David Sinclair on the Longevity Pill, Age Reversal Timelines, and Updated Protocols | EP #250

0:00This feels like another Wright Brothers moment. Once you can fly, everything changes, and I think we're about to learn whether we can fly or not. I'm pretty sure we can. The News Du Jour, you are days away from the first human epigenetic reprogramming trial. Three of the Yamanaka genes, a subset of them, they're going into the eye of a patient shortly to see if we can cure blindness. We find that every tissue that we go into as a field, we see benefits. Brain age reversal, improvement in memory, motor neurons, so ALS, the immune system, muscle, kidney, mentioned liver, skin. A true longevity therapeutic, when given, would work throughout the entire body.

0:41And that's the objective here. Is there an upper limit to how long humans can live? I'm not saying that, but I am saying that... Now that's a moonshot, ladies and gentlemen.

0:57David, please, I'm going to grab my hot water and lemon. What are you drinking? Coffee. Coffee, all right. I couldn't find any matcha. Well, you know, I mean, coffee actually is good for you. The studies show caffeine is, you know, I probably do about three cups. And I think it's also that decaffeinated coffee, It's all the other molecules in the cocoa, in the caffeine bean. Yeah. Coffee comes in and out of fashion, but the fashion is definitely in the positive right now for longevity. So it's not a bad way to start the day. Caffeine's fine. People ask me, is it okay to drink caffeine? And Serena and I drink tea all day pretty much until, you know, we can't take any more caffeine.

1:39But it is good. And we're going to talk about your longevity protocols as well. But what I'm excited about is to give everybody an update on our approach towards longevity singularity, to add that term together. The moment in time that we really know that we're extending the healthy human lifespan. Let's begin on the news du jour. You are days away from the first human epigenetic reprogramming trial. Tell us about that. Well, if you've been under a rock, let me tell you that we've worked out, maybe we can talk a bit about the science behind it, but we have a drug candidate that came out of my lab.

2:23It was published first in 2020 on the cover of Nature magazine, and the title on the cover was Turning Back Time. And we reported, and I want to give big credit to my student, Wan Cheng Lu, who worked for many years to try and find certain genes and combinations that could safely reverse aging, but not go so far that you could cause cancer or lose identity of the cell. And he found it. It took a long time. And in retrospect, it looks easy because we now know the answer, but it was tough at the time. And he was ready to quit. He was in my office almost crying. And I said, you got to try. I have a good feeling.

3:00And so he found three genes, Three of the Yamanaka genes, a subset of them. These Yamanaka genes, I think you all know, are what we use to make stem cells. But we don't want to use the technology to make stem cells. If I turned you all into a giant lump of stem cells, that would not be good. And mice die within two days if you use all of Yamanaka's genes. So anyway, we have three of the genes. We call them OSK for short. They're going into the eye of a patient shortly to see if we can cure blindness. having succeeded really well in mice and monkeys to cure their blindnesses. So, I know a number of you are investors along with me in Life Biosciences, so super excited about that, heading towards reversing blindness.

3:51What would be, in success, and fingers crossed, where would you head next? Which organ systems would you go after after that? Yeah, so what's remarkable about the technology is we didn't choose the eye because we thought it would work best. In fact, I was recommending against it because the eye, you know, curing blindness is not something that's easy. I thought the liver would be a good way to go. And that's probably the next place we go in the human body. What other labs and ours now are showing and seemingly now every month or so another lab publishes on this technology. So it's not just my lab, it's great.

4:28It's being reproduced and expanded now. That we find that every tissue that we go into as a field, we see benefits. And so it's not just the eye. We see benefits. Well, I'll just list my lab's work. Brain age reversal. This is all in mice currently. Brain age reversal, improvement in memory in old age and Alzheimer's models. Motor neurons, so ALS, which is clearly an incurable disease currently, but we think we can help there. The immune system, muscle, kidney, mentioned liver, skin. The list goes on. And the liver... Joints. A new paper came out from a different group just last week that I tweeted about.

