David Sinclair：GLP-1 无人谈及的副作用、实验室里的 AI 与失明逆转｜EP #251

David Sinclair

There’s a lot to say about GLP-1s. More and more data is coming out showing benefits to the heart and the brain beyond just weight loss. There is one downside that I need to point out, besides what’s known about the risks.

We’re working with companies and academics that do a lot of AI now. It’s accelerating our work exponentially. AI-driven drug design and looking at billions, and eventually trillions, of molecules to see which ones might reverse aging—we’ve done that already. We’re using AI to tell whether a cell is old or young just by looking at it very quickly.

My ancestors died in their 70s. My grandmother had a stroke in her 30s. The fact that my father is now living in a healthy way beyond what any of his ancestors probably ever did is testament to the fact that you can really change what your genes have given you. The one thing that is most powerful is your mindset. I think this is the most exciting time ever to be alive. I want to see as much of it as I possibly can.

Now, that’s a moon shot, ladies and gentlemen. A rare opportunity here. I think we have about 25 minutes for Q&A or so.

Sleep and exercise—I think you and I differentiate a little bit on that, because I like sleep. For me, I’m trying to get 8 hours, and I’m trying to be in the gym 5 days a week. You’re not as focused on that. Where do you stand on sleep and exercise?

David Sinclair

I would be sleeping a lot more and exercising a lot more if I weren’t traveling on an airplane most of the time and working in the lab. But I have a standing desk and a treadmill at home, where I try to read and work while I’m walking, at least. Movement is very important.

I used to work out a lot. I was a lot heftier. But life is taking over. At my age, Serena and I spend a lot of time traveling because we want to educate the world, and we have the opportunity to meet world leaders and industry leaders. That’s important for now, to help shape the industry.

You’re on a mission.

David Sinclair

It is a mission, and I’m sacrificing my health for that.

That’s what I say.

David Sinclair

Yeah.

Tom, let’s kick it off with you.

Tom

With this goal of longevity and the potential to live longer, can you comment on how either your research or research you’re aware of would affect the Hayflick limit? Is there a number beyond that that we’re not aware of? I’m curious.

David Sinclair

The Hayflick limit is when the cells divide too many times and run out of telomere length—the ends of the chromosomes. Leonard Hayflick was a good friend. He passed away not too long ago.

We’re studying that. We see some evidence that when we turn on OSK, telomerase is activated and the telomeres will get longer. If that’s not the answer, then we could combine our treatment with telomerase therapy and potentially get even longer life for the cells in our bodies. It’s an area of intense investigation in my lab, and it’s a really good question.

Tom

Thank you.

Thank you, Polly.

Polly

Thank you, Dr. Sinclair. I have a quick question. For those who are using GLP-1s, do you have any hypothesis in terms of how that can be used within your longevity protocols? What can we expect in terms of accelerating aging?

David Sinclair

There’s a lot to say about GLP-1s, and I’ll try to be brief because there are a few questions. More and more data is coming out showing benefits to the heart and the brain beyond just weight loss. That’s amazing, and I think GLP-1s have paved the way socially for what’s to come with longevity medicines. Longevity medicines will be much bigger than GLP-1s, but they’re great now.

If you’re not overweight or you don’t want to lose weight, talk to your doctor about microdosing. This all has to be doctor-supervised, of course. You can’t just go out and do it yourself easily, and I don’t recommend that.

It is very interesting that these drugs, which are getting better all the time, seem to have other benefits besides weight loss. But weight loss alone is the biggest benefit you can have for longevity, actually. We don’t say it often because it’s not socially polite, but being massively overweight is a great way to accelerate your pace of aging. Those drugs look really good.

There is one downside that I need to point out, besides what’s known about the risks. An increasing number of people are waking up blind because of it. It’s still rare. It’s about 20 to 30,000 people in the U.S. a year, which is still horrible. That’s one of the conditions that ER-100 therapy will be tested for, to see if we can reverse blindness.

Caused by neon drugs, or…?

David Sinclair

It’s called neon.

It can happen without the drugs, of course. That happens. We don’t actually know what causes it. It might be congenital, even.

