David Sinclair谈长寿药、逆龄时间表与更新后的方案 | 第249期

This 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 to you: you are days away from the first human epigenetic reprogramming trial.

3 of the Yamanaka factors—a subset of them—are 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. We see brain age reversal, improvement in memory, motor neurons, so ALS, the immune system, muscle, kidney, liver, and skin.

A true longevity therapeutic, when given, would work throughout the entire body. And that's the objective here. Is there an upper limit to how long humans can live?

I'm not saying that.

David, please. Can I grab my hot water and lemon? What are you drinking?

Coffee.

Coffee, all right.

I couldn't find any matcha.

Well, coffee actually is good for you. The studies show caffeine is—I probably do about 3 cups, and I think it's also that decaffeinated coffee—it's all the other molecules in the cocoa in the caffeine bean.

Coffee comes in and out of fashion, but the fashion is definitely positive right now for longevity. It's not a bad way to start the day. Caffeine's fine. People ask me, “Is it okay to drink caffeine?” Serena and I drink tea all day, pretty much, until we can't take any more caffeine, but 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 toward the 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. We have a drug candidate that came out of my lab. It was first published in 2020 on the cover of Nature magazine, and the title on the cover was “Turning Back Time.”

We reported—and I want to give big credit to my student Onecheng 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 the 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've got to try. I have a good feeling.”

And so he found 3 genes, 3 of the Yamanaka factors—a subset of them. These Yamanaka factors, 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 2 days if you use all of Yamanaka's factors.

So, anyway, we have 3 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 blindness.

Life Biosciences—I know a number of you are investors along with me in Life Biosciences—so I'm super excited about that, heading toward reversing blindness. What would be a success, and fingers crossed, where would you head next? Which organ systems would you go after after that?

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—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 are now showing—and seemingly now every month or so another lab publishes on this technology—is that we find benefits in every tissue that we go into as a field. It's not just my lab; it's great. It's being reproduced and expanded now.

We see brain age reversal, improvement in memory in old age and Alzheimer's models, and benefits to motor neurons—so ALS, which is clearly an incurable disease currently, but we think we can help there—the immune system, muscle, kidney, liver, and skin. The list goes on.

Joints.

Joints. A new paper came out from a different group just last week that I tweeted about. We all experience some kind of back pain or joint pain in our lives. There's not much you can do. This technology seems to regrow the joint and the cartilage and even the bone, which is great.

A really important point here: a true longevity therapeutic doesn't just work in 1 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 1 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. But if we'd said we were 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, 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 targeting, but a whole body is either going to require something like the lipid nanoparticle or even a chemical small molecule.

Talk about that. The current therapy that you've developed is using an adeno-associated virus, an AAV, and these gene therapies have traditionally been expensive—anywhere from $500,000 to $2 million per treatment. Is that a rough order of magnitude?

We want to treat millions of patients, actually. We're going after glaucoma. I hope it's not that expensive, but my goal is to bring the price down as fast as possible.

Just to lay it out, 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 your amazing graduate students have actually developed an alternate, and I think it's your entry into the Longevity XPRIZE as well, into the Healthspan XPRIZE, which looks to be—I don't call it magical, but the potential of it is extraordinary. Could you speak about what you've developed?

Sure. We developed this current technology that's going into humans shortly. In fact, patients are being recruited right now, so it's imminent. That technology for us in the Sinclair lab is 2017 technology.

Mm-hmm.

Actually, quite literally, I like to point out to my students that what we published is literally what is going into humans, which I've said to you separately: that's really rare—that your PhD student makes a drug that goes into humans—but he did it.

The point is, since 2017, we've been working in my lab on bringing the price down and finding new ways. The cheapest is a small molecule. A small molecule can potentially be made for a few cents a pill. And we find that the dosing—even with ER-100, which is the viral candidate drug going into humans—you only need 6 weeks.

In 6 weeks, some doctor may even know the answer as to whether this works in humans because it's going to be fairly obvious if someone can see again or not. We'll 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 visual 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.

We know OSK works. The gene therapy works. 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. We hope to put those into a clinical trial in humans within the next couple of months as part of our XPRIZE 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 3-molecule pill that you're taking cost for treatment?

