Life Extension Innovations, Moonshots & Snake Oil (with Celine Halioua & James Peyer)

Hey, it's Eric Newcomer. Welcome to the Newcomer Podcast. Probably my favorite episode ever this week, a conversation with James Pyer, the CEO of Cambrian Bio, and Celine Halioua, the CEO of Loyal. James is trying to help humans live forever, and Celine is trying to help your dog live as long as possible. We get into life extension and longevity, Silicon Valley's chase to fight off death. You've probably read about tech mogul Bryan Johnson. He was just profiled in Time, who's desperately trying to figure out ways to optimize his life, to drag it out as long as possible. Celine Halioua and James Altucher are skeptical of that effort. Uh, spoilers, we get into what's credible, the moonshots and the snake oil in the life extension and longevity space. If you're curious about Silicon Valley's effort to live forever, you want to fend off death. This is a great dive and with sort of serious players in this space about the effort to find drugs that will keep people and our pets living longer. Give it a listen. Celine and James, thank you for joining the podcast. Welcome.

Nice being here, Eric.

Yeah, thanks for having us.

Life extension, longevity, like things everybody wants for themselves and to know how they can live longer. And it's a fun space to talk about. So really, really excited for this episode. I mean, I think just start off, can you each give the sort of first 30 seconds how you came to the longevity space? Next 30 seconds, just like at the high level, and we'll dig into it more, like what your company does so people know who we're talking to. Celine, do you want to start us off?

Yeah, so I, I got interested in aging and longevity kind of indirectly. I was working— so my undergrad's in neuroscience, and then I have an incomplete PhD in health economics. And while I was doing research in neuro, we were working in a Parkinson's lab. And Parkinson's, a neurodegenerative disorder that, you know, is predominantly caused by loss of a certain type of neuron that is infamously difficult to treat with modern therapies. And I remember sitting in this lab thinking, why are we waiting until there's decades of damage and decades of neuronal loss to start trying to treat the patient instead of trying to understand what led to them having this loss of brain function? And so that kind of, long story short, led me into the aging field, which the way I think about aging drugs is preventative medicines for multiple age-related diseases at the same time. So not nearly as sexy as 120-year lifespans, immortality, saving Johnson Johnson, things like that. Sorry, I had to. We'll get into him.

We'll get into him.

We'll get into that, I'm sure. And now I run a company called Loyal. We're developing what we hope to be the first FDA-approved drugs explicitly designed to extend lifespan and healthspan. And we're specifically working on dogs.

Dogs. So yeah, that's the, that, that's the takeaway.

That's the hook.

You're starting with dog. It's easy, we'll get into it, but it's easier to extend the lifespan of dogs than humans because of regulation, right? I mean, it's a sort of regulatory—

it's honestly just a, like a logistics thing more than anything else, right? Like a dog, well, like one of the core ideas is that big dogs live very short lives. You know, a Great Dane might live 6, 7, 8 years while a Chihuahua lives 18 years. You can see aging And you can see lifespan in a dog in a much shorter period of time than you can of a person. If I give you guys a lifespan extension drug, I'm not gonna know if it works or not for a really long time. Good luck, like, getting some VC to fund that, not the less the clinical studies.

My wife's family has a black lab named Moon Unit that I've gotten very attached to.

And well, we're working on it, man.

Yeah, exactly. Chop chop. The, the realization that I, you know, you're getting attached to a big dog halfway through their life is sort of like, oh no, what am I doing?

Like, Anyway, I have a senior Roddy who I'm in love with and yeah. Yeah. So anyhow, that's what I'm up to.

All right, James, what about you? How'd you get into this space?

So my story starts in the late '90s when the, the aging space was really like academically in its infancy in a lot of ways. And we had just kind of discovered that there were these things inside of each of our cells called telomeres. That shortened every time a cell divided. And a couple of books got published in the late '90s when I was a student that said, hey, if we can extend, like prevent the telomeres from shortening and keep them long, then cells should be able to live forever. And then sure enough, like right after that, we were able to take normal human cells and let them divide an infinite number of times by keeping their telomeres long. And like that led to this explosion of, oh my God, is this the answer for aging? And it turned out not to be the case, but it kind of sent me down this path similar to Celine's story of like, this could be the core, not telomeres specifically, but like the study of why our cells and our organs stop working as we get old. That could be the key to keeping people healthy, the key to preventing diseases from, from happening in the first place. Around the same time, my grandfather was diagnosed with cancer. Which kind of went from 0 to 60 and he was, you know, treated, failed treatment, and was gone within a year and a half of his diagnosis. And I just saw how, to Celine's point about Parkinson's, like how futile it was to wait for decades of molecular damage, right? Decades of a disease to build up bit by bit. Cancer, I think, is a great example of this where it has to go through one mutation, big expansion, bottleneck, expansion, bottleneck, before ever even thinking about how do we treat this, how do we stop this from happening. And for the past 20 years, I've been either as a researcher or for the last almost 10 as a kind of investor, company builder, and now executive in this space, have been trying to ask the question, how do we take these discoveries from the academic world and understanding how our bodies age and turn those into medicines, um, with the thesis that's almost 100% aligned with, with Celine Halioua, that like this is not about, you know, longevity or even healthspan, that the, the best and highest use of these breakthroughs in our understanding is to create a new generation of preventative medicines that if you fast forward 50 years, people are going to look at this research now and kind of equate it with what happened in the first half of the 20th century with vaccines and antibiotics. These were the biggest killers of humanity, and now we've figured out ways of understanding how they work and how to get there before the disease, like, robs us of our ability to deal with them by becoming so complex and so, so damaging. Cambrian is, is kind of a unique company that I run. So, so we partner with academics who have made breakthroughs in aging research all over the world, who have figured out ways to create a drug that can target a different aspect of aging. And then we bring that into Cambrian and move that forward into human clinical trials. So we don't have any dog FDA stuff pending. Our strategy is slightly different, which is we find a drug that has the potential to slow these aging processes, to prevent disease, to extend healthspan. But we say, all right, well, this could be a great cancer drug. It could be a great drug for heart disease. It could be a great drug even for like a rare orphan genetic disease. So let's start there. And after we show safety and efficacy, then you can do something closer and closer to prevention.