5:14And so, yeah, we all experience some kind of back pain or joint pain in our lives. And there's not much you can do. This technology seems to regrow the joint and the cartilage and even the bone. Really important point here. A true longevity therapeutic doesn't just work in one cell type. It doesn't just work in hepatocytes. A true longevity therapeutic, when given, would work throughout the entire body. And that's the objective here. It definitely is. That's really our goal. The reason we're going after one tissue at a time is because it's untested technology in humans. and the FDA just recently allowed life biosciences to go into the clinic.

5:53But if we'd said we're going to inject this technology into the whole body, the FDA would have been, I think, a lot more cautious. So we're going tissue by tissue now, but I don't see a reason why as we learn more and we see more safety that we couldn't go intravenously. We need some technologies to be developed. right now we're using viral-like particles to target the eye and the liver. Those are great for targeted, but a whole body is either going to require something like the lipid nanoparticle or even a chemical small molecule. Let's talk about that. So the current therapy that you've developed, and it's using an adeno-associated virus, an AAV, and these gene therapies have traditionally been expensive, anywhere from like a half a million dollars to $2 million per treatment.

6:44Is that a rough order magnitude? We want to treat millions of patients, actually. We're going after glaucoma. So I hope it's not that expensive, but my goal is to bring the price down as fast as possible. And towards that end, I'm very excited about the other. So just to lay it out, right, the current treatments that are going into trials are using these adeno-associated viruses, which are an expensive mechanism for delivering the OSK. But you and and your amazing graduate students have actually developed an alternate, and I think it's your entry into the Longevity X Prize as well, into the Healthspan X Prize, which looks to be, you know, I don't call it magical, but the potential of it is extraordinary.

7:29Could you speak about what you've developed? Sure. So we developed this current technology that's going into humans shortly. in fact patients are being recruited right now so it's it's imminent that technology for us in the sinclair lab is 2017 technology and actually quite literally i like to point out to my students that what we published is literally what's going into humans which i've said to you separately that's really rare that your phd student makes it makes a drug that goes into humans but he did it But the point is, since 2017, we've been working in my lab on bringing the price down, finding new ways.

8:16And the cheapest is a small molecule. A small molecule can be made potentially for a few cents a pill. And we find that the dosing, even with ER100, which is the viral candidate drug going into humans, you only need six weeks. So in six weeks, some doctor may even know the answer whether this works in humans, because it's going to be fairly obvious if someone can see again or not, or see better. These chemicals could be very cheap. We've been working on them. We've been using mostly artificial intelligence to screen billions of molecules in silico. And we're now at the stage where we're in the lab using AI and visualization, machine learning, to tell us whether cells from old humans, 92-year-olds, their skin cells can be reversed back to a 20-year-old.

9:12And we know OSK works, the gene therapy works, and we're looking for molecules that do that. And I can say we already have a proof of concept, which is a cocktail of molecules, some of which we published on already a couple of years ago, and those we hope to put into a clinical trial, into humans, within the next couple of months as part of our next prize competition. Amazing. And how much might that cost, just to give people a sense of the price point, while the adeno-associated virus gene therapies are in the hundreds of thousands to low millions, how much might a three-molecule pill that you're taking cost you for treatments?

9:54Well, yeah, right now it is a three-molecule cocktail. Ultimately, if it reaches the market, it will be one. I don't plan on taking three to market. There's all sorts of reasons, including the FDA makes it very difficult to make cocktails. And they make you test each one and the combinations, which is... We will find one. But the three-factor molecules, they're expensive to make. They're hundreds of thousands of dollars right now to make it in a kilogram scale. But that doesn't have to be. with scale up, it really could be a lot less. I don't want to say how much, but, you know, one day I hope it'll be like metformin, which is, you know, it's pretty cheap.

10:36Anyone on the planet could afford it. When we were on Moonshot's pod together, and I encourage you guys to see that episode. It's an amazing dive that I did with David. You know, you'd predicted, you know, a couple hundred bucks a month as a potential range. So I just, it's really important to understand that this longevity revolution we're about to hit is not just for the ultra wealthy I mean one of the precepts of the health span X prize that dr. Jamie justice runs is that we are encouraging the deal you know development of therapeutics that are accessible to 8 billion people right it we uplift humanity as we do this.

