Cory Smith: Welcome to Galaxy Balance, the biofuturism podcast. Here we explore the frontier of biology and AI and ask what it will take technically, ethically, and societally to engineer the next phase of human life. From synthetic embryos to longevity escape velocity, we move past speculation to understand the conditions required for these breakthroughs and the future they set in motion. Today's guest on Galaxy Balance is Noah Davidson. co-founder and chief scientific officer at Rejuvenate Bio, a company emerging from the church lab focused on using gene therapy to treat aging itself as the root cause of disease. His work sits at the frontier of synthetic biology, longevity science, where the goal is no longer treating individual disease in isolation, but reprogramming biological systems to restore youthful function across multiple tissues. Noah's path reflects a deep integration of engineering and biology. He began in applied physics at Caltech and pursued biology and biological engineering at MIT and helped pioneer mammalian gene circuits and programmable DNA systems before joining the Church Lab at Harvard. There, his work expanded into gene therapy, viral vector design, and epigenetic reprogramming approaches aimed at reversing age-related decline. At RejuvenateBio, he's developing combination gene therapies that can rebalance key pathways in aging. effectively turning the liver into a biofactory for beneficial proteins and targeting multiple chronic diseases with a single intervention. The conversation explores what it means to intervene and aging at a systems level, how close we are to clinical translation of epigenetic reprogramming, and whether biology is becoming something we can truly design. Noah, welcome to Galaxy Balance.

Noah: Thanks for having me. Really excited to talk about what we've been working on at Rejuvenate for the past, I guess it's like seven years now. Yeah.

Cory Smith: Wow, lucky number seven. Best of luck to ya. So yeah, I always like to start with digging into your story. What got you into science? What got you into this field of anti-aging specifically, and why are you here today?

Noah: Yeah, mean science, think it's always seemed interesting as a way to bring the future towards today, you know? ⁓ I think ⁓ science fiction has played a huge role in my interest in science because sci-fi always seemed pretty cool. ⁓ know, Star Trek, Star Wars, all the cool tech and kind of magic that they had going on in the future seemed great and I wanted to be a part of bringing that toward, you know, what we can do today. And so that's kind of how I started at Applied Physics at Caltech was I actually wanted to do something related to space and traveling in space and fusion engines or something like that. realized I wasn't smart enough to actually do physics at that high level and kind of move toward biology where I thought if we could live longer, then I'll still be able to see all that cool science in the future. And if everybody could live healthier and longer than the world. be a better place. And that's kind of how I slowly moved from applied physics more into a biological setting.

Cory Smith: Excellent, and a timely, ⁓ opportune time to talk about space travel. You started there, we're interested in it, with the Artemis II mission. How did you feel when you saw that launch go off and now we're seeing some of the images of the whole Earth and now the images of the moon? A whole generation before us saw the Apollo mission and witnessed that and it was just the shadow in our life of we went there long ago but aren't doing it anymore. How do you feel ⁓ about this?

Noah: I, ⁓ it's, exciting to see any, anytime I feel like NASA does anything, I always, ⁓ see it a lot of my feeds and I'm always excited to like be into it. ⁓ just last night, I think I saw a SpaceX launch at my window here in San Diego. I could just see like, ⁓ their plume really high up, because at nighttime after the launch happens, the smoke is so high up in the atmosphere that it reflects the sunlight, even though it's completely pitch black out. And so it's very cool to see those launches. So just all that kind of stuff always gets me real excited. And I'm glad that space travel and launching things into space is becoming a lot more normal and exciting again.

Cory Smith: And just on a few key topics of the show, you brought up science fiction as well. So that's inspired me. I always ask every guest, usually towards the end. But since you brought it up in the beginning, ⁓ I've always been inspired by that. Like you said, the Star Trek vision and it has seeded so many thoughts into scientists and engineers' mind that it brought it to reality. A simple one, like in Star Trek, the doors opened. Those didn't exist before then. And now every kid grows up with that as commonplace. And tricorder, communication devices, the screen. A lot of this has been brought into reality, so I love that aspect of science fiction. ⁓ But one thing I've noticed is that a lot of more modern one is very dystopia. Zombie apocalypse, radiation, post-nuclear apocalypse after Earth. We really went through kind of a golden age last century and kind of ⁓ pessimistic view now. What do you think is ⁓ driving this change?

Noah: ⁓ I feel like sci-fi usually is a way to talk about society's problems or promises in a futuristic way. know, lot of Star Trek episodes take the problems of our current society and kind of drill down on a single episode of like, ⁓ what if this was an entire planet or race of people dealing with this one problem? I can't remember which show it was, but they did like social media as like a way to kind of adjudicate all trials and stuff on one episode of something. And ⁓ it was like, what if everybody could just like vote on their phone in a kind of a social media way, whether somebody's, ⁓ you know, ⁓ convicted or not. you know, obviously it was terrible. ⁓ But, you know, I think sci-fi is always a way of kind of diving deep into one aspect of society that we want to explore more. ⁓ in a new way. And yeah, I do think there was a lot more promising kind of outlook back in the past where we dig into these aspects, but more in a promising way. Now there does seem to be a little bit more bend on kind of the apocalyptic worldview, but you still have a lot of the new sci-fi coming out that's still kind of promising, you know, longer lives and better tech and traveling the universe. But it's kind of hard, you know, we're getting to a point where science fiction is almost magic when you start to extrapolate beyond, know, if you had general AI, you know, the culture series does, ⁓ but Ian Banks does a really good job at still being an interesting story, even though basically you have God-like powers roaming the universe. So I think it's, it's hard for people to conceptualize a good story once you have God-like powers, just with everybody having God-like powers. So, ⁓ that's kind of a challenge before, you know, cell phones or sci-fi now, you know, disguised basically magic as sci-fi at this point.

Cory Smith: Ian Embaick's great with the culture series. Amazing ship names as well. Very creative there. Sad that he passed away, but excellent series. And I believe I saw that social media one on ⁓ Seth MacFarlane's Star Trek-like reboot. That was excellent. And probably a black mirror about something similar, at least on like social media rating. But scary stuff, but interesting. I like how they bring those problems up. ⁓ So you brought up some with aging. Like, did any science fiction particularly...

Noah: Yeah. ⁓ that's what it was. Yeah, that's right.

Cory Smith: inspire you to get into the anti-aging field.