Right now, it is a 3-molecule cocktail. Ultimately, if it reaches the market, it will be 1. I don't plan on taking 3 to market. But there are all sorts of reasons, including that the FDA makes it very difficult to make cocktails. They make you test each one and the combinations. We will find 1.

But the 3-factor molecules are expensive to make. They're hundreds of thousands of dollars right now to make at the 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 1 day I hope that it'll be like metformin, which is pretty cheap.

Anyone on the planet could afford it.

We were on the Moonshots podcast together. I encourage you guys to see that episode. It's an amazing dive that I did with David. You predicted a couple hundred dollars a month as a potential range, so it's really important to understand that this longevity revolution we're about to hit is not just for the ultra-wealthy.

One of the precepts of the Healthspan XPRIZE, which Dr. Jamie Justice runs, is that we're encouraging the development of therapeutics that are accessible to 8 billion people. We uplift humanity as we do this.

I like to say that when technology first comes out and it doesn't work well, it's the wealthy who experiment with it. By the time it works really well, it's available to 8 billion people. That's going to be true here.

It is. I always talk about the Wright brothers because this feels like another Wright brothers moment—if it works, maybe even bigger than that. People said it wouldn't work. “This will never happen.” The New York Times, a few weeks before the Wright brothers took off, said, “It'll be a million years before humans fly.” Then they did it, and suddenly everyone said it could 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 1960s and 1970s. But it'll happen faster than that.

I can see a future where, 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.

Even if we deviate or things hit a snag—which I don't expect, but that could happen—it's going to happen. That's the real point here. Twenty years ago, I didn't know if it was going to happen in our lifetimes. I was trying to go as fast as possible, trying to get the word out to raise awareness and bring really bright students into the field.

That mission is still ongoing, but I would say it's been successful. Now I think the wave is such that it's going to happen in our lifetime. It would be crazy if it didn't. It may be sooner than we think. It may be that 2026 is the year we learn that age reversal is possible in humans.

This is part of our singularity, folks—part of this incredible moment of everything, all at once, everywhere, getting reinvented. It's speed-running Star Trek, as I like to say.

I want to say something about Peter. He does a lot of good for the world, and he's unique in doing that. One of the things that he's done, among many, for the field of longevity is the XPRIZE with Jamie Justice.

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, which 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 onstage together, but I'm 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. There was a negative stigma against doing work in this field, and yet you saw the potential and persisted, which is what great scientists and thinkers do, despite what your fellow scientists thought.

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. You've persisted, with Serena's support nonetheless. Thank you for that.

A couple of key questions here. Is there an upper limit to how long humans can live? Is it just 120 that we're aiming for, or 130? People say, “Okay, we might extend healthspan by an extra few decades, but we're going to time out.” What do you think? How do you answer that?

As I wrote in Lifespan, 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, right? We can live hundreds of years. That's already happening in the animal world, and some people live well beyond 100, up to 122, which is the maximum. There's a lot of room to go with what we already know is possible.

Can we go beyond that? Can we go beyond a whale, even? I don't see any reason biologically or, looking at physics, why there is a limit. It feels weird to say we can live hundreds of years, maybe thousands of years. I don't know yet how we're going to get there, but what I've seen in the last 5 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, but 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.

We don't know how many times, because we did it multiple times in the eye, and then the mice died of old age—but they had really good eyesight. We want to try and do this multiple times in a whole animal, and we're working on that.

I don't see an upper limit. I'm often quoted out of context saying, “Oh, we can live forever,” or that kind of thing. I'm not saying that. But I am saying that the mere fact that the Wright brothers could fly meant we could see that one day there would be the Concorde jet and people going to the Moon. It's the same with longevity.

Once you can fly, everything changes, and I think we're about to learn whether we can fly or not.

Yeah.

I'm pretty sure we can.

At the speed at which science is going—the work that we just saw from Layla, the work we're going to see from other speakers, the whole field of AI—there's this accelerating future in which the added time brings us all these additional breakthroughs that can add time, and then the exponent goes greater than 1.