The idea is you're picking drugs that you think would sort of be useful to the general person, or that have some reason why they would be preventative.

That's right. And so we can get into some aspects of this, but it looks actually like we're gonna be able to start our first preventative trial in human patients as early as the end of next year.

So you guys have both sort of hinted at this, but just defining the space, longevity, life extension, from what you're saying, like there's a sort of innocuous way to phrase it, which is just sort of preventative medicine, right? Or am I wrong in saying that like a core idea here is that most drugs are meant to treat people where something's like clearly wrong and they're somewhere outside of the human baseline and a key idea here is that even if you're at the human baseline or overperforming, are there drugs we should give you earlier in your life that, that give you a better outcome? Is that the right way to think about it? Would you quibble with anything or add anything there?

What I've found has been kind of the aha moment when I'm trying to— it's a lot of my job fundraising and also activating and educating pet parents and vets is, you know, explaining what is this aging thesis. And the way I think about it is that as we get chronologically older, the cells that make up our body accumulate damage, they, you know, accumulate mistakes, et cetera. And these are inherently things that occur over time. And a disease that's associated with this damage or decaying or loss of resiliency or loss of function depends on where it's happening, right? So if it's happening in your brain, it might lead to dementia or neurodegenerative disorder. If it's happening in your joint, it might lead to osteoarthritis. Arthritis, it's happening in your immune system, it might lead to cancer. And these things are classically thought of as completely unrelated diseases, right? Having osteoarthritis is considered mechanistically very different from having Parkinson's. And at the end stage, they are, they are very mechanistically different. An OA drug isn't going to most likely positively impact dementia, but the underlying drivers that led to a patient developing these diseases, the processes of aging, the processes of damage, are conserved, or that's the thesis of the field. So if you develop a drug that targets the way a body breaks down over time, it may have a positive impact on these classical diseases that are today thought of as totally separate. And one like nice, you know, anecdote to that is the only lifespan extension study that's been run to completion in dogs was actually run by the dog food company Purina in the late 1990s. It was a caloric restriction study, which is kind of the OG way to extend lifespan. It's one of the reasons why Tech Bros, intermittent fast, and they showed a 2-year lifespan extension in Labradors. But more interestingly to this thesis, they showed a 2-year delay in incidence of cancer and osteoarthritis. Again, two seemingly unrelated—

If they do what? Sorry, what's the—

Caloric restriction.

Oh, okay.

So they, these two unrelated diseases, cancer and osteoarthritis, there was a delayed incidence of almost 2 years in these dogs who were calorically restricted. Compared to the dogs that weren't. And so that suggests that these dogs are potentially aging at a slower rate or aging more healthily, which is why they lived longer, but also why these unrelated age-related diseases developed later in life. So that's how I think about it.

And we can do this pharmacologically as well. So like Celine Halioua said, like the OG way of extending lifespan in animals was to just reduce their number of calories. And like you go into this, your body goes into this like, famine preservation sort of mode. Some processes run slower, but overall your lifespan is extended. And there's now more than 80 different drugs or genes that you can tweak that— not in dogs, which are bigger and more complex and live longer. My background is as a mouse geneticist. So, so, you know, I, I live in the world of mice more than dogs, but in mice, you know, their natural lifespan is only about 2.5 years. So you can run these studies in mice really, really easily and with large numbers to get good statistical confidence. And a drug like— there's one called rapamycin that a lot of people know about and talk about, which hits this, this pathway called mTOR. mTOR is one of the key pathways that is on when we're eating 3 meals a day and gets kind of cranked down when we're not eating 3 meals a day, right? When you eat once a day or, you know, if you're reducing your number of calories. And just by giving small amounts of this drug to mice, you can increase healthy lifespan by like close to 20%. And you get exactly that same phenotype that Celine is talking about, where it's that the reason that the mice are living longer and healthier is because their memory is working better, they get less cancer, their skin is in better condition, their joints are in better condition. And it's all of these things happening at once because you're fiddling with something core to how cells and tissues function properly, not waiting for like trying to untangle this very, you know, disease-specific knot.

What's the name of that drug?

It's called rapamycin.

Are people taking that?

So this is a—

Triggered.

This is a whole can of worms. So rapamycin is actually an FDA-approved drug, and the things that it is FDA-approved for are— and it's sort of like, it's got a couple of variants, but it was first approved as an immunosuppressive therapy for people who are getting kidney transplants because large amounts of this drug actually suppress your immune system. And then it was kind of approved for two other things, which is treating sort of mid to late stage cancer patients to prevent their tumors from growing. And then finally, there's a specific rare disease that— where this, this pathway is cranked up that causes epilepsy. And giving this can reduce the number of seizures. So those all three are like high doses of this, and it's never been widely experimented in low doses in humans. Some people are self-medicating, but man, we just don't know very much. And the difference between a low dose and a high dose and like when you jump into potential side effects versus when your dose is too low and there's just gonna be no benefits, we have no idea.

In America, Am I allowed as an individual to take a drug off-label of my own direction, or what sort of the freedom an individual has to take a drug that's prescribed for one thing and mess around with it for other reasons?

So there's two levels here. There's first what your doctor can do. So a physician in the United States is allowed to prescribe a drug off-label with no restrictions. If your doc said, hey Eric, like, take this drug, it's for breast cancer, but you know, you have whatever and I want you to take this, like, there is no authority that can stop the doctor or you from making that decision. There are two sort of like upstream ways that that happens less. First is that your insurance company may not pay for that drug, and there are prohibitions from— let's say I run the biotech company that created that drug for breast cancer. I can never tell the doctor, oh, please also, right, you know, recommend it for, I don't know, cough or something like this, right? So upstream, those are the protections we have in place, but the doctor-patient relationship is pretty open. Yeah.

Do you consider like Ozempic, Wegovy to be life extension drugs.

