day, you don't want to wait till you're old and there has, you know, it's potentially there might not be any life extending therapies at all. available and you want to make sure that you have some sort of, let's say, backup solution if that's the case, some sort of insurance. Not to mention that we're all starting, we're all currently at different stages of our life. I mean, our roadmap, when we're thinking about how to build it, one of the questions was, who is it for? Is it for people who are 30? Is it for people who are 10? Is it for people who are 70? What you would prioritize would be very different depending on where you currently are and how much time you have left and because we're coming from a philosophical perspective that aging and death are bad things. This isn't a philosophy podcast but maybe the one thing I'll say on it is, quote, "From Andrew Steele," which is that aging and death are not the moral solution to any problem. If you think that aging or death are the solution to a problem, maybe you just haven't spent enough time thinking about what could be a better solution to that problem. For our roadmap, we're covering a wide range of approaches because some of them, like cryopreservation, might be the only plausible bet for somebody within their lifetime. Maybe I'll make one last pitch for bios' thesis. That's just that, even if you could solve aging, just through bioengineering or replacement, there are other forms of death that have nothing to do with aging. It could be you just get into some sort of accident and you need some sort of emergency medical procedure to put everything on pause before just a slow down time to give you more time to intervene. Even if we solve aging, I think people still develop ways for preservation just for other kinds of causes of death or injuries or medical conditions. Other things to discuss is, is there not already other plans out there? We did do a survey. There's a lot of plans that some of you might be familiar with, such as the foresight, technology tree, Aubrey DeGrey's SENS/The Hallmarks of Aging. Many people have written articles, and there's longevity facts. Lifespan diet has a rejuvenation roadmap. Open longevity has a research roadmap. We couldn't just direct our members to them and say, "Here you go, there's the plan," because they were missing elements that we thought were really important. What we want to build, and our plan is, again, focused on indefinite lifespan specifically. A lot of these other plans are more broad, and they sometimes are simply categorization systems for everything that people are doing. They don't really say what's important, what the potential impact of different paths might be. They just include everything. In other cases, they are specific, but then they're just pushing a particular agenda of a particular person or organization rather than trying to be objective. Then we wanted to be very specific in terms of objectives and technical milestones, all the way down to levels of projects with time and cost estimates. That's a heavy lift, but we think that's actually pretty important. The reason is that if you want investment in the space, if you want talent to move into the space, you kind of need to have specifics on that level, because otherwise it's hard for people to have confidence that they're choosing a path that is feasible. Back to the aspect of potential impact, you have to decide how to distribute the resources. Himedi has a limited amount of resources. We're currently not making longevity a major priority. The resources are very limited, but even if you have a lot more resources, which we hope will be the case in the near future, you have to decide how to distribute them. The plans that we saw didn't provide any logical system for differentiating between different strategies and how the how resources should be allocated. That, to us, was very important in how we design this plan. That's what a lot of our conversations are going to be about in future episodes, digging deeper into the rationale behind different strategies. One question that some people might ask is, do we need to plan even to solve aging? What do you think Mark? Yeah, it's actually a hard question because we really can't predict the rate or even how progress will go in areas where there's open science questions. If you had asked people a year before, CRISPR was discovered, how would we be doing gene therapy? They wouldn't have been able to tell you we would be using RNA-guided nucleases that were evolved as a immune system against bacteria phases. Science often happens in sort of intermittent steps often because of an unexpected discovery or a new tool that was developed often as well. Right now, everybody's very interested in transcriptomics because we developed single-cell RNA sequencing. But if we had developed single-cell proteomics first, maybe everybody would be focused on that. Yeah, making a plan end-to-end to solving aging is the point isn't necessarily that you can possibly predict what that will look like, but that you do need to have some sort of way of making strategic decisions with the best information available and then distributing resources based on that. And when you look at the way that current resources are distributed, paths that are known to be in the best-case scenario, very low impact on lifespan and health span, are getting a lot of money right now, whereas other areas that we've been investigating, including replacement and biostasis, particularly reversible-crouse-tasis, that are extremely promising in terms of the potential gains get almost no money. And so we really wanted to, I think, from a strategic perspective that doesn't really make much sense. And it seems that often the case, sometimes the only reason is because people don't actually know about those areas of research. And so having a plan that provides an overview of all of the different things people are trying and why they're trying them, I think will help people make better decisions as to where to allocate both talent and capital if they're optimizing for lifespan as they're returned on investment. Yeah, I think it's both, you know, obviously giving an overview for people for where they should put their time, they're like allocate talent and also a capital, but even just like convincing people that they're, that you can put capital and time into these sort of things. Without a concrete plan, it makes it very difficult for funders to believe that there's an actual outcome here. If it's just only just a category of different research areas that people could fund, then this could be just like an endless black hole of money and time. And it's not clear that there's actually some, some way to actually solve this. And like maybe a good example from the past is, you know, in 2002 around that time Elon Musk got interested in figuring out what was the plan to get to Mars, right? He literally was trying to find the plan to get to Mars, went to the NASA website and found that there was no plan. So then he had to create his own plan and by doing so, you know, this could actually happen and you could sell this vision to talented people, right? To join SpaceX, but also funders to invest in this. So you need some sort of concrete logical narrative of, you know, step one, step two, step three, how this is actually going to happen with some details. And I think that makes it much more attractive for people to get involved. Yeah, and we're excited to share this journey that we're going on with you. Building this roadmap is ambitious. It's going to be hard work. And we actually also want your help. We want your feedback. We want your recommendations on who we should talk to, on what might be missing. Speaking of future episodes, coming soon, you'll be able to listen in on some of our conversations with experts in the field. So for our first episode, we've interviewed a reason from repair biotechnologies. And he's also the author of the fight aging blog, which we highly recommend everybody check out at fightaging.org. And then our second podcast will be with Alexander Fedinstev, he's a researcher on ex-usellular matrix aging. And then our third podcast episode will be with Jose Luis Rican, who's head of theory at RetroBioSciences. And we're going to try to deconstruct their mental models for how they're trying to solve the problem of aging. From there, we're going to continue talking with people on all aspects of the roadmap, on those three topics that we discussed, advanced bioengineering, replacement, and biostasis, but we'll also be bringing in people from adjacent fields, people who might not even be consider themselves longevity researchers, for instance, they might be in synthetic biology or artificial intelligence and developing tools that are necessary or can accelerate the rate of progress. Right now, you can go to the longevity botek fellowship website and see the current version of our roadmap. And in addition to that, we have a recommended reading list. Our goal here is to help the people that are serious about this, that want this to be their career. And there's no way around the fact that these are extremely difficult problems. And it does require a lot of learning, a lot of education, and a lot of accumulated experience if you're going to make significant contributions. If you don't currently work on these problems, what you'd like to, you can apply to the longevity biotech fellowship. We run that. It's a nonprofit organization with a mission to help you have the most impactful career you can as a scientist, entrepreneur, investor, or even community organizer. So yeah, definitely check us out at longbiofellowship.org and subscribe to wherever you listen to podcasts. And we'll see you soon. [MUSIC PLAYING] [MUSIC PLAYING]