I want to go back to that Moonshots podcast we did, because there are a number of members in the room here who are part of FOSL, the Friends of Sinclair Lab. When I interviewed David—it's a year ago, I think, although it feels like ages ago—at my Moonshots podcast studio here in Santa Monica, David was glum. I asked, “What's going on?” He said, “Our funding just got cut because of the battle between the White House and Harvard. I have to let all of my graduate students go. My dean has said, ‘You've got to let them go.’”

It was like, “What? No way?” Hopefully this is your Juno move. When you see a problem that exists, your answer is, “No, I'm going to solve it.” At that moment, I spun up. I said, “Okay, listen. Let's create something called Friends of Sinclair Lab. I'll contribute the first $50,000, but let's ask the Moonshots audience to participate.”

We announced it, and Max Song spun up a few QR codes and a website instantly. Thank you, Max. The outpouring of support was nothing less than extraordinary. The budget you were getting from the government that got canceled—how much was it per year?

It was in the millions, all of it.

A million? $2 million? $3 million?

Something like that, including the fellowships that my scientists had brought with them. Their careers got cut short, too, at the time.

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 all.

I want to hit on this because there's a perversion in the way we fund science. When you write a scientific grant—and I'm going to say this for you so that you don't have to say it and get dinged by anybody—my understanding and experience is that if you're trying to propose something radical for a grant, the people reviewing it don't want radical science. They want predictable science, where they know the answer is going to be there.

You're writing a grant for something that might take a year or 2 to get funded. It is retrospective, reactive, and backwards.

And there's a 10% chance you get it.

A 10% chance you're going to get it. What I love is that through the Friends of Sinclair Lab, some people have given us $50,000. I don't see any of this. All of this goes to his research.

To all of the Friends of Sinclair Lab.

Some have given up to $1 million. This money goes directly to David and his graduate students. It's genius. Where the highest signal is right now, let's do that experiment. Let's do that experiment. Let's do that experiment.

It has. We're actually in better shape now, thanks to you and all of the Friends, than we were a year ago. 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. We've got PhDs, professors, and some of the smartest minds in the country who are just at their computers typing grants all day instead of doing the work. But it's really changed how we do science. We're going so fast now.

An example of that is that every second month, we have a Zoom call and the Friends get together. On the last one, 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.” Then one of the members—

Brett Blundy, who's a member of our community here, is one of the benefactors for the Healthspan Prize and one of our benefactors at XPRIZE as well.

Brett said, “How fast can we cure this?” I said, “Well, let's do it.” 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. What I want to do now that this model is really proven to work brilliantly is teach the best minds across the world that this is a much better way of doing science. Everybody benefits. The world benefits, and the members benefit. I think it's very exciting for the members because they get to—

They get personal relationships with you. They're texting you, visiting the lab, and having dinner with you and Serena.

Yeah, and they get the same feeling I do as a scientist. We make discoveries, and how exciting is that—to learn before humanity does how the world is going to look in the future? That's the best part of being a scientist: learning things that you just didn't think could even be possible before everyone else.

It truly is extraordinary. I want to thank all of you who are members of Friends of Sinclair Lab, FOSIL. You might even share your thoughts about it during the Q&A here.

Oh, I just want to say about the FOSIL program: We have about 70 members.

So, how many?

70.

70. Wow, it's been—

Wonderful. But we are going to limit it because if it gets too large, it's not a community. There will be a waitlist. If you're interested, please either write to Peter, Max, and Marissa, who's down the front—she's my chief of staff—or reach out to one of my team if you want to be involved in supporting that.

Marissa, would you stand up for one second so people can see you?

She'll give you her business card.

Or reach out to one of my team if you want to be involved in supporting that.

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. I 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 toward 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—

Yeah, so you guys are on the airplane all the time.

Yeah, that's our downfall. What I wrote about in Lifespan still holds true. If you haven't got the book, or if you do, check out page 304. That is the basic speed run, if you would.

But don't post this. This is between friends. 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.

Okay.

This is also for my father, who is now 86 and in perfect health.

So, Mom, if you're listening, please take note here.

The 3 main ones that we've been taking for over 15 years—you remember the good old story of 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. That's mixed with some olive oil, 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.