Guest

So, you talk a lot about eating stressed plants. Why should we eat stressed plants, and which is your favorite plant?

David Sinclair

The xenohormesis hypothesis is what you’re talking about, which Conrad Howitz and I published about 15 or 20 years ago. The idea sprung from the fact that resveratrol and a whole bunch of plant polyphenols—which you probably know: quercetin, fisetin, and all these others that other scientists are now claiming credit for—we showed back in the early 2000s could activate SIRT1, the enzyme.

How’s that possible? Why is it that aspirin is so good? Most pharmaceuticals, at least in the 20th century, were derived from natural molecules. What is going on? It’s not just coincidence, we think.

We think that we’ve evolved to sense stress in the plant world so that we have a heads-up that we’re going to run out of food, and we hunker down and get ready for starvation. It’s a good signal. Before we could see the plants dying, we would sense them with our body.

When you eat stressed plants, what we see is that the high level of polyphenols in a stressed plant will give you that signal of adversity. I’m all about adversity mode, as you know, versus abundance mode. That’s the idea.

I look for xenohormetic plants. Serena would say, “Eat the rainbow.” When you go for colored plants, dark leafy greens, and colored vegetables, it’s great. My favorite one right now is broccolini, very lightly steamed, and maybe—

Olive oil and lemon?

David Sinclair

That’s a good one, yeah. Or just salt and pepper, but olive oil definitely is another one on there. Olive oil is full of these polyphenols, especially if you get the really bitter ones. It’s good.

Awesome. Let’s go to Danny on Zoom. Danny, where are you calling in from? What’s your question?

Danny

Hello again. I’m calling from Israel.

You’re in Israel this afternoon?

Danny

Yes, I’m in Israel. It’s evening, and I’m here. I’m so happy to hear the presentation. Thank you, Dr. Sinclair, or Professor Sinclair.

I was wondering, connecting your presentation and the previous one about Lila, what’s your opinion, and how can you join forces? Or maybe you’ve already joined forces, because both of them are mind-blowing. So, help us.

David Sinclair

I was hoping you would ask that question. We’re doing a lot with AI, not with Lila yet. I haven’t worked with Jeff, but backstage we hope to.

We’re working with companies and academics that do a lot of AI now. We can’t survive without it in my lab, and it’s accelerating our work exponentially. We’re doing now what would have taken hundreds of years before. It’s amazing.

Some of the things we’re doing include AI-driven drug design and looking at billions, and eventually trillions, of molecules to see which ones might reverse aging. We’ve done that already. You can imagine the excitement in the lab now.

We’re using AI to tell whether a cell is old or young just by looking at it very quickly, and we can look at millions of cells within 10 minutes or so. The other area that we’ve actually submitted a paper on is collaborating with a group called Cadence. They’re similar in that, but not identical. They’re not competing. I just checked on my phone before I came on stage.

Cadence is a scientific agentic system that we use for longevity. We fed it a lot of transcriptomic data, and it actually made a discovery that we hadn’t thought of about how to look at biological age with that data. We’re using AI as scientists as well, to give us ideas and even be creative in that way.

If anyone tells you AI can only do what we’ve taught it, that is the biggest bunch of BS you’ll ever hear. AI can be just as smart and creative as we are, and even more so in the future.

Amazing. Okay, let’s go to Graeme.

Graeme

Yes. We hear often that your genetics are not as relevant to aging as what you do in terms of behavior and—

Great question.

Graeme

—nutrition and so on. At the same time, we see that often longevity seems to run in families. When you have a family where somebody is a centenarian, often there are other people who are centenarians as well.

How can we explain that, and why aren’t we using genetics as part of the tool set that we use to drive longevity?

David Sinclair

We should. We really should. I analyze genomes for people with a longevity bias, and maybe you guys do that at your clinics.

There’s been a bit of a bomb thrown into the field recently, with a paper just a few months ago that challenged the idea that only 10% to 15% of our lifespan is genetically determined. They said it’s closer to 50/50.