Noah: ⁓ nothing, there's no like movie or show that was like this, because they never really do longevity in a way that's interesting. It's always kind of boring. ⁓ you know, a of the sci-fi stuff, either that or it's the bad guy who's trying to live forever. You know, like Voldemort was trying to live forever. ⁓ usually going after longevity is seen as kind of a selfish, ⁓ pursuit. ⁓ people going after the fountain of youth, but

Cory Smith: you Yeah. you

Noah: It's really not when you're doing it from a societal benefit type of way. When you're doing it for yourself, obviously, yeah. But when you're creating therapeutics that should be able to everybody on the planet, you know, it's no longer kind of this ⁓ negative pursuit. It's actually beneficial for the world to keep everybody healthier, living longer. So there's no real book or series out there that I can point to that I was like, ⁓ that's the one. It was more just the excitement about the future that I found that really drove me wanting to be around. long enough to see all the cool stuff that's gonna happen. And then what really honed, what we're working on at Rejuvenate is I got my dog Bear and I wanted to make him live longer and healthier and be around with me. And so that kind of really drove like, how do we apply this general interest in longevity to something that we can do today to make people and pets lives healthier and better.

Cory Smith: Excellent. I'd recommend one for longevity that has that not villain view is Robert Heinlein's Time Enough for Love. They have a character Lazarus Long. There's a few books, Methuselah's Children and Time Enough for Love. And they actually, it goes back to the 1800s. A big philanthropic group paid the longest living humans to have babies. So they essentially enriched all these traits over hundreds, many generations. And they got these families that could naturally live multiple hundred years. Then they implement rejuvenation treatments and it's very exciting. They have a war with the regular humans and there is conflict, but at the end they create this phenomenal society that has different values when you can live multiple lifetimes. Let's transition into Rejuvenate Bio. I'd love to hear about the origin stories, ⁓ what motivated you to start this company and what were the goals and what has it transitioned into?

Noah: Yeah, the original goal was basically born out of my love for my dog. I got him my first year of my postdoc and I didn't really know what I wanted to do when I joined Georgia's Lab except that I thought working on longevity would be cool. And then when I got him, it really focused kind of what the problem is is that we have nothing to make the people and pets we live longer, healthier lives. And... So Rejuvenate's core mission is to treat the root cause of basically getting older and having comorbidities and multiple morbidities that ⁓ don't really have like a centralized way of thinking about this treatment. So ⁓ we already have lots of genes that we know make mice live longer and healthier, and they've never really been translated out of the lab. And so I thought, well, gene therapy, as you know, back in 2012, finally coming of age, ⁓ we can finally just take what we know works in mice, translate it into dogs and people, and create a therapeutic that can make them healthier and live longer and not have the problems of obesity, heart disease, kidney failure, diabetes, et cetera, et cetera. And so ⁓ the work in my postdoc was kind of proving this idea. And ⁓ I took a couple genes that we know make mice live longer, kind of three of the top. ⁓ life extension genes, Clotho, FGF21, and then anti-TGF-beta-1, basically because it's involved in most inflammatory processes in fibrosis, which is involved in most diseases, and ⁓ did all different combinations of those three genes and showed that one combination can treat all four different diseases, heart failure, kidney failure, diabetes, and obesity. There's also been published reports that it can increase your immune system, decrease cancer, make you cognitively better. Just kind of these magic proteins that when you actually are treating aging, you're treating you, the system, to make it better and holistically better overall. You're not just trying to play whack-a-mole with these diseases that pop up as you get older. You're treating everything together and making the whole system.

Cory Smith: Have you treated your dog? That was one of the goals. Has he received the trial of it?

Noah: That was one of the goals. ⁓ I would have injected him. Unfortunately, he ended up having what's called gender of myelopathy. ⁓ Basically the ALS of dogs and the therapies that we were working on don't really treat ⁓ ALS. And so I didn't really have anything kind of ready to inject him with even if I could. I can't be like that guy in Australia that cured his dog's dog of cancer. ⁓ Even though I did try, I did try to come up with something for it, but there really just isn't anything great out there for kind of ALS yet. ⁓ kind of some of the next gen stuff we're working on, epigenetic partial reprogramming, I think, could definitely work. But at the time that he had the disease, it just wasn't really ready for primetime, ⁓ even pre-primetime for him. ⁓ So just unfortunate, but ⁓ so he didn't get to take a part in kind of the reason that rejuvenate exists.

Cory Smith: It's good segue. Epigenetic partial reprogramming, very hot field with David Sinclair's Life Biosciences gonna lead a trial later this year. You were on some of the first papers that showed this in vivo and have been behind some of the driving force behind it. It's always a tricky avenue because enough dose will fully reprogram them into stem cells that has a cancer risk, a tumor risk. So getting the dosing right seems very critical. What are your thoughts on the upcoming clinical trials and the field as a whole?

Noah: Yeah, I think the field as a whole is super promising and the clinical trials are very exciting. ⁓ It is the, yeah, so I collaborated with Sinclair Lab when I was in the church lab with the lead author on that paper, Yenchen Liu, and ⁓ he basically had the idea of turning ⁓ the Yamanaka factors into like a treatment via gene therapy. And at the time, I was already collaborating with Sinclair Lab on some other gene therapies and so I was there to kind of help Yen Chen kind of create the gene therapy version of the idea of the partial reprogramming and then he took that work and showed that he could, you know, regenerate the optic nerve and tissue there. Really exciting stuff. He's an amazing scientist and it was a great collaboration and that's the work that is now going to be put into a clinical trial ⁓ for Nanion. disease, so really exciting there. You know, I rejuvenate. And what's great about that is it's an immune-privileged environment, you know? They're going into the eye. I think it's a great place to work. And ⁓ really excited to see what happens there. The dose is important, and cycling it and turning it on and off is a really important aspect. That's what was shown in both Yenchen's paper as well as our paper at Rejuvenate where we were able to increase the lifespan of mice using the same technology. Basically, we took them out to 124 weeks of age before we even started the experiment. So that's like equivalent to an 80 year old human. So we let them get really old. Actually, half the mice died before we even started the experiment. ⁓ so we have to start with twice as many mice, get them really old, and then we have half as many mice to start the experiment. And then we showed that the mice that got our therapy lived longer and healthier. Kind of we reversed some of their age with this therapeutic. And so we turn it on for a week and then we turn it off for a week and then we turn it on for a week and we turn it off for a week. And we did that for their entire rest of their life. And so that's similar to the way that the technology is used in the Sinclair paper as well with Yenchen. You turn it on and off because you don't want to have it on forever. That could cause know, downsides. are very powerful genes that you are resetting the epigenetic landscape. I think with OSK though, it's been shown several times that even just turning it on permanently won't really cause teratomas, cancer, or complete reprogramming because you're missing one of the four important factors, which is ⁓ MIC, CMIC, which is actually the cancer causing version ⁓ protein that's involved in that cocktail. And so... OSK, I think, is actually safer than people think. It's not really going to cause cancer, even if it was on 100 % of the time. We in our lab have done somewhat experiments like that where we put it on permanently. We don't even induce it. And the mice were fine, and they didn't get cancer. We didn't take it out beyond a year, but it was interesting to see that it was actually not that bad to have just those three genes on permanently. I still think it's better to cycle it because you're messing with the internal dynamics of cell type. So you're not letting a liver cell be a liver cell or a neuron be a neuron. You need to reverse the clock but then let them be what they are. And having those genes on permanently is kind of messing with that internal what we are ⁓ information.