That's a good one. It's an activator of SIRT1, which is a longevity enzyme we've worked on for many years. By the way, I haven't told this publicly, but the sirtuins, if you know about them and you've read my book, are very important for the reprogramming. 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&M's. You will not live longer. The third one is a glucose-lowering medicine. There are 2 choices, and I cycle between them. Serena and I do that.

Metformin requires a prescription. That's a type 2 diabetes drug. It's relatively safe as a medicine. We take a gram a day of that, but it can give you a stomach upset. There's a natural version of metformin, which is known as berberine, and it has a lot of clinical data as well, including benefits from lowering blood glucose. Your glucose levels are really important, so look at glucose, look at pasta, and look at carbs, especially processed carbs.

If I could just add to that, one of the things that we found at Fountain Life looking at our members is that the number one thing that correlates with heart disease is not your HDL, your LDL, or your Lp(a). The number one thing that correlates to heart disease is your hemoglobin A1C, your glucose levels. Thank you, buddy.

Well, good. There's a whole symphony. We carry bags of supplements, so it would take a while to go through those, of course. A new one that we've added in the last couple of years is nattokinase. If you haven't heard of it, it's an enzyme. I'm sure you know it.

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. You need a fair amount. If you look at the clinical trials, I think it's at least 8,000 units of that. Do you know how much? 10,000—Serena's telling me from the crowd. So, 10,000 units. I think if they gave them six, it didn't work. It took a year, so you need to be consistent.

I'm doing the experiment. I'm going to have another carotid ultrasound to see what my IMT is. As you know, as a trained physician, that's 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. You can get a CT scan, which involves radiation, and we know in my lab that radiation accelerates aging. So, if I can help it, I prefer to avoid radiation. Ultrasound is very safe, and you can do it in 20 minutes on your neck.

Yeah.

Do you guys do it?

We do, and those of you on the longevity trip every year, we give you a carotid scan. Yeah, good. In terms of food, you've gone vegan.

Mostly.

I struggle because there's a lot of good food out there. I'm a sucker for Japanese sushi, but it's Serena who inspired me. I always need to credit her with a big change in my life. She taught me a lot, and last night at a gathering we had for the Friends of Sinclair Lab, I freely admitted that what turned me on with Serena was her talk about navitoclax and dasatinib as a senolytic. I thought, “Wow, this woman's amazing.” I keep talking chemicals. It's turning me on.

How do you feel about alcohol?

I've changed. Again, Serena's inspiration. Before the data came in, which is now damning for alcohol, even 1 glass of alcohol a day correlates with a smaller brain, I stopped drinking alcohol a few months after I met Serena. You, too?

No, no. I've been drinking much less, much to the chagrin of someone who is my spouse, who's a sommelier.

Wow. Yeah, it's unfortunate, but we've got to be driven by the science, not by what we want. I would say that a few times a year it doesn't hurt to celebrate with a bit of alcohol, but daily is what I was doing. Serena said, “What are you doing? You're eating cheese and red wine every night.” And I said, “It's the Mediterranean diet. What are you worried about?” So she said, “No, stop it. Eat this and see what happens.” Within a month, my biomarkers—my inflammation—went way down, so I've stuck with it.

And I think the benefit of alcohol is the social lubricant, in terms of helping you relax and enjoy yourself. One of the biggest challenges I have, David, and I think perhaps for you, is the pace of travel, work, and stress. It's a countervailing force.

It is. Again, Serena changed my life because I'm very hard on myself. If I'm not number 1 at something, I'm not happy. I lived most of my life until I met Serena on edge, ruminating, and stressing that I wasn't good enough. It was really a bad thing.

Then she came along and said, “Just try to breathe. Chill.” She taught me meditation, which I'm still trying to work on, but I have learned not to worry so much.

It’s hard to do if you’re an A-type, like probably most of us in the room. But it’s changed my life as well. I’m sleeping better. I think I look better. I feel better because if you’re always tense, it’s going to accelerate your aging. That’s proven.

The other thing that really helps, which is worth knowing, is your blood pressure, your cholesterol, and your blood sugar. These are good ways to live longer. Get a pet, get a partner, but just make sure that you’re socially surrounded by people who love you, and you’re not lonely, because loneliness will kill you.

More hugs in your life. Yeah, let’s hear it for that.