11:20And so, you know, I like to say that when technology first comes out and it doesn't work well, it's the wealthy who experiment with it. And by the time it works really well, it's available to 8 billion people. And that's going to be true here. It is. I always talk about the Wright Brothers because this feels like another Wright Brothers moment that if it works, maybe even bigger than that. But the Wright Brothers, people said it wouldn't work, this will never happen. New York Times a few weeks before Wright Brothers took off said it'll be a million years before humans fly and then they did it and then suddenly everyone said it can be done but it wasn't for everybody, it was for the wealthy to fly initially in the early part of the 20th century and even up until the the 60s and 70s.

12:03But it'll happen faster than that. I can see a future where within, you know, certainly within our lifetime, we'll have these pills available. The important thing is I'm not the only one. I may be most advanced in the work that we're doing, but there are lots of people and lots of money behind us. So even if we deviate or things hit a snag, which I don't expect, but that could happen, it's going to happen. So that's the real point here is 20 years ago, I didn't know if it was going to happen in our lifetimes. I was trying to go as fast as possible and trying to get the word out to raise awareness and bring in really bright students into the field.

12:47That mission, it's still ongoing, but I would say it's been successful. And now I think the wave is such that it's going to happen in our lifetime. That's something that would be crazy if it didn't. And it may be sooner than we think. It may be 2026 is the year we learn that age reversal is possible in humans. Yeah. This is part of our singularity, folks. Part of this incredible moment of everything all at once everywhere getting reinvented. And it's speed running every speed running Star Trek. I do want to say something about Peter is, you know, he does a lot of good for the world and he's unique in doing that.

13:28One of the things that he's done among many for the field of longevity, the X Prize with Jamie Justice. And if you've donated to that prize, Thank you. It's a wonderful cause. And I can tell you that I would not be putting our chemical cocktail that we've now tested extensively in animals into people if it weren't for the XPRIZE. We're trying to accelerate the future. Yes. Thank you, buddy. Thank you, Peter. A couple of points to pull out. We could spend days on stage together, but trying to consolidate. I think people need to understand as well that the conversation around longevity and the pioneering work that you did early on had a lot of pushback.

14:15A lot of people, there was a negative stigma against doing work in this field. And yet you saw the potential and you persisted, which is what the great scientists and thinkers do, despite what your fellow scientists or, you know. And so I just want to thank you for that. It's not easy. I've been on the inside. You're a dear friend and I've heard the trials and tribulations and you've persisted with Serena's support nonetheless. And thank you for that. A couple of key questions here, and I just want to pull these out. Is there an upper limit to how long humans can live? Is it just 120 we're aiming for or 130 we're aiming for?

15:10People say, okay, well, we might extend health span, there's extra few decades, but we're going to time out. How do you answer that? Well, as I wrote in Lifespan, the book, there is no law that says we have to age. Anyone who says that there is a limit doesn't know what they're talking about. It's doable. We can live hundreds of years. That's already happening in the animal world. And some people live into their whale beyond 100 up to 122 is the maximum. So there's a lot of room to go with what we already know is possible. Now, can we go beyond that? Can we go beyond a whale even? Well, I don't see any reason biologically or looking at physics why there is a limit.

16:03It feels weird to say we can live hundreds of years, maybe thousands of years. And I don't know yet how we're going to get there. But what I've seen in the last five years has blown my mind. The fact that there's a reboot system in the cells that can not just make a cell healthier, but literally reset it so it is young. Not just behaves young, which is what we did for the first 20 years in the field, is young and stays young. It's reprogrammed, literally. The fact that there's a backup copy and that we now know you can reboot the cells over and over again. over and over, we don't know how many times, because the mice actually, we did it multiple times in the eye, and then the mice died of old age, but they had really good eyesight.

16:51So we want to try and do this multiple times in a whole animal, and we're working on that. So I don't see an upper limit, and often I'm quoted out of context saying, oh, we can live forever, or that kind of thing. And I'm not saying that, but I am saying that the mere fact that the Wright brothers could fly, we could see that one day there would be the Concorde jet and going to the moon. The same with longevity. Once you can fly, everything changes. And I think we're about to learn whether we can fly or not. And I'm pretty sure we can. Yeah. And at the speed at which science is going, right, the work that we just saw from Lila, the work we're going to see from other speakers, the whole field of AI is, you know, there's this accelerating future in which the added time brings us all these additional breakthroughs that give us added time and the exponent goes greater than one.