You wanna start?

You're the human guy.

Okay.

I can say in—

put, put, put, put that on my tombstone.

The human guy. I'll say this. Um, my, my favorite little anecdote about weight appetite suppressants is that one of the bigger, uh, dog drug failures was a drug that was a weight loss drug. For dogs, it was approved years ago, that worked predominantly by suppressing their desire to eat. And it was a huge market failure despite the fact that dogs have a very high incidence of obesity, just like humans. The reason being is that people, they perceive their dog wanting dinner or wanting a treat as love. And so when the dog suddenly isn't hounding you for dinner, isn't hounding for a treat, and it's just kind of ignoring you, they're like, oh God, my dog doesn't love me as much. Like, no, she did. So one of the things we explicitly look at in our studies is ensuring it doesn't reduce desire to eat and doesn't reduce weight because it would probably be a commercial failure. So I will not be doing Ozempic for dogs, but James, I'm sure you have more human biology—

Yeah.

—expertise here.

So what I would say on the more critical side, jumping off from what Celine Halioua was saying, is that Ozempic is not a drug that I think is suitable for everybody. Right. We're not going to end up in a situation where really healthy people who have a great diet and exercise are in relatively good shape, but aging, should go on Ozempic. Right. But it is a really damn good drug for obesity, and it looks like the effects are just really powerful for obesity and for type 2 diabetes. Like, this is worthy of its blockbuster status. The main drawback that makes this from a risk-reward perspective, good for diabetics and people who are obese, but not good for people who don't have those things, is that when you stop eating, because that's the way that this drug works, right? You, you feel full even if you haven't eaten that much. When you're not eating, you consume more fat for calories, but you also consume muscle. So even for these people that have a lot of extra fat, about a third of the weight that they lose is actually muscle mass. And if you look in people who are older, right, so in your 20s and 30s, if you lose a little bit of muscle mass while you're cutting off a lot of extra adipose tissue, you can then hit the gym and rebuild that muscle mass. But like once a person is about 60 or so, like rebuilding that lost muscle is really hard and it increases your risk of all sorts of other things, right? It basically makes people more frail. So they're more likely to fall, more likely to get orthopedic or sports-type injuries if they lose a bunch of muscle. And so talking our own book here a little bit, similar to what Celine's talking about in her dogs, the drug that Cambrian has that is furthest along, and it's actually already treating human patients, is a drug that also targets— it's kind of like the flip side of the Ozempic GLP-1 coin, where Ozempic makes you eat less. But what if instead your body thought it was exercising more? And so the same kind of group of people that have been studying aging biology have known that exercise is one of the best things we can do for aging since forever. And the main way that our body gets the positive benefits of exercise translated into increased muscle mass and more calorie consumption is by activating a pathway called AMPK. And Cambrian has the first drug that activates AMPK safely that has already started human trials. And what we see is just like in, in obesity studies, you see the same sort of thing where like you can put mice on a high-fat diet and they lose weight even if they're eating more than, than mice off the drug. How many people are in that trial? So it's been in, in about 100 people so far. And then the study that we're doing will have about another 50 people treated over the next year.

And do you own that drug outright or is it sort of a minority stake or how does that actually work?

So the way that Cambrian works is we own a majority stake in every drug in our pipeline underneath us, but we don't own 100%. We kind of share that upside usually with specific scientists that have kind of been working on those, those products, sometimes other investors as well that have been working on these products since before we got involved. So we're not like a private equity group that's coming in and acquiring things. We're coming in and we're taking a controlling stake, but leaving upside for other people that are, wanna ride this train along with us. It's a cool business model. Yeah.

Celine, while we're talking around books, yeah, what's the drug that you have that's farthest along for dogs?

Yeah, so one thing I wanted to quickly note, and then I'll answer your question, is what James is saying about safety is super key. It's like actually one of our key philosophies when I started the company is the drug might not work, but it shouldn't do any harm. The way to think about the safety of an aging drug is it— and I believe this is a quote from an ex-FDA individual— is that it needs to be basically as safe as water. And the reason being is because if I'm giving you a drug today to prevent something you may or may not get in the future and it kills you tomorrow or maims you tomorrow, that risk-reward is not acceptable. Or even having an increased risk of something bad happening to you, like increased frailty, is not acceptable. So that's one of the challenges of the field. And one of the reasons, like, James and I are working on relatively simple drugs, so to speak. There's a lot of companies that are doing these, like, really sexy, you know, epigenetic reprogramming, gene therapy, da da da. And, like, might work, might not work. We'll see. But at least I can't speak for James. I'm pretty sure you're mostly doing boring molecules. I'm only doing boring molecules. And that's because safety is so important and you just don't want to introduce variables when you don't know how something will behave in the body. I think that's also been key And this is an interpretation, they haven't said this to me explicitly, but I think that's been key to a lot of our success with the regulatory bodies is demonstrating safety far and beyond what is required of us legally. To answer your question on Tocanar, Tocanar Brook, I was trying to think of like a metaphor, like a dog. Our furthest along drug is a daily drug for old dog lifespan extension. So for dogs of almost any size, any breed who are already showing signs of aging. And, you know, if everything goes well, we're running towards it being on the market in 2025, really 2025. So lots of work. I know, I know. It's so cool.

Lots of work to do.

So I mean, you, you've passed some trial or is it the same with dogs where you have trials or? Mm-hmm.

Yeah. So we've completed the safety studies awaiting FDA feedback, but it, looked really nice. We've completed the efficacy work, awaiting feedback from the FDA. And then the thing that kind of determines our go-to-market timeline is actually manufacturing. And manufacturing is like a pain in the ass. It's hard, don't get me wrong, but it's a great problem to have because it's completely physically possible to manufacture a beef-flavored pill at scale. It's really just like, how operationally competent are we? Are we going to pick the right supply chain partners? Are we going to manage them correctly? Are we going to see around corners? So, you know, if we're wrong and like we're a quarter delayed or something, it's not a binary existential thing, assuming the FDA agrees with the technical packages that we believe are very strong, showing that the drug does what we think it does.