Cory Smith: Excellent. And that cycling is achieved, at least in that paper, through dox-inducible promoters. I believe the clinical vectors use that as well. We don't have all that information, but I've seen reports that it's inducible and largely inferred that it's dox-inducible. What do you think of the clinical use of an inducer? I believe it's one of the first times it's been used in a clinical trial.

Noah: Yeah, think, I don't think it's the first time using a clinical trial. There was a clinical trial for a cancer drug where they were inducing killing of the cells using an inducible system. I think that sends it out there. But as a therapeutic,

Cory Smith: kill like a cell ⁓ kill switch. I've definitely seen it as kill switches, but as

Noah: Not a kill switch, like to turn on the gene that, I guess like a kill switch, but it's part of the therapy. It's like you infect the cells and then turn on the kill switch to kill the cancer.

Cory Smith: Hmm. Okay, excellent. And I know Gamito uses it to develop their cells, but not as like turning on something that's therapeutic once it's delivered.

Noah: Yeah, I think this might be the first time as a therapeutic to turn on the of the payload that you actually want on. So on that respect, I think it might be the first time. ⁓ I think inducible systems are great, especially for things. It's like a nice hybrid where you have the additional safety of having it off for a permanent therapeutic, right? So gene therapy is great because it's permanent. Gene therapy is not great because it's permanent.

Cory Smith: Yeah. Yeah.

Noah: You know, so like you have no compliance issues with a permanent therapeutic. However, it's going to be on all the time. The inducible system is a nice hybrid of current, you know, drugs versus next gen gene therapies where you get kind of this permanent therapeutic in your body, but it is off and safe until you take the inducible system. think doxycycline, the RT, specifically the reverse tetracycline transactivator that comes from bacteria. ⁓ might not be the best long-term solution for an inducible system. There are lots of people working on different inducible systems. know, Mark Lajoi, another church lab alum has other inducible systems for his company. He's got cell therapies that he's working on. And, ⁓ you know, we're working on different inducible systems. And I think the downside of using bacteria is that you have the potential of an immune response. So I think going into that is a great idea. I don't know. I'm not involved with that company, so I don't know exactly what they're using, but if they are using the RTTA, ⁓ they had to do safety and stuff in primates, so I'm sure they saw that they didn't have an immune response, and that might just be because it's in the eye. I don't know what you would do if it was in the liver, and I think having something that's not bacterial-based long-term is probably better, especially if you want to get to millions of people. The safest, most orthogonal thing you can create would probably be better. Having an inducible system that is not bacterial based would probably be better to reach other tissues and organs.

Cory Smith: So your current therapies at RejuvenateBio are all constitutive, with the three genes, you're your first generation of therapies.

Noah: Yeah, our first gen therapies were genes that we know, it was basically like, what's the simplest, most powerful thing we could do? It's take advantage of how gene therapy works, which is an always on kind of mobility. And secondarily, it's like gene therapy can't get into every single cell on your body. You we just don't have that technology yet. But what we can do is get a lot of liver cells. And so what genes can we over express permanently from the liver? to affect system-wide benefits. And that's how we chose kind of the three proteins, FGF21, Clotho, and anti-TGF-beta1. They go systemically to your entire body, provide benefits throughout, and can be on permanently without any downside or negative thing. That's how the mice live longer. They were on permanently in the mice, and the side effect was an increased lifespan.

Cory Smith: Excellent. And so as you stated, one of your goals is to develop therapies for both dogs and for humans. How do you balance that as a single company? How do you prioritize your focus and what are the timelines look for both of those?

Noah: Yeah, think the goal for me was a lot of research was already being done with dogs as a preclinical model, like a lot of the gene therapy research specifically. ⁓ The first gene therapy approved in humans in the US was SPARC therapeutics, and a lot of their preclinical work that they did to get into humans was done in dogs. They had these dog models that were blind, and they made the dog see again. And I think part of the... Somebody had a great PR idea where they gave these, you know, dogs that were fixed with the gene therapy to the kids that were fixed with the gene therapy. So it's kind of cute. But, so a lot of work had been done in dogs as a preclinical model and I was like, well, why can't we double dip? Dogs need therapeutics to make them live longer and healthier. So do people. Why can't we use dogs as a preclinical model, get a therapy both for dogs and humans kind of?

Cory Smith: ⁓ Yeah.

Noah: have a middle stop off along the way, have a therapeutic for dogs that we could be selling, and then support our human programs, because human timelines are a lot longer. The best case scenario for an animal health drug, would say, is three to four years to get it approved. ⁓ And for humans, you're looking at at least seven to 10 years for approval. And then dollars-wise, it's more like 12 to 15 million to get a dog. therapy approved and for humans, you know, you're looking at a billion or something. You're a couple hundred million. So the timelines and the ⁓ dollars spent made ⁓ animal health kind of a really attractive idea. Especially if you have a very large market in the animal health, you know, some of the best-selling drugs right now in animal health are bringing in a billion dollars a year. So it's definitely not small. It used to be much smaller, but everybody loves their pets and animals. It's grown huge and You know, there's like 90 million dogs in the US, and we're going after heart failure first in dogs, and about 10 % of all dogs get that, you you're talking about millions of patients that need this therapy. And so, no, go ahead.

