David Sinclair: The GLP-1 Side Effect No One Talks About, What AI Found in His Lab, and Reversing Blindness | Q&A EP #251

0:00There's a lot to say about GLP-1s. More and more data is coming out showing benefits to the heart, the brain beyond just weight loss. There is one downside that I need to point out besides what's known about risks. We are 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. And if anyone tells you AI can only do what we've taught it, that is the biggest bunch of BS you'll ever hear. My ancestors died in their 70s.

0:35My 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. There's one thing that is the most powerful, 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 moonshot, ladies and gentlemen. A rare opportunity here. I think we have about 25 minutes for Q &A or so. And sleep and exercise, I think you and I differentiate a little bit on that because I'm like sleep for me trying to get eight hours and I'm trying to be in the gym five days a week.

1:20You're not as – where do you stand on sleep and exercise? I would be sleeping a lot more and exercising a lot more if I wasn't traveling on an airplane most of the time and in the lab. But I have a standing desk and I have a treadmill at home where I try to read and work while I'm walking at least. Movement is very important. So I used to work out a lot. I was a lot heftier. But, you know, life is taking over. 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. And that's important for now to just help shape industry.

1:59You're on a mission. It is a mission, and I'm sacrificing my health for that. That's what I say. Tom, let's kick it off with you. Yeah, so in this goal for longevity and the potential to live longer, if you can comment on how either your research or the 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. Yeah, so the Hayflick limit is when the cells divide too many times and run out of telomere lengths, the ends of the chromosomes. And Leonard was a good friend. He passed away not too long ago. We are studying that. We see some evidence that when we turn on OSK, that telomerase is activated and the telomeres will get longer.

2:47But we have a solution. If that's not the answer, then we could combine our treatment with telomerase therapy and get even longer life, potentially, for the cells in our body. But, yeah, it's an area of intense investigation in my lab and a really good question. Thank you. Thank you. Polly. Thank you, Dr. Seclair. I have a quick question. For those that are using GLP-1s, do you have any hypothesis in terms of, like, how can that be used when your longevity protocols? What can we expect in terms of decelerating aging? Well, there's a lot to say about GLP-1s, and I'll try to be brief because there's a few questions.

3:33more and more data is coming out showing benefits to the heart, 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. And the longevity medicines will be much bigger than GLP-1s, but they're great now. I think if you're not losing weight 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. But yeah, it is very interesting that these drugs, and they're getting better all the time, seem to have other benefits besides weight loss.

4:09But 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. But yeah, those drugs look really good. There is one downside that I need to point out, besides what's known about risks, that is that there's an increasing number of people waking up blind because of it. It's still rare. It's about 20 ,000 to 30 ,000 people in the US a year, which is still horrible. And that's one of the conditions that ER100 therapy will be tested to see if we can reverse blindness caused by drugs.

4:51It's called Nyon. It can happen Even without the drugs of course, that happens. We don't actually know what causes it. It might be congenital even. So you talk a lot about eating stressed plants. Why should we eat stressed plants and which is your favorite plant? Oh well, so the xenohromesis hypothesis is what you're talking about, which Conrad Howitz and I published, oh gee, about 15-20 years ago. The idea is that it sprung, the idea sprung from the fact that resveratrol and a whole bunch of plant polyphenols, which you probably know of, quercetin, physetin, all these ones that are now other scientists are claiming credit for, we showed back in the early 2000s could activate SIRT1, the enzyme.

5:36So how is that possible? And why is it that aspirin is so good? And most of the pharmaceuticals, at least in the 20th century, were derived from natural molecules. What is going on? It's not just coincidence, we think. And 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. And it's a good signal. And before we could see the plants dying, we would sense them with our body. So 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.

6:11And I'm all about adversity mode, as you know, versus abundance mode. And so that's the idea. So I look for xenohermetic plants. Serena would say, eat the rainbow. So when you go for colored plants, dark leafy greens, colored vegetables, it's great. My favorite one right now is broccolini, very lightly steamed. Olive oil and lemon? 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, but it's good. It's got a bit of olive oil every day is a prescription. Let's go to Danny on Zoom.

6:51Danny, where are you calling in from? What's your question? Hello again. Hello again. You're in Israel this afternoon? Yes, I'm in Israel. It's evening and I'm here and 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 already you join some forces because both of them are mind blowing. So help us. Yeah, 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.