What's the mechanism for this drug?

Yeah, so kind of what James was talking about earlier with caloric restriction, when we started the company, we wanted to take as little biological risk as possible, right? Like it is almost certainly true that you can extend a dog's lifespan with a drug. 'Cause we've done it in everything from, you know, yeast to mice all the way up, and there's correlation data in people. So it'd be weird if that wasn't possible also in dogs. The question then, what was the highest probability and also safest thing that we could use in dogs to show that a drug can be approved for lifespan extension? And so as I mentioned earlier, the only lifespan extension study that I'm aware of that's been run to completion in dogs is that Purina Lifespan Extension Study, which was using caloric restriction. And so the drug emulates. The benefit or the molecular impact that is had on the dogs when they calorically restrict, specifically working on metabolic fitness and then also fat tissue function and the age-related decline of fat tissue function.

Cool. I mean, we've sort of touched on sort of different parts of life extension. You both have invested also and sort of see this space just sort of like a framework of sort of the different categories of longevity that we're sort of seeing from what you're saying? You're like, okay, we're like simple molecule to sort of the most like far out there, which you, you said like epigenetic, or like just give me this sort of roadmap of the different buckets of this that are happening right now.

I can take a shot at that one.

Yeah, I know that's like bucketing the world with frameworks.

Yeah, yeah.

And he's, he's the real investor. I just— you invest, right? I did. I was at Longevity Fund and I like invested a little bit personally, but I'm a much better founder than I am investor.

So the way that I look at the space, I'm going to give a title to 3 different buckets. I'm going to call them innovations, moonshots, and snake oil. And I think— spicy!

I love it. Come with the spice, James.

Like innovations, moonshots, and snake oil. Yeah. Hell yeah.

Who's going to be in the snakehole?

Loyal. So, so I would describe innovations as anything that looks an awful lot like other preventative medicines that we can, like, draw a direct line from that work to us. Right. And there is a series of preventative medicines that I think are really going to be useful comparators to the first true drugs that we think of as coming out of the longevity or aging biology space. That like everyone's going to draw comparisons to, like statins, right? Exactly. So we already talked about Ozempic, which I think is going to have a lot of competitors because a lot of these drugs are going to come in for cardiometabolic disease. Statins is the other fantastic example where like you have a risk factor and you start giving people a drug based on their risk factor to prevent heart attacks and strokes. And so, so I think those parallels, which like Celine Halioua already touched upon, they are every single one of them small molecules that have a really good safety profile that target well-understood molecular mechanisms, mostly having to do with treating metabolic health. There's this big mess of cardiometabolic, like how our heart works and how our, our metabolism work. That's sort of where the first wave of innovations— I call it the first dominoes to fall— are going to be in that innovation bucket. My second bucket is moonshots, which is like, we have some really powerful, interesting ideas, many of which are getting funded, that are sort of like a next layer of where this space could go. Things like, you know, probably the interface between innovations and moonshots is like biologics. We have, for example, there's a protein that's naturally produced in people that when it's present, prevents a woman from going into folliculogenesis, right? Prevents someone from ovulating. So, so with an injection of this protein, one could potentially completely control ovulation, which we think if you then maintain the ovarian reserve could prevent menopause. Like, that's a cool-ass idea, right? It's more complicated than a small molecule daily pill that's affecting metabolic disease. But like, that's the kind of cool moonshot type approach that— one of the ones that we're taking. There's also stuff like reprogramming the epigenetics of a cell is one that's talked about a lot, to like a more immature state so that then it can become— kind of repair damaged tissues is another moonshot that has like some really promising data coming out. Especially there's a company called Life Biosciences that has reversed eye, like, like eye diseases or optic nerve damage in monkeys already. And like, so that will be probably used for more specific functions, right? Like in the menopause case, it'll probably be used in IVF first. The epigenetic reprogramming will probably come out in like nerve degeneration in the eye first. And then if it's safe, if it's really, really safe, then it can expand, especially if it can walk in the sort of footprints in the snow made by the innovative drugs, right? And one of the reasons I'm so excited about the work that Celine is doing is because of the strategy that she's taken in dogs. Like, she's jumped ahead of the rest of us, you know, just human people, in terms of talking about this multi-disease prevention, correcting metabolic dysfunction to prolong healthspan. And like, hopefully that will allow us to walk in Loyal's footsteps a little bit as we talk about doing this in people.

Yeah, you guys are welcome. I think you should take a tax on all the longevity companies. Like, you guys need to give me like 5% of your funding, especially the epigenetic companies that raise like a billion dollars.

I mean, and to be honest, I, I want to say like this, this moonshot category, I, I don't want to throw any shade at that because I think that those techniques and technology and the biology underlying a lot of this is really damn exciting. It, it's—

throw some shade. I can throw—

well, yeah, we're all waiting for the snake oil category. Come on.

Okay. And then the third one to be thrown here too, though, right? The third one for me is then the snake oil category, which is basically everybody who is taking advantage of the fact that longevity has become one of the biggest let's call it mega trends of like fascinations of people, especially in the developed world over the last 3 or 4 years, and realize that even without validating any new technologies, we can just like sell stuff to people who are scared of their own mortality and scared of their own decline the way that humans are.

If you're super rich, post, post wealth, what do you want to spend your money on? Like living longer, higher quality of life. And if, especially if you control a venture fund, not even your money, what do you want to throw it at?

Things that could— yeah, it's interesting. I think that where the bigger bucket of snake-oily things are living is outside of the venture-backed company space. It's more in the direct-to-consumer space, stuff that's like, we want to sell stuff to people now, what can we sell, what can we make profit on today? That's the biggest snake oil bucket where like the red flag that jumps in my mind is like, okay, Is your R&D and clinical trials, is that coming out of an actual R&D budget or is it coming out of your marketing budget so that you can run ads on Facebook and Instagram saying clinical trials suggest this? And if it's the latter category, it's probably in the snake oil bucket. I think there's been a bunch of efforts over the past 3 or 4 years to try to establish some kind of standard around what good looks like. And it all kind of funnels down to, are you going to run clinical trials to test whether this thing actually works before you start selling it? And if the answer is yes, you're probably in bucket 1 or 2 if you're serious. And if the answer is no, or you say you are, but you've really got no shot at it and there's no real plan there, you're probably in bucket 3.