Cory Smith: I was gonna ask the drug product are they intended to be both for dogs and humans? Do you have a specific surrogate that is just for dogs or do you use the human gene exact same viral vector all the components or did you always intend to have two different versions one for dogs one for humans?

Noah: That's a really important point. Thanks for bringing that up. They're different. So dogs, we have the gene therapy with the dog version of the gene. And then for humans, we have the human version of the gene. ⁓ This decreases the risk of immunogenicity, where the immune system would recognize human proteins in the dog and be like, wait, these aren't dog proteins. We have to kill off these cells. And so ⁓ definitely reduces the immunogenicity risk associated with these kind of advanced therapies.

Cory Smith: Yeah.

Noah: So they're the same genes though, they're just coded for dogs. So it's the dog version of FGF21 and the human version of FGF21. ⁓ And so yeah, we have the dog version. We're kind of two years away from getting conditional approval in animals for mitral valve disease, for dogs mitral valve disease. ⁓ We've also done a lot of work on manufacturing. You we're working with AAV. This is a gene therapy technology that has been getting ⁓ know, $2 million price tags for a single dose of this therapy. We've been able to kind of use some newer technology for manufacturing that reduces the cost of manufacturing, you know, close to $100 for a dog. And this allows us to make millions of versions of this therapy for the millions of patients that we plan to treat in animal health. And for humans, the way this translates is that... ⁓ It probably is a one to two thousand dollars to make this therapy for humans and then you're getting a decade of benefit So I really think bringing down the price point an increase in manufacturing ⁓ Because we had to for animal health you can't sell, you know a ten thousand dollar Therapy in dogs because people pay out of pocket. Nobody's gonna be paying for something that you have to charge fifty grand for So we really had to bring the manufacturing technology to a place that it would allow us to sell into the animal health market So that you know pet parents can actually afford something like this. so bringing it down to the kind of $100 mark allows us to sell it for low thousands of dollars and pet parents can definitely afford a life-saving treatment that is permanent, a one-time dose, and then their dog has it forever. So I think it's really exciting, but focusing on the animal health allows us to make... more virus that can treat millions of patients for humans. Because the scale just never was there. Everybody goes after orphan indications in humans. And that's treating tens of thousands of patients. With these therapies, we want to be treating millions of patients. now with this newer technology, we can actually make enough virus to treat millions of patients, let alone at a cheaper, more beneficial cost.

Cory Smith: So for dogs you have to go for a specific indication mitral valve, but since it's general aging, is there benefit to just giving it prophylactively early? Does that give them a lifespan boost and have you looked at that?

Noah: ⁓ so, you know, whenever you go to the FDA to get a drug approved, you have to have some indication, something that's going to be on the label of this drug is intended to treat X. You can theoretically go for a more general aging claim. ⁓ you know, there are other companies out there doing that and I think there is a path forward, especially in dogs to doing something like that. It's more costly to go after aging in general and you have to have a much higher. number of dogs in your clinical trials to prove something like that out. ⁓ We thought the best first place to go would be to go into a large indication for an age-related disease to kind of show that it's safe, show that it's effective, and show that gene therapy has a modality in animal health is where people want to be. And so we're going after mitral valve disease, but there's no reason we can't do something called indication expansion where showing it works in kidney failure, showing it works in obesity, diabetes. And then eventually just showing that all cause mortality is decreased in the dog population if you take this prophylactically. So I think the best way to go about going after an aging therapeutic in dogs might not be to directly go after aging, but to get it out into the world, vets have the ability to prescribe off label a lot of times. So you might see a large population of people, dogs getting this therapy prophylactically ⁓ once that's shown to be safe and effective. ⁓ you're able to get that data and show that you can actually treat aging ⁓ as well. So I think in the animal health world, ⁓ the quickest way to show anti-aging might be to get it for specific indications and do indication expansion. And definitely for humans, I think that's the best way to go. Like how do we get it into millions of people? Well, we go after some of the biggest diseases, heart failure, kidney failure, obesity and diabetes. And we've seen a lot of success. It's kind of like the GLP-1 story. We had this idea. to do this before GLP-1s were a thing. And so it's really nice to see GLP-1s bearing out exactly what I thought would be possible. Instead of a laundry list of ⁓ problems, you get a laundry list of benefits with GLP-1s, right? You can treat diabetes, obesity, it's been shown to work in heart failure, kidney failure patients, ⁓ and even some cognitive benefits. ⁓ and they just keep on adding things to it. So I think that's kind of the idea of what we wanna do with our therapies as well is go after the general problems you see with people as they get older and pets too. ⁓ And so yeah, we have to have something on the label. For animals, we're going into mitral valve disease first. ⁓ That could be expanded into other heart failure indications. Kidney failure is also a big one and this therapy we've already shown in mice that can treat kidney failure. ⁓ FGF21 is kind of a better GLP one, if you will. You don't eat less, you still lose weight, and you ⁓ don't lose muscle mass. So I think there's potential here to ⁓ be really good for obesity in dogs as well. People love to their pets treats and ⁓ aren't getting them out for enough exercise, so here's a nice way to keep them healthier and living.

Cory Smith: I always had pets growing up, golden retrievers, and because of the inbreeding for many of these breeds, they're prone to problems. Golden retrievers have hip problems, for example. Are there certain breeds that you're targeting that you know are at risk for mitral valve disease?

Noah: Yeah, there's a, I actually had golden retrievers growing up as well. ⁓ And they were, they are, they, ours were always overweight. ⁓ Mostly my dad wouldn't stop giving them treats. And, ⁓ but yeah, and they also had a lot of cancers too, which is just always terrible. Apparently there's like a bifurcation with goldens where ⁓ once you get past a certain age, the goldens can live to like 14 years, but the ones who don't make it usually have died of cancer or something. And so like you have this kind of bimodal population in goldens, which is interesting.

Cory Smith: Yeah, wonderful dogs.

Noah: ⁓ Specifically for mitral valve disease, going off topic there, there's kind of this poster child for mitral valve disease. They're called Cavalic King Charles Spaniels, and up to 80 % of these dogs get mitral valve disease. It's kind of crazy. And they've been doing a lot of breeding work to kind of get rid of this in the population, but it shows up later. You generally are breeding the dogs before they even have a problem, and that's kind of why we can't... ⁓ why cancer kind of stays around. We have kids before we even know we're gonna have cancer. And so those genes get passed on and kind of accumulate in the population.