7:44We are 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. And some of the things that 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. and 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.

8:27The other area that we've actually submitted a paper on is collaborating with a group called Cadence and they're similar but not identical. They're not competing. I just checked on my phone before I came on stage. Cadence is a scientist 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. And so we are using AI as scientists as well to give us ideas and even be creative in that way. And if anyone tells you AI can only do what we've taught it, that is the biggest bunch to BS you'll ever hear.

9:10AI can be just as smart and creative as we are, and even more so in the future. Amazing, okay, let's go to Guilherme. Yes, so we hear often that your genetics are not as relevant to aging as what you do in terms of behavior and 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's 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? We should. We really should. And I analyze genomes for people with a longevity bias, and maybe you guys do at your clinics.

9:57Now, 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. And 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. So 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 and blood work and beyond. Wearables, of course, are important too. Serena and I weigh ourselves down with wearables.

10:46But all of that, that's the future of health. And 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. But your point on genetics is well noted. And most physicians don't bother doing whole genome or even exome sequencing. And 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 and what's actionable and what's just for fun.

11:29Yeah, there's no question that understanding your genetics in order to predict what's likely to happen to you, right? So when you come through Fountain, we're looking at two different things immediately. One is what's going on inside your body that you need to know about right now, right? Very important. And secondly, what's likely to happen to you in the future so we can optimize you. And I would put genetics into two categories here. The first is your lifestyle impacts your first 70, 80 years, meaning it's dying 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.

12:15And 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. Right. And your genetics will tell you what to focus on and change. My father is the best example. With Ashkenazi Jewish heritage, our genome sucks. We die typically, my ancestors die 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. Ebeneesh? Yeah, Professor Sinclair, thank you for your health tips.

12:54A couple of quick things. Fountain Life I did last year and recommend it to everybody. Your tips on atherosclerosis and how to reverse that would be useful. But also, I'm from the UK. We run 22 care centres, 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 and we've got many that are living into their hundreds already?

13:33Is that a question for Peter or for me? For yourself in terms of what can they do in terms of living longer and also reversing atherosclerosis as well? Yeah, so I mentioned natokinase, 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 the 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 that's also another way that has been shown to not just slow down plaque but he can even have some reversal effects but I haven't seen anything as powerful as natto kinase yet in the literature there's one size of course oh do you know 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 an you've heard me quote this out the wazoo there was a national academy of sciences study done that looked at those who are optimists versus pessimists and optimists were living 15 % longer than pessimists.

14:59So you're never going to die? So, I mean, and, and, and very, and very truly, um, uh, you know, I don't talk about immortality. I do talk about health span. I do talk about reaching longevity escape velocity. Um, you know, 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 IPEC on zoom. Hi, IPEC. Hi. Hi. Hi. This is Ipek from Istanbul, Turkey. And thank you. Thank you for this amazing session. So my question is, from the investment perspective, as investors entering in the longevity field, what biomarkers or clinical signals should we watch to identify companies genuinely diverse in biological age?

15:49so you're asking about investment opportunities in this area i'm sorry ipec no no for the kpis what kind of kpis should we watch in in a longevity company so what kind of kpis in a longevity company yeah uh it should be the same for all companies in biotechnology technology. One of the non-KPI's 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 and uh yeah a lot of biotech companies run out of money yeah it's their it's their number one cause of mortality is uh is capital deficiency yeah and if the team is is has a track record of raising money that's helpful because there's there's ways to raise money and then there's ways not to raise money and if if they've never done it then they can they can run into trouble yeah um but the the team is important because the reputation of the team everything stems from that.

17:09They don't just do a good job and your biotech is like a maze that you need to get through. And 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, which has been fortunate. But there are some big obstacles that you can hit. But also 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.

17:42All right. We've got seven minutes. I'm going to get through as many questions as we can. Carl, good morning to you. Hi, good morning. We'll try to keep the questions and the answers short so we can get to some. 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 a long-term risk of anabolic compounds greater than the systemic risk of chronic low muscle mass and sarcopenia? Well, okay. So there's been a lot done on this, actually. So if anyone's really interested, you could dig in and look at the work of Shalender Basin, B-H-A-S-I-N, who's run many trials, particularly on testosterone.