The snake oil companies are, you know, you could argue that they're like trying to get things to consumers immediately. Drugs take years to get approved, da da da da. But the thing that they don't realize, like the biggest hurdle I have to overcome when I'm educating veterinarians and regulators about what we're doing is that it's legit, right? Like the number one pushback we get is, it sounds too good to be true. Or is this, is this really real? Is this just like, you know, Fountain of Youth stuff? And that's dangerous. It's dangerous for a field 'cause it means legitimate skeptical people are not gonna engage in it or much more difficult to engage in it. So all the kind of, you know, we're here to make 1,000-year lifespans, even 120-year lifespans, like maybe it's possible, but leading with that is just so unnecessarily controversial. It's often just an attempt to get, you know, earned media so more people will buy their thing versus leading with, you know, good science and that these are preventative medicines to reduce risk of future disease, which is the most consensus thing on the planet, right? To reduce the risk of developing a future disease. Cheaply and safely. So yeah, these people piss me off. What are people that sold?

You know this space. I mean, it's like, they're sort of like vitamin type pitches or what?

Vitamins are common.

Yeah. So I think there's also a bunch of like interventional stuff that can be done without regulation. So there's a big push in stuff that, and like the big tragedy for me is some of these things may actually be helpful. We just don't know cuz no one's really, like, there were— people are so busy selling this that no one's really asking the scientific questions, right? So there's, like, people out there, you know, offering tens of thousands of dollars for your daily hyperbaric oxygen containment. And, like, you know, you got to do these ice baths, and you got to do these skin treatments, and you got to do this, you know, plasma exchange. Yeah, okay, that— yeah, okay, like, those things do exist.

Blood transfusion in the room, like, do you Where does that fit in in this? Because I mean, Blood Boys, I feel like that's what sort of the regular person's taken from Silicon Valley or the show or whatever.

So I think it's a perfect, like, microcosm of both the scientific potential and the hucksterism and snake oil possibilities of this. Because like, if you go down to what got people excited, there are some mouse experiments where you took young plasma put it into an old mouse, and the old mouse just got better in a lot of ways, right? And you take the old plasma, put it into the young mouse, the young mouse behaves worse. Figuring out why exactly has been actually kind of a fraught scientific odyssey where we still don't have good answers as to why after almost 15 years of looking at it. And there have been some companies. The one that I'm most admiring of is called Alkahest. Which spun out of Tony Vizcarra's lab at Stanford and actually created what they called drugs based on chronokines. So things that either go up as you age and therefore you want to remove, or go down as you age and therefore you want to replace. And they were able to use this to say like, oh, well, these could be good drug targets. And they were actually bought by the biggest plasma company in the world called Grifols, which is a Spanish pharma company. And they were— it's like positive story, both from a pharma perspective and from a venture kind of like investment perspective. So like, that's a nice little story that I can get behind, and I have a lot of respect for the people of Alkahest doing something hard and pioneering. And then on the other side, you have like, whether it's people trying to open individual clinics or, or physicians or non-physicians who are like, ooh, I'll bet we can sell plasma for whatever, $4,000 a pint to people who heard about these mouse experiments and for whom we have really no evidence that this will help them. But, you know, there was a piece in The Guardian or whatever saying that it worked, parentheses, in mice. And like, that's that snake oil bucket. And like, I would say 98% of the conversation that we hear in the media or out in the lay press is about that second bucket. And 2% is about the actual science that has been making some positive steps. And there's a couple of other companies that are trying quietly to do some hard but interesting work in that space. We're not one of them, but I have a ton of respect for those people. And I think that the core scientific insight, like, there's probably something there that could be important, but we just don't know exactly what it is yet.

All right. I feel like this is the time to bring up Bryan Johnson, which I have generously not led this conversation with. But you know, he's the rich guy who's, you know, doing a bazillion different things to extend his life, recapture his youth. The media is like fascinated by it, you know? Yeah. As serious people in the space, what do you make of what he's trying to do?

I, yeah, my short answer is I think the best thing Bryan Johnson could do to extend his lifespan would be investing in Loyal or Cambrian or another legitimate aging company. Doesn't have to be us. I understand the grift. But I think he doesn't understand pharma and drugs and the reality of actually getting something approved. I don't think he's ever going to work on getting something approved. Or statistics, you know, science, physics, you know, all these things, which is fine. You don't have to. I mean, I can't code, right? But it actually slows down the progress of the field. Like, the biggest issue I have to worry about when I'm fundraising is making sure people don't feel like we're the next Theranos or like other illegitimate thing that's going to embarrass them. Embarrassment insurance, chump insurance, is a huge thing that I have to build into everything I do when I'm fundraising for this company. And I'm a really fucking good fundraiser, right? So think about like how many people who have like interesting scientific concepts, new drugs that should get piloted that just aren't happening because there's such a negative bias when you're coming in with this field. It's not just because of him, but he sure as hell isn't helping. And I wish he would use his platform to educate in a way that would promote the entire field and not become a problem that I, I literally have to explain away probably once or twice a week.

Are there things that he's doing that make sense or don't? Or I don't actually know all the different— do you have a sense of what he's actually doing.

People are constantly experimenting with their own sort of personal fitness to try to make themselves healthier. This is something that at different scales we're all doing, right? Many of us are taking some supplements, whether it's just a multivitamin or fish oil or more exploratory things beyond that. We change our diets, right? People go keto, people do paleo, people skip breakfast, right? So like that kind of playing around with diet and exercise and supplements is something that so many people are doing day to day by themselves. And this is just sort of like a, you know, 2020s internet, like look at the far extreme and shine a spotlight on that version of what people have been doing forever. But as far as scientific value, like what this could give to the community of like understanding something, there is zero value in any of the stuff that he is doing. Like, Anyone who has thought about, like, how we move from theory to truth in medicine knows that you have to change one variable at a time. You have to do it in a large number of people, and then you can start learning little things. And it would take years to learn little things. So saying like, hey, I'm gonna change this and that, and I'm gonna combine 20 different things into my protocol and like what's going to come out of it is like, I feel a little better, I feel a little worse for one person, there's no scientific value in that. There's only media value in it.