So, it's somewhere between 15% and 50/50. We don't know exactly, but that's very difficult to modify. At a minimum, I can say science says at least half of your lifespan is up to you, and the rest may be fairly determined. But we should be looking at the genome and the epigenome, blood work, and beyond.

Wearables, of course, are important too. Serena and I have weighed ourselves down with wearables, but all of that, as you know, is the future of health. Already, companies like Peter's are allowing the pointy end of the spear to do that, but I think eventually it'll be normal to be monitored and to have something that tells you ahead of time if you might have a heart attack next week. You could go in and get a medicine before it actually happens. That's the future.

Your point on genetics is well noted, and most physicians don't bother doing whole-genome or even exome sequencing. They should, because it is important, and we need to actually—and I'm working on this—educate doctors about what genes are important to look at, what's actionable, and what's just for fun.

Yeah, there's no question that understanding your genetics is important in order to predict what's likely to happen to you, right? When you come through Fountain Life, we are looking at 2 different things immediately. One is what's going on inside your body that you need to know about right now, which is very important. And secondly, what's likely to happen to you in the future so we can optimize you.

I would put genetics into 2 categories here. The first is that your lifestyle impacts your first 70–80 years. Meaning, you don't want to die from something stupid that you could have prevented. If you're getting from 80 to 100 or 110, genetics is going to play an outsized part of that later part. And then the therapeutics that are coming out of David's lab and others are about overcoming your genetics and going further. So that helps you understand the role there.

David Sinclair

Right. And your genetics will tell you what to focus on and change. My father was the best example. With Ashkenazi Jewish heritage, our genome sucks. My ancestors typically died in their 70s. My grandmother had a stroke in her 30s. So the fact that my father is now living in a healthy way beyond any of his ancestors probably ever is testament that you can really change what your genes have given you.

Abinish?

Abinash

Yeah, Professor Sinclair, thank you for your health tips. A couple of quick things. I did Fountain Life last year and recommend it to everybody. Your tips on atherosclerosis and how to reverse that would be useful. But also, I'm in from the UK. We run 22 care centers, some of the best in the UK. We have 1,600 residents—wonderful older people, average age of 90. We have the oldest person in the world living with us, Ethel Catram, who's 116 and going strong.

What are the tips that I can take back in terms of our wonderful residents, how they can continue to have a health span when they're in their 90s? We have many who are living into their hundreds already. Is that a question for Peter or for me? For yourself, in terms of what can they do to live long, in terms of living longer, and also reversing atherosclerosis as well?

David Sinclair

Yeah, so I mentioned nattokinase, which is probably the most natural way to do it. There is evidence that lowering LDL sufficiently can also have some reversal effects, especially if you get your inflammation down, and there's a sweet spot of LDL. But it's not a fact based on science that getting rid of LDL is your goal.

So if you have high LDL, try to get it really low. There are some really good medicines now that are even better than statins, like the PCSK9 inhibitors and others to come. But that's also another way that has been shown to not just slow down plaque, but can even have some reversal effects. I haven't seen anything as powerful as nattokinase yet in the literature.

There's one thing that is the most powerful: your mindset. Your belief that you can live longer, your belief that there's a revolution coming, your belief that you are needed in society, the belief that you have purpose. Right? There was—and you've heard me quote this out the wazoo—a National Academy of Sciences study that looked at those who are optimists versus pessimists, and optimists were living 15% longer than pessimists.

So you're never going to die?

David Sinclair

So, very truly, I don't talk about immortality. I do talk about health span. I do talk about reaching longevity escape velocity. I think this is the most exciting time ever to be alive. I want to see as much of it as I possibly can. Period. All right, let's go to Ipek on Zoom. Hi, Ipek.

Ipek

Hi. This is Ipek from Istanbul, Turkey, and thank you for this amazing session. My question is from the investment perspective, for investors entering the longevity field: What biomarkers or clinical signals should be watched to identify companies genuinely reversing biological age?

So you're asking about investment opportunities in this area? I'm sorry, Ipek.

Ipek

No. For the KPIs, what kind of KPIs should be watched in a longevity company? For investors.

What kind of KPIs in a longevity company?

Ipek

Yeah.