18:27And the summary of his work, which is spanning decades, is testosterone doesn't extend lifespan. So it's not anti-aging, but it does prevent falls, and it's good for you overall metabolically. Muscular and skeletal health. 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. It's a decision between you and your doctor. 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.

19:07That's the most important. But there's also a lot of good evidence that for women, a hormone replacement is not dangerous in the way that was previously thought. I think the evidence has come out strongly in favor of hormone replacement recently. 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. Dr. Sinclair, thank you so much for being here. I have two questions. One on ALS, which you mentioned. Since there's so many variations of ALS and the Lou Gehrig disease, can we expect a cure for all of them anytime soon?

19:43And secondly, for retinal macular degeneration, there have been clinical trials in the UK. Is there a cure out there soon or to be expected? Yeah. Well, I can talk about the results in the animal models because that's what we have. And I'm always driven by data, not just by hope, although I'm very hopeful. What's been very surprising about the OSK ER100 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.

20:32And by the way, we're also working on sensory neurons as well in the body, hearing, eyesight, spine. To answer your question, Kelly is seeing that the regrowth of motor neurons back to the muscle is possible using OSK therapy. And even with the chemical compound cocktail, which means that there is some hope that the disease isn't just going to always be progressive, that 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, my former student who left and went to MIT, Won Chang Liu, has a paper that he's hopefully going to publish soon, and work in my lab in collaboration with the Korean lab.

21:23All three of us have shown that both wet and dry macular degeneration are reversible to some extent in gold-sanded animal models. So that's also on the radar of life biosciences to try ER100 in those diseases, you know, pending results in glaucoma. Sorry, we have time for two more. Matthias and Mike 5, and then we'll go to you, Perla. Yes. You say Matthias? Yeah, I'm sorry, Matthias, Mike 1. David, thank you so much for your work. I read your book in 2019, and back then I amped up my belief to live until 120. Then I met my wife. She amped me up to 150, and now longevity escape velocity soon. So I believe in the power of mindset, but what I see is that the research is also what Lila Science is doing, for example.

22:11It seems it's very physical and physiological and biological, measurable, empirical, and we kind of think these things are objective and measurable. but at the same time we say things that are not measurable like mindset they are so subjective still and I see such a void in between there and 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 in between and I wonder how you think also starting to meditate now thanks to your wife so what's this void and how do you think also about this gap there yeah yeah yeah so Serena's introduced me to Joe's work it's almost like I planted your question.

22:51I know we didn't. We are trying to bridge that. And again, Serena was the inspiration for that. She said, you know, your mind can change everything. It can make your immune system better. And I said, yeah, come on. You know, I'm driven by data. I don't believe it. She says, you know, often what we in the more metaphysical woo-woo spaces, I call it, turns out to be real later in science and scientists are just behind. And then a paper came out a few months later after we had this discussion that showed that manipulating the nerves in the brain of a mouse that is involved in mental thought does send signals through nerves all the way down through to the gut, and then you get more immune cells in your gut by changing the brain.

23:38So first of all, I said, honey, okay, I believe it now. And then I decided to study it, And I have a student in the lab whose name is Allegra. Again, friends know her. And 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 I believe that there will be evidence, if not proof, that 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.

24:24A short question. Dr. Sinclair, my longevity research focuses on genetics, molecules, and lifestyle. But we spend about 90 % of our lives indoors, our houses, our offices. What role do you think the health of our indoor environments, air quality materials, microbial, and light place in human longevity? Good question. And I've never been asked that. My indoor environment, it used to be horrible. Again, before I met Serena, I was drinking tap water, often straight out of the tap. No cup. I don't do that anymore. But what we've done with our households is air is filtered almost in every room. So HEPA filtration.

25:07I feel so much better. I had a a nasal drip for decades. So air quality is improved, water quality, plastics are out, 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 the indoor environment, what I want to use your question as a launching point for something is 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 the abundance world. No offense. No, none taken. It's true.

25:47But it kills us. So we need to stress our bodies. We need to make our bodies think that things are a little tough. So 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 uh we have a steam room in one of our bathrooms these are shown especially sauna hot sauna to be beneficial why because then the body gets go and try the the health sauna here right i have one of those in in my office and i will go and do a 20 30 minute sauna uh with infrared it's amazing it's quick you can always squeeze that in plus red light all of these different elements.

26:27Again, 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, right? Be selfish about that for yourself.

27:00Thank you.