Cory Smith: And for these trials, do you use that type of spaniel for your trials to prove this drug?

Noah: Super similar. ⁓ yeah, we connected with the Cavalcade, Chinchilla, Espana clubs. ⁓ Obviously they're very excited about some treatment that would make their dogs that the ones that they love live longer and healthier. ⁓ so our pilot study, we did a pilot study in people's pets at Tufts University. The first one is concluded now. We enrolled 18 dogs. I think something like 13 of them were Cavaliers. ⁓ and the other five are kind of other small dogs. Mitral valve disease is more of a small dog disease. Most large dogs don't get mitral valves. They get a different form of heart failure. ⁓ But yeah, we were excited to see that we were able to increase their lifespan ⁓ with this therapy. the current drug that's approved for mitral valve disease is called pimovendin or vetmedin. ⁓ It is an inodilator. It makes the heart pump harder and ⁓ opens up the blood vessel so there's not as much load on the heart. So it doesn't really treat the underlying cause of the disease, the mitral valve or the pathology of heart failure. You know, the heart is going to get a lot of fibrosis, a lot of damage, it's going to remodel, eventually go into failure and... The current medicine doesn't do that. So, you know, there really is a huge unmet need for mitral valve disease patients to have something that is disease modifying. And, you know, our data is showing that we can stop fibrosis, stop the remodeling, ⁓ and allow the heart to function better for a longer time. And so we get, you know, one to two years of increased lifespan in this population, as well as stopping the remodeling and making these dogs generally healthier. ⁓ And that's what we saw on our trial at Tufts. And we're probably gonna open up another trial in the next, you know, ⁓ six to 12 months to enroll some more dogs. So I think that's gonna be an exciting part of what we're doing. So we'll put out an announcement there. ⁓ But yeah, no, it's ⁓ really exciting and very, you know, ⁓ appreciative of the CKCS Dog Club. They've been extremely supportive and getting the word out to people made enrollment for that study really quick. know, lot of pet owners were very happy to have something that could actually help their dogs live longer and healthier. ⁓ Yeah, it's been great to work with them.

Cory Smith: you brought up a key disease mechanism, fibrosis. Not only for the heart, but for the liver. It's great that you can slow down or stop that progression. And it's often taught in the textbooks that it's irreversible after it gets to a certain point. Are there any signs that you can reverse this or any thoughts on how we might crack that? Because that seems to open up a lot of clinical opportunity.

Noah: Yeah, I mean if you look at you know, scars for instance, you know, that's the most visible form of fibrosis. You get a scar and when you're younger, they disappear a lot easier, quicker, better. As you get older, they disappear a lot slower. They still disappear. They get, you know, smoother, less, but it takes a long time and they're not that great at completely ever going away, but they do get better. And the reason they get better is because they have time. They're not getting constantly re-injured. With a lot of diseases inside the body, that injury is still constantly there. know, when you get a cut on your skin, that's a one and done situation and then it heals. When you have liver disease or heart disease, that is constantly an insult to the heart or the liver and it's creating more and more fibrosis and more and more damage. So what our therapy is able to do is kind of stop that negative feedback loop and stop the damage signal from propagating into fibrosis. So basically it's giving it time to heal. So we don't directly decrease fibrosis, like we're not over expressing something to chop up fibrosis cells or fibrosis tissue. ⁓ What we're doing is creating an environment to allow the body to heal and kind of make those scars smoother, less pronounced, better. So we do see some reversal in ⁓ remodeling and fibrosis, but it's kind of a slower. ⁓ consequence of stopping the damage signals from continuing that cycle where you're going to get more more of fibrosis and more pronounced. So it's allowing the body to kind of smooth out the fibrosis and heal itself ⁓ by giving it that correct environment.

Cory Smith: Excellent. And I wondered if you could walk us through your drug product exactly, especially for the audience who might not know as much about how this is, just because you envision how you make this drug and how you deliver it into the dog and how it takes effect. Just walk us through the whole process.

Noah: Yeah, so AAV as a technology is a one and done solution. You know, a single one time intravenous injection allows a lifetime of benefit. And so what we're doing is we're kind of doing an app or a software update to the cells in your liver. We do a single injection and then the DNA, sorry, the virus gets into the liver cells. It drops off some DNA, basically some new code, if you will, some new software. And then that DNA expresses the proteins that we want to provide the benefit. For our animal health therapeutic, it is a combination of two proteins, FGF21, fibroblast growth factor 21, and anti-TGF beta 1. ⁓ So soluble receptor for TGF beta. ⁓ And what's that doing is decreasing the amount of TGF beta. Think of it like an antibody. And... ⁓ Those two proteins are produced in the liver and then secreted from the cells into the bloodstream and then they go everywhere in your body to provide a benefit. And so that's the way our therapy works is it's a single injection, intravenous injection, goes to the liver and produces proteins that go everywhere in your body. So with GLP-1s, right, you do a subcutaneous injection of the protein itself and then that protein goes everywhere in your body. We're delivering the DNA, the instructions to make that protein forever inside you. So instead of having to weekly injections, it's a one and done solution. ⁓ These proteins, FGF21 and anti-TGF-beta1 have a number of different benefits, ⁓ both metabolically and fibrotically. And so that's why going after aging directly allows us to treat numerous different age-related diseases. Doing it the way we're doing it systemically allows us to treat numerous systems at the same time and holistically help the patients. ⁓ But... you know, as we discussed previously, you have to go after a specific indication to get your drug approved. And that's kind of where the intelligent design of what you're gonna do first really matters, because you want your first thing to be successful so that you can get to all the other cool and beneficial things beyond.

Cory Smith: And so you have multiple genes. Is this two different AAV vectors, or are they small enough to fit into one single?

Noah: We did a lot of engineering to actually make them fit into one vector. And one of our lead scientists, ⁓ Chris DeSolis, did a lot of the work there where he was able to come up with a way to fit them, package them into a single vector. It started out as two vectors. When we were actually doing a lot of the early science, we had two separate vectors that we were just expressing a single protein from each one. But now it's a single virus. So much simpler manufacturing and a much simpler design. but a lot of work went into making that possible.

Cory Smith: actually met Chris. He's a listener to the show. I met him after Chris Bradley at Matter. He's now working at Matter Biosciences. He was on the show and talked to them a little bit. Yeah, excellent. Glad he could work on that. And was there any titration to the levels between those two genes? Do you have the same promoter, the same expression level target? Did you do anything to get the right ratio between them or does that not matter?