17:48I want to go back to that Moonshot podcast we did because there are a number of members in the room here who are part of Fossil, F-O-S-L. It's Friends of Sinclair Labs. So when I interviewed David, God, I don't know, it was a year ago? It feels like ages ago. It's a year ago, I think. At my Moonshots podcast studio here in Santa Monica, David was glum and I was like, what's going on? And he was like, our funding just got cut because of the battle between the White House and Harvard. And I have to let all of my graduate students go. My dean has said, you gotta let them go. And it's like, WTF, what?

18:28No way. And I mean, it's like whenever, I mean, hopefully this is your judo move. When you see a problem that exists, your answer is no, I'm going to solve it. And so at that moment, we sort of, I sort of spun up. I said, okay, listen, I'm going to, let's create something called Friends of Sinclair Lab. I'll contribute the first 50K, but let's ask the Moonshot audience to participate. And we announced it. Max Song spun up a few QR codes and a website instantly. Thank you, Max. And the outpouring of support was nothing less than extraordinary. I think, you know, your budget, the budget you were getting from the government was how much that got canceled then?

19:18How much per year? It was in the millions. A million, two, three million? Something like that. Yeah, including the fellowships that my scientists had brought with them. Their career got cut short, too, at the time. And we were able, over the course of the next few months, to bring in, I think, on the order of$6 million of private annual support. It was amazing. Thank you. Now, I just want to hit on this because there's a perversion in the way we fund science, which is when you write a scientific, I'm going to say this for you so that you don't have to say it and get dinged by anybody, but this is my understanding and experience of it.

20:03If you're trying to propose something radical for a grant, the people reviewing it don't want radical science. They want predictable science that they know the answer is going to be there. And you're writing a grant for something that might take a year or two to get funded. It is retrospective. It's reactive. it's backwards. And there's a 10 % chance you get it. And a 10 % chance you're going to get it. So what I love is that through the Friends of Sinclair Lab, some of the people have given us 50K. And I don't see any of this. All of this goes to his research. I'm so grateful to all of the Friends of Sinclair Lab.

20:41Some have given up to a million. This money goes directly to David and his grad students' genius. like where the highest signal is right now, let's do that experiment, let's do that experiment, let's do that experiment. It unleashes you to do work on the cutting edge. It has. We're actually in better shape now, thanks to you and all of the friends, than we were a year ago. And we can actually go so fast, it blows my mind. We used to be limited by these grants, and I was spending half my time writing grants. Literally, it's a lot for scientists. And the system's broken, clearly. It's a huge waste of capital.

21:18We've got PhDs, professors, some of the smartest minds in the country who just are at their computers typing grants all day instead of doing the work. But yeah, it's really changed how we do science. We're going so fast now. An example of that is, so we have these bi-monthly, every second month we have a Zoom call and the friends get together. And on the last one, so my student was presenting her data and she said, sorry, I couldn't present last time. My kidneys are failing. I had dialysis today. I need a new kidney. And then one of the members. Brett Blundy, who's a member of our community here, he's one of the benefactors for the Healthspan Prize, one of our benefactors at the XPRIZE as well.

22:01Brett said, how fast can we cure this? I said, well, let's do it. And he goes, all right, I'll fund that project. So we can get started within weeks of an idea instead of years, if ever. It's amazing. It's the way science should be done. and what I want to do now that this model is really proven to work brilliantly is to teach the best minds across the world that this is a much better way of doing science. And everybody benefits. The world benefits. The members benefit. I think it's very exciting for the members because they get to... They have personal relationship with you. They really do. They're texting you and they're visiting the lab and they're having dinner with you and Serena.

22:40Yeah. And they get the same feeling I do as a scientist. We make discoveries. And how exciting is that to learn before humanity does about how the world is going to look in the future? And that's the best part of being a scientist is learning things that you just didn't think could even be possible before everyone else. It truly is extraordinary. So I want to thank all of you who are members of the Friends of Sinclair Lab Fossil. and maybe you might even share during the Q &A here your thoughts about it. I want to spend the last few... Oh, I just wanted to say about the Fossil Program. We have about 70 members.