Yeah, this is such a meme with Silicon Valley tech people. I cannot tell you the amount of tech people I've heard talk out. They started to do these like massive combo studies. They're like, wow, pharma's so dumb, they only use one drug at a time, but aging is complex and they should use multiple drugs at a time, and we're gonna do these combo studies. And I'm like, One, like the path to getting that approved is like good fucking luck. But two, you can't actually attribute and tell, like aging is such a complex thing. We haven't even gotten one thing through. You're not gonna be able to then like start like all the other way and have like multiple things that you're permeating over a long period of time. Like these studies take, even for us in dogs, we're running a pivotal lifespan extension study. It's gonna be at least 4 to 5 years. And that's in dogs. Like in people, it's gonna be way longer. So like usually if somebody's saying, oh, pharma is so dumb, why didn't they just realize XYZ? The answer is they have realized and there's probably a reason they're not doing it. And there's a lot of other things wrong with pharma to be clear that like, you know, me and James are like, you know, working on countering, but they're not dumb.

That was exactly my question. I mean, yeah, it seems like a premise of some of the longevity spaces that there's something wrong with pharmaceutical industry, sort of traditional medical investing, drug development? Like, another way of asking that is why should venture capitalists who aren't experts in this be the ones asked to fund something that sort of suggests that there's something broken about the traditional model or that this is fundamentally different in approach? I see that on, you know, some of the moonshot ones you guys are talking about. But if you're positioning yourself as more as we believe in standard clinical trials, we want to be incrementalist to the extent that's possible.

Yeah. So I would say this is probably the stake around which I've built my whole career and something that I've brought to what attribution I can claim for it myself versus all of the other people who have been kind of touting a similar idea. But the fund that I built before Cambrian and now Cambrian as one of the larger sort of drug developers in this space. Was premised around the idea that it's not that the FDA is broken. It's not that pharma is dumb and ignoring this. It is in fact that we are at the precipice of a brand new revolution in science that is just now ready and mature enough for drug development. And it is this fertile ground of new science that is going to make the great drugs of the next 10 or 20 years in the same way that like You know, 20 years ago you'd want to be studying basic mechanisms in cancer, which made the best drugs of the 2010s and the, and the 2000s. And like 15 years ago, you might have been wanting to study basic mechanisms of metabolism and obesity, which led to like the GLP-1s and these sorts of things. Now, this is not different than the rest of pharma innovation, and it's going to create drugs that are going to be the most important drugs of the next 10 or 20 years. That's the investor pitch and the pitch to pharma and to the FDA that is both most rooted in what the actual scientific reality is and gives the most upside for people spending their time and money making this space happen. So I think that's like the stake. I, I always called it the stepping stone approach to kind of bringing these aging drugs to their best and highest use, which is try to find whichever way makes sense to make those discoveries coming from the basic biology of aging show that they're safe, effective, and ultimately profitable, right, as quickly as possible. And then you can start doing what me and Celine are most excited about, which is what happens when you start giving this sort of tool into the hands of someone where they can use it for prevention before they get sick. And that's not an easy thing to do first because you need to know in humans that something is really safe and really effective before you can start doing that, generally speaking.

Yeah. One thing I will say here though is that I think Loyal is a really good example. So I agree with everything James said. Like, one of the things we've done is like we try to be— we like the hill we die on, the hill that we're radical on, is a drug approved for lifespan and healthspan extension and everything else. We are extremely traditionally competent on, right? So like, I'm, you know, the young techie founder, da da da, whatever, of the company, but like my executive team are experienced pharma executives, right? Like they're the best possible people for the job. One thing I will give tech a lot of credit for is Loyal never would have been funded by traditional biotech investors or biotech funders, right? I was 24 years old when I started the company. It was basically my first job. Like I worked for Laura, but it was a two-person fund. We were working on dogs, we were working on lifespan extension, and we didn't have anything, right? It was an idea and an insight, and insight that ended up being correct, but nothing else.

Who took the first bet?

Laura and Greg Rosen. Greg's at Box Group and Laura's at Longevity Fund. And then First Round and Collaborative Fund were also big investors in the seed round. And I mean, we'll see, but like, so far so good. But This is definitely something that like, I don't think I could have walked into the traditional East Coast biotechs. They would've laughed me out of the room. They would've said like, apply for our associate program. Like, we'll consider you maybe. Actually, just kidding. You didn't even like finish your PhD. Go home. And so I think there's a line where I take that very seriously that I've brought like most of my investors. I'm one of the first times they've invested in a biotech or company like this. I take that responsibility super seriously. Because I want them to invest in more companies after us and more weird companies. But again, it's like, I don't take advantage of that situation by being radical and like doing shit that like reduces probability of success. Like, we still are very conservative in everything else except for the radical core ideas of, you know, a young solo founder woman can build a dog longevity company and a consumer brand around these pharmaceutical products and like hopefully get it approved for lifespan extension. So it's, it's a balance, right? But I think like a lot of these snake oil people really take advantage of the fact that the average Silicon Valley person doesn't understand science or how a drug gets approved at all.

Yeah, you know, there's this sort of meme that Silicon Valley, you know, hasn't been friendly enough to women. I mean, certainly there aren't sort of as many women founders as you would like, but it's interesting that you're saying in some ways that you found VC sort of more open to the idea of sort of a young founder type, at least, than you think would have been.