Noah: Yeah, has. Now he just moved to San Francisco. ⁓ I don't think there's a stoichiometric ratio that we need to hit. It's more of, do you have enough of each protein to be therapeutically relevant for the indication you're going after? So can you make enough of it? And that's the question for these two genes that we needed to answer. And they are not the same promoter, ⁓ but they are both powerful promoters and, you know, one gene expresses better than the other. So we had to figure out which promoter to put on which gene and why, but we do get therapeutically relevant levels of both genes ⁓ the way that we've designed it.

Cory Smith: And a big thing about viral therapies is the tropism. Unfortunately, the liver is easy to target. What safety or studies did you do to see where else it goes, even to a minor extent? And what were you concerned about that you ruled out in your talk studies?

Noah: So we haven't done formal talk studies yet. That's on the docket for later this year. And that's where we will do those full bio distributions, what tissues it actually goes into. There's a lot of literature out there though that supports what our, we're using AAV8. ⁓ It's one of the, I wouldn't say first gen, but second gen AAV vectors, very well known, very well characterized. ⁓ Came out of Jim Wilson's lab and ⁓ It primarily infects the liver. It does get some muscle tissue. ⁓ gets a little bit everywhere. But what we've done specifically is we made it limited to the liver. So we put a liver-specific promoter that makes it so that we are only expressing these genes in the liver. So even if it gets into your heart or your muscles, it won't be on there. It will just be hanging out as some extra DNA cargo. But the genes won't be expressed from there. We purposefully limited it to liver to make it ⁓ simpler from a safety standpoint for the FDA. ⁓ These genes could be expressed everywhere. I think it wouldn't really matter, but I think ⁓ from a safety and ⁓ regulatory process, was better to have it limited to the liver to avoid any ⁓ questions that might arise if there ever was a problem. It'd like, it's only expressed in the liver. We only have to look in the liver to figure out what's going on. ⁓ That was a design from the beginning that we did. And that was actually advice from Kathy High, who ⁓ was the founder ⁓ of Spark Therapeutics. She's on our SAB. ⁓ she was like, ⁓ this is early days, way before, before we even launched from the church life, she was like, why don't you just express it in the liver and make it only liver? And I was like, okay.

Cory Smith: That's good to have multi-layered safety from the FDA's perspective. So the FDA controls both the drug. What's the approval process like for a PET therapeutic?

Noah: Yeah, it's very similar. We call it FDA light, ⁓ only in the sense that ⁓ it's quicker and usually less ⁓ patients, ⁓ but it's still the same. It's through the FDA. It's called the CVM Senator for Veterinary Medicine, and they regulate animal health products. And it's kind of the same way that CBER regulates AAV gene therapies for humans. the CVM regulates animal health drugs. And so we go to the specific center at the FDA, and then we have to show safety and efficacy, same as humans. ⁓ The interesting thing is that dogs are both a lab animal as well as a pet. So when you're doing your safety studies in lab beagles or lab dogs, ⁓ that data is akin to a phase one trial in humans where you're actually getting safety data in your target population. So it's an interesting area because you get a lot of relevant data from a translations perspective to de-risk your technology before you even have to go into the real world because ⁓ dogs are the intended population. So ⁓ you show safety and efficacy, just the same as humans, except ⁓ the lines are a little blurred on what pre-clinical and clinical is because the animals are the same that you use pre-clinical and clinically. ⁓ So that's why it's kind of what we call FDA light. It's the same, but it's shorter and ⁓ usually less animals, depending on how good your drug works.

Cory Smith: So what are the major challenges to get this therapy into dogs? You say you have your talk study, what are the challenges? And particularly funding wise, it's been a difficult environment for fundraising to complete some of these projects. I think for the first time in a while, many have very exciting therapeutics, even clinical data, but can't fund to get through the rest of the process. What is your outlook on that?

Noah: Yeah, you know, we started in 2018 ⁓ with the idea of doing both animal and human health. And most VCs and investors were like, why are you doing animals? Nobody, just do humans. It's a bigger market. Nobody cares. And then ⁓ the people who want to invest in animals are like, why are you doing humans? Just focus on the animals. And so the whole idea was that aging has not been proven out in animals or people.

Cory Smith: you

Noah: Gene therapy for large indications has not been proven out in any place and gene therapy for animals hasn't been proven anywhere. And aging is a huge problem. It's gonna take a lot of money. I mean, you see these companies raising hundreds of millions, if not billions of dollars like Altos to tackle aging. It's cause it's a huge problem. It's gonna take a long time. I didn't wanna be reliant on the funding cycles and the VCs solely for making sure that we can execute these goals and treat aging for the long term. And so I always kind of thought of the animal health, human health as kind of a bootstrapping method so that we can both solve needs in both cases, for animal health and human health. ⁓ People love their animals. I love bear. That's why I even started with the animal health perspective. ⁓ But it's a quicker route to ⁓ monetary freedom. And so once you have a therapy out there selling hundreds of millions of dollars, you could support human development at that point when you have to run large-phase clinical trials that cost hundreds of millions of dollars. And we wouldn't be reliant on raising rounds of funding. We'd be self-sufficient. That was kind of always the idea. ⁓ Everything took a little bit longer, and the funding cycles actually hit us a little bit. But ⁓ we survived. We're thriving. I wouldn't say thriving yet, but we're doing great and we're about to close our series B and we're doing something called a WeFunder, which is ⁓ kind of this new alternative source of fundraising that ⁓ biotech has started to become interested in just because traditional biotech fundraising has been difficult these last couple years with interest rates and so forth. ⁓ And what WeFunder allows is for everyday people to invest in ⁓ biotech companies or any company. where they wouldn't normally have a chance. People usually don't get to invest in a cancer therapeutics company before it's public. And it's usually only public once it's in human clinical trials. And that's a long time from the inception. So if people really care about something, they can't get involved unless they're an accredited investor or know somebody. And so what WeFunder does, it allows people to get access to things they care about that they want to invest in, that they want to be along for the ride. And generally, pet parents are very passionate. people that care about their animals and they want to be along for the ride. And I think WeFundr is a great opportunity for people to get involved with things they care about. So a recent fundraising success on WeFundr has been Siren Biotechnologies. They're treating ⁓ cancer in people using gene therapy and they raised close to four and a half million dollars on this platform. So it's definitely proven itself as a fundraising mechanism. ⁓ This series B that we're closing right now should be the last. fundraising that we need to do, we should be getting to commercialization with our animal health product. And then that basically gets us out of this ⁓ need to raise capital in the private markets. ⁓ We'll be semi-independent at that point unless we want to take on capital and expand more quickly or something like that. that's what's great about the animal health angle is that this last series B that we're doing and we're opening it up to this WeFunder community because I think people care about animals and want to be along for the ride and I want to let them. ⁓ But it should be our last fundraising round hopefully that we need to take which I think will be interesting from a biotech, you know, Normally you have to raise series D, E, F, go public, all these things. Technically we won't have to.