David Sinclair

It should be the same for all companies in biotechnology. One of the non-KPIs is who's the team. The team counts for probably 50% of my investment decisions. And then cash on hand, obviously, valuation, their runway. Biotech needs to raise a lot of money to get there, so you don't want them to be struggling for cash.

How far advanced are they? Are they anywhere near the clinic, or is it another 10 years away? That's important.

Yeah, a lot of biotech companies run out of money. It's their number one cause of mortality: capital deficiency.

David Sinclair

Yeah. If the team has a track record of raising money, that's helpful, because there are ways to raise money and there are ways not to raise money. If they've never done it, then they can run into trouble.

The team is important because the reputation of the team—everything stems from that. Your biotech is like a maze that you need to get through. If you've done it before, you know the way. And there are some wormholes to go quicker.

If it's an inexperienced team, let's say it's a group that just came out of academia, that's quite challenging for them unless they have really good mentors, which I've had over the years, and I've been fortunate. There are some big obstacles that you can hit. But the reputation counts because the money can come in with the reputation of the people. And like you say, without the money, you're not going to get very far.

All right, we've got 7 minutes. I'm going to get through as many questions as we can. Carl, good morning to you.

Carl

Hi, good morning.

Okay, try to keep the questions and the answers short so we can get to some more questions.

Carl

So, David, if skeletal muscle is one of the strongest predictors of metabolic health, insulin sensitivity, and survival with aging, how should longevity science think about pharmacological muscle enhancement? Is the long-term risk of anabolic compounds greater than the systemic risk of chronic low muscle mass and sarcopenia?

David Sinclair

Mhm. Well, there's been a lot done on this, actually. If anyone's really interested, you could dig in and look at the work of Shalender Bhasin, B-H-A-S-I-N, who's run many trials, particularly on testosterone. And the summary of his work, which is spanning decades, is testosterone doesn't extend lifespan. It's not anti-aging, but it does prevent falls, and it's good for your overall metabolic—

Muscular and skeletal health. Yeah.

David Sinclair

For sure, which is important, right? A lot of people die from breaking bones and falling over and get frail, and then the last 10 years of their life are not fun, anyway. So definitely, talk to your doctor about that. If you're low on DHEA, you can fix that with a supplement.

But mostly it's making sure that you're moving and making sure that you're not letting your muscles waste away. That's the most important. But there's also a lot of good evidence that for women, hormone replacement is not dangerous in the way that was previously thought.

David has come out strongly in favor of hormone replacement recently.

David Sinclair

It is now. And if someone's told you that it might cause cancer, that was an old study that's been really disregarded now.

Let's go to Sandeep on my phone.

Sandeep

Hi, Dr. Sinclair. Thank you so much for being here. I have 2 questions. One on ALS, which you mentioned. Since there are so many variations of ALS, or Lou Gehrig's disease, can we expect a cure for all of them anytime soon? And secondly, for retinal macular degeneration, there have been clinical trials in the UK. Is there a cure out there soon or to be expected?

David Sinclair

Yeah. Well, I can talk about the results in the animal models because that's what we have. I'm always driven by data, not just by hope, although I'm very hopeful.

What's been very surprising about the OSK/ER-100 therapy is that it's working in such broad diseases. I mentioned ALS, and Kelly Rich is a remarkable postdoc who the Friends of Sinclair Lab know well. She is working on ALS in the lab and also using aging as a model for that as well, because we do see degeneration of motor neurons.

And by the way, we're also working on sensory neurons in the body—hearing, eyesight, and the spine. To answer your question, Kelly is saying that regrowth of motor neurons back to the muscle is possible using OSK therapy, even with the chemical-compound cocktail. That means there is some hope that the disease isn't just always going to be progressive. We are showing, at least in animals, I think for the first time, that it is a reversible condition, which is really good news.

And you mentioned macular degeneration. We have a lot of data on that, both at Life Biosciences, the company, and in my lab. My former student, who left and went to MIT, Wang Tang Lu, has a paper that he's hopefully going to publish soon, and we have work in my lab in collaboration with a Korean lab. All 3 of us have shown that both wet and dry macular degeneration are reversible to some extent in gold-standard animal models. So that's also on the radar of Life Biosciences, to try ER-100 in those diseases, pending results in glaucoma.