Oh, totally. I mean, there's such There's a ton of sexism in SF, like, don't get me wrong. Like, the way I always explain it is, like, when I walk into a room, the assumption of my competency is not zero or positive, like it might be from a traditional, like, bro founder. It's usually negative. And then I have to work within that conversation to get them to zero and positive, which is frustrating because I might, like, I have a lot to learn, etc. But I am a really good operator. Like, we've gotten this company really far in 4 years. With a lot less money than a lot of the other groups have had. And again, starting from zero. But I've kind of gotten like— I used to just get so pissed. Like, I remember I pitched one fund and afterwards I called the partner. I was like, do you not realize your stupid GP was mansplaining longevity to me the entire time? Like, I got so, so irritated. And now I'm just like, whatever, it's fine. I'm going to be richer anyhow than these guys. And like, I'll create my own fund and support people building interesting stuff, but you just got to play the game to win the game, and the game has the rules it has.

So I've just been wondering this whole time, is Loyal only about dogs, or is this like a roadmap to humans? I'm sure there's a world where it's like you get the perfect drug, you're, you're ready to go, but like, how do you think about it in terms of your focus?

So it's both. Loyal has, I believe, a relatively like hard but straightforward path to a multi-billion dollar company just off of dog aging drugs. Just if you look at comparable market-sized dog drugs like heartworm preventative. Heartgard makes half a billion a year. Flea and tick, NexGard made $1.2 billion last year of revenue, high margin revenue. So there's a clear path there. And if we only do that, that's really awesome. But dogs are also the best, or one of the best biological models of human aging, 'cause they've co-evolved with us, they've shared an environment for tens of thousands of years, and most importantly, to develop age-related diseases over time. So a dog gets cancer, not due to, you know, a shit ton of inbreeding like a mouse has, but just environmental factors. A dog gets, or thought to get neurodegenerative disorders, dog gets dementia. That's actually something we've looked at, cognitive decline in dogs. It's one, my favorite study we ever ran was a cognitive decline study in dogs. They get osteoarthritis. And so if something works in reducing the onset of cognitive decline or cancer or whatever in a dog, which we'll learn in this 1,000 dog companion dog study we're running later this year, starting later this year. It's not one-to-one to work in a human, but it's a sure as hell really awesome biological insight that might translate over. So yeah, I mean, my goal is to build an aging pharmaceutical company. I think aging's gonna be larger than oncology. There's no one oncology company. There's no one, you know, Parkinson's company. There's gonna be many. And I wanna build one of the defining ones. And hopefully James does too. And we'll be able to talk about the good old days.

James, you can go after a bunch of drugs at once, I guess. So you sort of get to hedge your bets.

Yeah, I think I know where you're going, which is something along the lines of like, we get asked a fair amount, what does— like, are all of these people who are trying to do real drug development within this broad aging biology space, aren't they all competing with each other? Isn't everyone like trying to get the first drug to increase healthspan? And that will be like the pot of gold at the end of the rainbow that one person wins. And it's really fascinating because this ecosystem, this kind of community is uniquely collaborative within any tech or biotech or pharma kind of competitive landscape that I've ever seen because so many of the drugs are targeting completely different things, right? So like you have Ozempic and like Novo Nordisk has their GLP-1, right? And then Lilly has their GLP-1, and it's— you're going to take one or the other, right? And like, they both wanted to go, and they were like head-to-head competing with each other. Celine's drug and all of our drugs, they don't even target the same molecular pathways. They're just kind of coming from the same broad field of how we studied cellular biology. So Cambrian has 15 different drugs in development, and none of them are targeting the same two things. This is something so much broader than just like, oh, we found a new way to treat obesity, like, and it's this pathway, which is how you get real head-to-head competition. This is instead like, we've just opened the doors to hundreds of new ways of approaching cellular dysfunction at its core, of which some will be right and some will be wrong. And they're even going to be approved for different things first. And then once they're approved, when you get the first one, that is approved for healthy lifespan extension, then that will be a tide that raises all ships because now there are footprints to follow towards a prevention study in the way that the most successful statin was like the third statin that was approved, not the first one.

I was just going to add quickly on here. So Loyal is kind of like mini Cambrian in that way. So we have 3 programs that we're developing concurrently. And the way I thought about it, and this was actually like a pretty big fight we had in the early days on the board because like the traditional tech company only develops develops one product, right? And you focus all your energy on that one product. But the big difference between tech and biotech is that your product is locked in, right? Once you start doing your studies, that is your final product. You might do like different formulations, etc., right? But the active ingredient that's driving the lifespan extension is locked in. And so there is nothing you can do. There's no iteration. There's no product-market fit finding you can do to make a drug work if it doesn't work. I always say there's a god in biology, even if you're not religious, because it is predetermined whether our drug will work or not. It's about us finding the truth as effectively as possible. And then there's other execution bits we can do to increase probability of success post that binary truth. But that's core importance. So what we did is we have 3 programs, 2 around large dog lifespan extension, 1 around old dog lifespan extension, that share a really concrete core. That is, you know, how do we prove to the FDA that the drug works? What does the pivotal lifespan extension study look like? You know, the regulatory strategy, like all these different things. And it's the idea that a drug could be developed to extend lifespan extension, and then it's slightly different mechanisms or active ingredients on that. So almost everything is shared that is able to be held true, and then we're able to externalize out the risk that we can't control, which is the binary yes/no whether the drug works. We're now beyond that. Like, we, we have positive data for our drug programs, which is great. But that's how I designed the company early on, because I was also very cognizant of the fact that if our first drug failed, it would just blow out in general the opportunity of me or anybody else to build a dog longevity company, even though our first drug failing would have not been at all reflective of the validity of the thesis.

Right. There's an expected amount. Not every drug works, even if you're operating perfectly.

Uh, this is the hardest part of pharma that only statistically only about 12% of drugs that start clinical trials get approved. And within biotech companies, it's slightly better. They do better than pharma, or we do better than pharma, but still like nearly 20%. And that's the highest that you get from a statistical average.