Cory Smith: That's an exciting alternative. you're interested in investing or checking out more, we'll put the link in the description of this video if you want to check it out. And is there a certain window of time that the round is open for?

Noah: ⁓ The series B will have kind of a series of closings. ⁓ I think that's how it's done on WeFunder. You get to ⁓ kind of say, Tronch one is done. We're gonna keep it open though if more people want to invest and then Tronch two will be done. There is a limit to this particular form of fundraising on WeFunder. You're only allowed to raise four million in any given year ⁓ from non-accredited investors. So that's this reg CF. form that you have to fill out. So there's that monetary limit but we'll probably keep the round open for like three-ish months, see where we're at and if we hit that $4 million limit it's closed but if we don't we'll probably do a tranche and then maybe close again.

Cory Smith: Excellent. And so that will get you through the approval and commercialization for this dog therapy. And what's next? mean, you know, heavily focused on the commercialization, distribution, marketing you'll have to have as well. But what's next for you scientifically after this for rejuvenate bio?

Noah: Yeah, so, ⁓ but just to make a point on the commercialization efforts, we actually, for Animal Health, know that we are not commercialization experts. ⁓ You know, we're scientific experts, good at building companies, getting the science from the bench into the real world. But we've partnered with ⁓ four or five ⁓ animal health companies at this point for different projects that we're working on. And ⁓ specifically for our matcha valve disease, we've partnered with Fibro Animal Health. and they're gonna be the commercialization arm for our therapeutics. So we don't have to build up a sales force, we don't have to understand how to get it to vets, supply chain and all that. Once we get it approved, we hand it off to them and be like, okay, sell this therapeutic for us, thank you. so, you know, building up a whole sales force and organization, that's a different company. I think we play best in the building aspect and the new science and the translating, and that's what I think we should focus on in the near term for sure.

Cory Smith: Okay. That's smart.

Noah: Scientifically, what's next? ⁓ Partial reprogramming, I think, is part of the more interesting tech out there for longevity. ⁓ It's definitely not solved. know, OSK is a great starting point, and I can't wait to see what that clinical trial brings. ⁓ There's a lot of companies out there also working on partial reprogramming, know, like New Limit, Retro, Altos. And I think the main thing is that everybody keeps coming up with new factors that can do partial reprogramming in different ways. So... I think there's going to be a better cocktail out there. There might be better modalities to deliver these things. There might be better ways to go after it. But I think partially programming that essential idea of reversing cell state to an earlier version, Benjamin buttoning everybody, I think that's the reality. And that's, think, where the tech is going and what I'm excited to work on ⁓ kind of next.

Cory Smith: Yeah, very exciting time for anti-aging. know particularly for even VCs and funding, it's really getting a lot of attention and I think we're at a critical point. But recently on another podcast, George was quoted saying, do you think, when will longevity escape velocity be here? Essentially the point where if you live up to this point with all the new therapies coming out, most people could live forever. Not that you won't die from accident or a car accident, things like that, but you won't die of biological age. to saying how do we know it hasn't happened already? What are your thoughts on where we are to that point and just the whole concept of longevity escape velocity?

Noah: I would never be one to disagree with George, that's for sure. He's usually right more often than, I don't know if he's been wrong. ⁓ So ⁓ I think it might be here. It depends how old you are, right? Are you 90? You might not be in the Longevity Escape Velocity crew, but are you 20, 30, 40? Where's the cutoff? I personally think we might be existing in the Longevity Escape Velocity in the next. decade will have something that can meaningfully decrease people's biological age and make them healthier. So I think we might be there for some subset of the population. It might be very exciting times. yeah, the whole idea of being a mortal, you know, not dying from biology, but not immortal, and still being able to be hit by a bus, you know, I think it's interesting.

Cory Smith: Yeah, and is there any other things you do in your life to promote longevity? Clearly there's exciting therapeutics and these things are really gonna take it to get it completely over the edge, but do you practice meditation or diet? What are your personal practices for healthy living or longevity?

Noah: Exercise and diet I think are the two biggest, exercise, diet, sleep. I think that's the classics and the things that people have the most control over. ⁓ I think some of the low dose GLP-1s might be interesting from an inflammatory perspective as long as you're making sure that you have enough muscle mass and working out and that sort of thing. ⁓ ⁓ I think some of the PCSK9 inhibitors might be more of a generalized class of longevity type drugs because everybody has issues with cholesterol ⁓ at some point. You're eventually going to have clogged arteries regardless of how healthy you are. So I think having a PCSK9 inhibitor ⁓ might become kind of a standardized thing at some point. ⁓ There seems to be like no downside to it. But yeah, I think those things are the most interesting ⁓ drugs and things that people can do is basically exercise, eat right, stay healthy, ⁓ and sleep. Decrease your stress, because stress really is a killer. I mean, I'm graying from having kids and all the stress that I have, I feel like I've aged at least a decade in the last two years of just having kids, so. I think kids are not helpful for the longevity front. ⁓ yeah.

Cory Smith: Hahaha. difficult to balance that sleep component with with kids that you mentioned. ⁓ So all of longevity, do you use any devices like ⁓ Apple Watch or a Whoop? And what do you think about these biometric feedbacks that you can get from from some of these devices? I Whoop received recent government grant to study their biometric specifically towards longevity, and I think it's a very promising field once we can collect enough data on that front.

Noah: Yeah, mean, I have an Apple Watch. It tracks the sleeping and the activity. don't really, it's not really actionable for me. It's kind of like, oh, you didn't sleep well last night. I'm like, yeah, I know. So I don't know. I think it's interesting to track it. Longitudinal data isn't valuable. So just from that perspective alone, having your own longitudinal data is something that everybody should be interested in doing.