Sorry, we have time for 2 more questions: Matthias and mic 5, and then we'll go to you, Perla.

Matthias

Yes. Did you say Matthias?

Yeah, I'm sorry—Matthias, mic 1. Sorry.

David, thank you so much for your work. I read your book in 2019, and back then I believed I would live until 120. Then I met my wife; she amped me up to 150, and now I believe longevity escape velocity is soon.

So I believe in the power of mindset, but what I see is that the research is also—like what leader science is doing, for example—very physical, physiological, and biological, measurable and empirical. We kind of think these things are objective and measurable, but at the same time, we say things that aren't measurable, like mindset. They're so subjective still, and I see such a void between the two. There are people like Joe Dispenza doing these subjective things, and I think it's very powerful, but I feel like there's such a gap between them. I wonder how you think about that. I'm also starting to meditate now, thanks to your wife. So, what's this void, and how do you think about this gap?

David Sinclair

Yeah, Serena has introduced me to Joe's work. It's almost like I planted your question. I know we didn't, but we are trying to bridge that. Again, Serena was the inspiration for that. She said, "Your mind can change everything. It can make your immune system better." And I said, "Yeah, come on. I'm driven by data. I don't believe it."

She said, "Often, what we call the more metaphysical, woo-woo spaces turns out to be real later in science, and scientists are just behind." Then a paper came out a few months later, after we had this discussion, that showed that manipulating the neurons in the brain of a mouse that are involved in mental thought sends signals through nerves all the way down to the gut. Then you get more immune cells in your gut by changing the brain. So, first of all, I said, "Honey, okay, I believe it now."

Then I decided to study it, and I have a student in the lab—his name is Allegra. Again, the Friends of Sinclair Lab know her. What she's doing is manipulating the sensory nerves in the body, rejuvenating them, and we expect to see broad effects on the body that meditation has been saying for years, potentially thousands of years, is a good thing. So there, I believe there will be evidence, if not proof, of how the mind overcomes matter and can do remarkable things, like cure diseases that even medicines cannot.

Amazing. Perla, we're going to close with you. A short question.

Perla

Dr. Sinclair, my longevity research focuses on genetics, molecules, and lifestyle. But we spend about 90% of our lives indoors—in our houses and our offices. What role do you think the health of our indoor environments—air quality, materials, microbiome, and light—plays in human longevity?

David Sinclair

Good question, and I've never been asked that. My indoor environment used to be horrible, again, before I met Serena. I was drinking tap water, often straight out of the tap—no cup. [Laughter] I don't do that anymore, but what we've done with our household is have air filtered in almost every room—HEPA filtration. I feel so much better. I had a nasal drip for decades.

So air quality is improved, water quality is improved, plastics are out, and Teflon is out. We do try to get fresh air, right? You don't want stale air. And we don't sit a lot if we can help it. We're always moving.

But what I want to use your question as a launching point for is something: we've built a world that's very comfortable. Enough food, we've got chairs, even our suitcases have rollers on them. This is killing us. We are no longer in an adversity world; we're in an abundance world, no offense.

No, none taken. It's true.

But it kills us. So we need to stress our bodies. We need to make our bodies think that things are a little tough. With air conditioning, we never feel cold, we never feel hot. Change that. You can get a sauna; red-light sauna is great, dry sauna is great. We have a steam room in one of our bathrooms. These are shown, especially a hot sauna, to be beneficial. Why? Because then the bodies get into a good—

Try the health sauna here, right? I have one of those in my office, and I will do a 20–30-minute sauna with infrared. It's amazing, it's quick, and you can always squeeze that in. Plus, red light, all of these different elements. Again, mold is a killer. Understanding what you're breathing, what you're drinking, what you're eating—listen, you've got to worry about what's coming into your body, what's coming into your body physically, as well as what's coming into your body mentally.

What are you listening to? Who are you spending time with? What's on your walls? All of these things impact your health. Be selfish about that for yourself.