The Bryan Johnson idea, I think, you know, people are so excited about it partially, you know, because people want to know what to do with their own health. I mean, it's like, you know, like you sort of said, we've had Atkins, we've had, so, you know, intermittent fasting, you know, there's so many, so many things. And, and certainly I obviously like what, what you should do on a societal level to prove a drug versus what an individual who is actually aging right now and not, cannot wait for, for things, you know, for drugs to get approved. Those are sort of very different considerations. And, you know, you, you both are sort of measured and science-based. So probably the, the last people to sort of like push on everybody what, what you think they should do. But I am curious what you would recommend for people now that's sort of available to them, or like, are, yeah, are you taking anything sort of strange yourself? Like, I'm curious in terms of just like an individual, like, who've looked at this space, how you approach and what you recommend to your family and friends.

So I think one of the best predictors slash like rough categorizers of whether somebody is a charlatan or not is like how much they work on their own personal longevity. Like all of the people who are like super legit in the field, like Laura Deming, the Longevity Fund founder, is like a very famous example of this. They often do things that are like negatively selected for a lifespan extension, right? So like when I was working at Longevity Fund, all we ate at the fund was like chocolate Cheerios and dandelion chocolate. And I was like, the meals we had at the fund. You know, having— pumping up your blood glucose levels that high, not good for longevity. I don't do anything like— I work out, I guess, but hey, I'm like not doing longevity drugs for myself. And I think that's actually a really important thing to like keep cognitively— like, I think people who intertwine their fear of mortality into their pursuit of aging drugs become dumb, right? Because it's a fear-based way of approaching the field. Versus a logical way. They're like, oh God, I have to find something because it's my mortality on the line, versus I see this as like my thing to help other people. And like, I try to think about it as other people and try not to focus on myself. Maybe that'll get harder as I get older, I don't know. But I think it's a pretty good predictor.

You don't take vitamins or anything?

I think literally nothing. Like, I'm trying to eat more vegetables. I'm vegetarian, but Like I live on frozen and canned vegetables. Okay. Like I am, don't do anything I do. Just maybe if the drug gets approved and your vet says so, prescribe to our drug and don't steal it. But no, otherwise I don't do anything. James, what's your approach?

So I'm like a decade older than Celine is and, and I still get called like the young kid on the, on the biotech block most of the time. And I take a little bit more of an experimental approach like we were talking about before. I think almost everybody that I know is thinking about, especially like, so for example, in my, my family, we've had 2 people die of Alzheimer's in the last, you know, in the last 5 years. My boyfriend's mom is starting to show signs of this. And so we're thinking, okay, well, what can we do to maximize the time that we have healthy to be around and to be with each other. And so there are things that I'm doing. I think the best like validated things that we really know will work is don't get diabetes, regularly exercise, eat fruits and vegetables, get enough sleep, don't change time zones every week or two. This is one. Yeah. This is one that like I was, I was in Europe last week. I'm in Europe next week. Like, it fucks with you for like a while.

I get sick every time I come back from a big time zone change, every single time without fail.

So, you know, I do play with some supplements, but like there are some that have real evidence behind them, the best of which is fish oil for the prevention of heart disease. I have two grandparents who died of heart attacks in their 50s, and so like I care a lot about my heart health, you know. Beyond that, we just don't have a lot of evidence. And so whatever, you know, people are doing, like they can play with this or that, but it's just like, it's not backed by facts until it is. And a big part of, I think, this whole field, and if there's one message that I would love someone listening to this to walk away from is like, ultimately we need to create new truth in order to know new things. And the only tool in medicine that we have for creating new truth is running randomized placebo-controlled clinical trials, which will create one little new piece of knowledge at a time. And like, that just takes a long-ass time. And this is all brand new science where we have a pretty good idea that like it might work in mice, but before we know that it will work in humans, and especially with the diversity of humans that exist, which is way more than the diversity of mice, like it's just going to be a while before we can think about how this longevity science is going to impact everybody's day-to-day life. There's just not that much outside of the, the stuff that we knew before, you know, 10 years ago that we've just gotten more and more evidence. The placebo effect is so fucking strong that it would outperform almost any drug on the market today. So until you can disentangle what scientifically is going on at their mechanistic level versus what's kind of happening at the psychosomatic or the placebo level. Like, we just don't know. So what I advise people is like, get excited, do things, like try stuff, right? Be healthy, be active, enjoy life, think that you're going to live a really long time. And then also try to do these basic things that we know are supported by like the physiology underlying your body. If you have high cholesterol, take a statin. If you're overweight, like exercise, have a good diet, maybe end up on one of these obesity or metabolic drugs that are pretty good if your doctor recommends. But like apart from that, wait until the science comes out and see if we have like novel mTOR inhibitors or caloric restriction mimetics or AMPK activators that will be coming not that far in the future if they show to be safe and effective that could be used for people. But that's really like the next frontier. This is why this whole longevity space, it's gonna create a world that is so different than the one that we have now because it will be grounded in truth instead of in speculation. Great.

I think that's a great endpoint for the show. Thank you both for coming on.

This is fun. Welcome. Celine, I always love doing podcasts with you.

Yeah. This was sincerely one of my favorite episodes. I mean, it's such a great topic. So thanks so much. My pleasure.

Yeah, thanks for inviting me. That's our episode.

Thanks to James and Celine. Shout out to Tommy Herron, our audio editor. Riley Consella, my chief of staff. Young Chomsky for the theme music. Annie Nguyen for booking the guests. Please like, comment, subscribe on YouTube and subscribe to the substack newcomer.co. Thanks so much. Goodbye! Good-bye— goodbye? G'day...

good bye?! Bye-ya-good-byeee!! Byeeeeee!!! Buuuyyye!!!! Buhhbyyyyyyeee!!!!! Baahhhhyehhhhyyyaaagghheeyaaaaghheyaaaaaaaggheeeya-a-haha!

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Oh my god I'm so bad at this game damnit!

It's okay if you suck it doesn't matter to me anymore oh well then that sucks for someone else haha. Okay let's try again here we go back into our base now because there was no point of doing anything out on land right away anyway uh yeah thank goodness guys thanks very much everyone have an awesome day stay safe