Cory Smith: Hahaha.

Noah: But it hasn't been that helpful to me in changing anything that I do. More just as somebody who likes data, it accumulates data in a longitudinal way. If there ever was a problem, like, hey, your heart rate is this. I'm like, oh, that's normal for me. My heart rate's always 55, you know? So, I don't know. I think it's always good to have longitudinal data, but I haven't really seen, for me personally, any, you know. behavioral change come from these activity models. So I had an aura ring for a little while. It was kind of similar to an Apple watch. I don't know. Yeah.

Cory Smith: And so we've talked about certain like partially programming one modality to address aging. A few others have been mentioned. Any other new modalities that you're excited about, new approaches for therapies that listeners might not know about?

Noah: I think the epidemic partial reprogramming is interesting and kind of a ship of Theseus idea is interesting, you know, ⁓ for those aren't familiar, it's like the ship left the harbor, but along the way damage happened and basically every single part of the boat had to be replaced. Is it still the same ship when it comes back to port? And it kind of happens with us every day. We're replacing cells inside our bodies. So are we even the same person today? that we're gonna be in 20 years from now. ⁓ There's no argument to say no. ⁓ But ⁓ I think idea of cell replacement tech is interesting. It's not a very tractable technology at the moment. It'd be a very personalized medicine approach. But imagine if you could replace ⁓ your liver, your heart, your lungs, your kidneys with younger, better functioning versions of themselves. at the moment. ⁓ It'd be a very personalized medicine approach. But imagine if you could replace ⁓ your liver, your heart, your lungs, your kidneys with younger, better functioning versions of themselves. So this idea of kind of replacing each body part with a better functioning version is interesting. ⁓ So instead of trying to reprogram the ones you have, get new versions of the ones you have. So this idea of kind of replacing each body part with a better functioning version is interesting. ⁓ So instead of trying to reprogram the ones you have, get new versions of the ones you have. I don't know to what extent you can take that idea, but that's another kind of idea that I've seen some recent scientific traction in the papers that ⁓ people have done that with immune cells at a minimum, showing that you can rejuvenate. take younger immune cells, put them into an older person and get a benefit. So I think that's an interesting idea.

Cory Smith: Yeah, Chris Bradley previously talked about the ship of Theseus idea. I think it's very interesting. There's actually an ARPA-H project specifically for that for brain tissue. I think it's very interesting. Sets out to replace first parts of the brain, but it asks that exact question of if you could make full cortical replacement tissue, not just specific neurons, but whole sections of it that have the vasculature, astrocytes, microglia, the whole population. And you did, it could integrate, incorporate memories. Could you just replace your brain?

Noah: Mm.

Cory Smith: continuously and it goes back to I believe the Odyssey, the ship of Theseus that it left, but every plank has been replaced. Is it the same ship? I know there's an adage of like your grandfather's hammer. The shaft has been replaced three times, the head's been replaced four times, but it's the same hammer. You functionally, it has functional overlap, but all the parts have been replaced and least the matter in our body, except maybe the neurons, the cells do do get replaced and if not the cells, the atoms are getting largely replaced out.

Noah: Yeah. Yeah. Yeah.

Cory Smith: very interesting philosophical and perhaps biological solution to aging.

Noah: I mean when you go to sleep at night are you even waking up in the same body? You don't know? Consciousness, is it really the same you?

Cory Smith: Yeah, yep, very interesting questions. So coming to the end here, but I want to loop back into science fiction. We had a great talk. You recommended the Culture series by Ian ⁓ Banks. Any other science fiction you've read recently that you were excited about or want to share or recommend to the audience?

Noah: I, ⁓ you know, Brandon Sanderson's, I really like his stuff. ⁓ Robert Jordan, that's more epic fantasy, but, ⁓ Dennis Taylor has kind of some fun series, The Bobaverse, that's kind of a longevity story, basically, he becomes an AI and can live forever inside the machine. Yep. ⁓

Cory Smith: Yeah. Von Neumann machine space.

Noah: Yeah, I don't know. I read a lot of them, ⁓ generally like most of them. They always bring some new perspective, some aspect that they explore that's usually interesting. I think giving you my list of books might tell you too much about myself, though.

Cory Smith: Ah, well, George recommended The Bobba Verse as well. That was his recommendation. So in good company there. And I've actually tracked all my books. Happy to share it with you as well. And the audience. I've tracked since 2017. Been tracking every book. And I actually have a future read list that has over 2,000 books. So multiple decades of stuff. I never have to think of another book again. Just go right into the next one. And uh...

Noah: ⁓ he did? That's funny. 2000, wow. Yeah, you got to do audible at 2x so that you can just listen on your way wherever you go.

Cory Smith: Yeah, try that, but I like the regular pace. You get more through, but I just, I'm like, maybe 1.25, but if it's too sped up, it's not as enjoyable to me. Yeah.

Noah: you That's what I do for my enjoyment reading. I do the 1.25. But for like knowledge-based stuff, like kind of more factual, I do the 2x. But yeah.

Cory Smith: Yeah, I can handle that, definitely. And I like to do what I work out. It's great. Audiobooks are great. George likes audiobooks as well, he told me on the show. So, closing question. I always like to give the advice, the lessons that you've learned are invaluable. If you could look back to rising college students, rising graduate students, what advice would you give them to keep up with the times and ⁓ pursue a career in science?

Noah: ⁓ nice. ⁓ I think if you're passionate about science, definitely should go all in. ⁓ I don't think it's going to go anywhere, even with AI. I think AI will always be kind of a helpful tool. ⁓ So if you find something you're passionate about scientifically, I think you should go for it. I think the most interesting things seem to happen at the interface. ⁓ not just going full-throated into biology, but how do we apply AI to biology? So those kind of interfaces seem to be where people push the boundaries the fastest and make the biggest progress. so my advice to people would be, go all in on something that you're interested in, but also maybe go in on a second thing and see how you can connect the two different things. Because I think where the connections are is where a lot of the interesting stuff happens.

Cory Smith: Excellent, thank you Noah. I really appreciate you taking the time with us and sharing what Rejuvenate Bio is doing and best of luck getting through your Series B and getting this into therapy for dogs and hopefully this will be the big neck commercial product that can ultimately make them live longer.

Noah: Thank you. Thanks for having me. It's been great.

Cory Smith: Thanks.