23:22How many? Seven-zero. Seven-zero, wow. It's been wonderful. But we are going to limit it because if it gets too large, it's not a community. But there will be a wait list. But I think today, if you're interested, please either write to Peter, Max, and Marissa, who is down the front, my chief of staff. Marissa, just stand up one second so people can see you. And she'll give you her business card. Or reach out to one of my team if you want to be involved in supporting her. Yeah, and it's not a commitment, but we'll tell you more about what is involved and what the community is like. I mean, it's sort of like throwing yourself a touchdown pass in the longevity game.

23:57I think of it that way, but I'm not a sports guy. Let's talk about your longevity protocols, David. What are you doing right now to maintain your boyish-like complexion and physique and head you towards longevity escape velocity? Well, thank you. I'm not sure that I deserve that, but it's kind. Definitely too many days on the road with Serena for... Yeah, so you guys are on the airplane all the time. Yeah, that's our downfall. But what I wrote about in Lifespan still holds true. So if you haven't got the book or you do, check out page 304. That is the basics. Just speed run if you would. All right.

24:48All right. But don't post this. This is between friends. I mean, I suffer from my face showing up on people's websites selling products. So this is an issue. You're not promoting any products. Very clear. Yeah. And this is also for my father, who is now 86 and in perfect health. So, Mom, if you're listening, please take notes here. Yeah.

25:14The three main ones that we've been taking for over 15 years, you remember the good old story resveratrol in red wine? That's still a staple for us, and we've got some really good data that we're going to submit to Nature on that. So that's mixed with some olive oil or some yogurt or a small amount of something oily or proteinaceous, a lot of protein, so it dissolves. If you just drink resveratrol or take a pill, it mostly passes straight through you. So that's a good one. That's an activator of SIRT1, which is a longevity enzyme we've worked on for many years. And by the way, I haven't told this publicly, but the sirtuins, if you know about them and you've read my book, we find that they're very important for the reprogramming.

25:59So the early work from my career is all linked into the information theory of aging, which is the basis of our work now. Resveratrol, NMN. NMN is nicotinamide mononucleotide, but online it's called NMN. Don't confuse that with M &Ms. You will not live longer. And then the third one is a glucose-lowering medicine. So the one of choice, well, there are two of choice, and I cycle between them. Serena and I do that. So metformin requires a prescription. That's a type 2 diabetes drug, relatively safe as a medicine. We take a gram a day of that. But it can give you a stomach upset. So there's a natural version of metformin, which is known as berberine, which has a lot of clinical data as well that has benefits as well, including lowering of blood glucose.

26:55And actually, your glucose levels are really important. So look at glucose, look at pasta, look at carbs, especially processed carbs. If I could just add on that, one of the things that we found at Fountain Life looking at our members is the number one thing that correlates with heart disease. is not your HDL, your LDL, your LP little a. The number one thing that correlates to heart disease is your hemoglobin A1C, your glucose levels. Thank you, buddy. Yeah. Well, good. I mean, there's a whole symphony. We carry bags of supplements, so it would take a while to go through those, of course. But a new one that we've added in the last couple of years is natokinase.

27:43If you haven't heard of it, it's an enzyme. I'm sure you know. I take that as well, yeah. Yeah, my father's on that now too. It's really the only thing that's been very clearly shown in large trials of 1 ,000 plus people to reverse plaque in the body. It's also natural. It's an enzyme that comes from natto, the Japanese breakfast that smells like vomit. Oh, my God. Some people eat natto. Serena likes natto. I hate it. So I take the pills. And you need a fair amount. If you look at the clinical trials, I think it's at least 8 ,000 units of that. Know how much? 10 ,000, Serena's telling me from the crowd.

28:21So 10 ,000 units. I think if they gave them six, it didn't work. And it took a year, so you need to be consistent. But I'm doing the experiment. I'm going to have my carotid ultrasound again to see if my IMT, as you know, as a trained physician. And that's also another thing. Make sure that you're not going to die from something stupid like a stroke or a heart attack if you don't need to. So you can get a CT scan, which is radiation, which we know in my lab accelerates aging. So I prefer to, if I can help it, avoid radiation. But ultrasound is very safe. And you can do it in 20 minutes on your neck.