Inside the World’s First Age Reversal Trial | Lifespan with Dr. David Sinclair - S2, Ep. 4

22:14Dr. David Sinclair:Well, it's this study where they talked about 80 ,000 images of the back of the eye. This is data with the UK Biobank. And they could use AI to look at the differences over time as to what happens. And they could very accurately, within I think three years, predict how old somebody actually was just by looking. And that's about as non-invasive as it gets, right? It's just a photograph. Yeah, it's a great measure. I think in the future, doctors should be using that. And maybe there will be machines for that. The other thing that was interesting is that it helped predict all causes of mortality.

22:48Dr. David Sinclair:And so you could say, well, this person, even though they're, let's say 50, their eyes are more like 60. And that predisposed them to diseases that would eventually kill them. Yeah, this is really important because knowing how old the eye is, an important measure of overall health. There's another team of researchers from Australia that demonstrated in 2022 that the biological age of the cells in our retinas are also a predictor of mortality. that's called the retinal age gap which is the difference between the actual biological health of an eye and then the person's chronological age since birth this number is interesting a two percent increase in the risk of death from any cause for each year of difference between a person's actual age and the older biological age identified by the eye so if your eye is six years older than the rest of your body that translates into a 12 increase in risk of death as we're talking about the aging of the eye should note that there have been studies in the past demonstrating a strong association between say like retinal cell thickness and biomarkers for Alzheimer's disease.

23:52That's worked out of a team from Seoul National University in 2021. And other researchers have observed that the eye and the brain share common mechanisms of aging and disease. And what I'm getting to here is that you're pretty sure that there's a pretty strong connection between how our eyes experience aging and how our brains experience aging?

24:11Dr. David Sinclair:Well, for sure, the same structures exist and the same process of aging occurs in the eye and the brain. The information theory of aging is now showing that. Interestingly, people have, even before they knew this theory, they were looking at correlations between retinal diseases and, say, Alzheimer's disease or mild cognitive impairments. And it was shown, actually, just recently in the last couple of years, that by looking at the changes that are happening to the retina, you can predict Alzheimer's way before you have any symptoms. And is this why it's been so important in the Sinclair lab to examine the eye?

24:48Or is it just that the eye was a convenient mechanism to examine aging?

24:52Dr. David Sinclair:We chose the eye because the student at the time, Wancheng Liu, was excited about the eye. And I wanted to do the liver because I figured that would be easy. But he thought the eye was the place to go. And he was smart about it because he realized that if it worked, we could more easily go into human studies with the eye than the liver, because we're giving genes that are delivered with a domesticated virus called an AAV. And in the eye, there's already a drug on the market using an AAV to correct a genetic defect for retinitis pigmentosa, a genetic disease. Yeah, we're going to talk about that a little bit toward the end of this episode.

25:24But because that was already available, what he observed was that if we are able to show that reprogramming works in the eye, there's already a mechanism to deliver whatever that is, yeah?

25:37Dr. David Sinclair:Yeah, I guess it's not obvious to everybody, but to us, we go on the assumption that if we figure out why eyes age at a fundamental level, it'll be true for every other cell type in the body. And so far, it looks like that's the case. We're now reversing the age of the brain in mice, using the same technologies that we reversed blindness in mice a few years ago. And when we talk about reversing blindness in mice, this paper that came out in 2020 that showed that genetic reprogramming using three of the four Yamanaka factors could recover youthful epigenetic information and restore vision in mice.

26:11That was a really seminal paper for your lab.

26:14Dr. David Sinclair:It was a really nice milestone, and I was very proud of the team. And we wrote about it in our book Lifespan before it even was published. It took a long time to publish it because peer review takes a while, especially with something this radically new. But it came out in, when was it? December 2020. And ever since then, we've been pushing forward pretty hard. We've made a lot of progress on this work. Originally, we quote unquote, just showed that we could improve vision in old mice and mice with glaucoma and even mice that had damaged optic nerves. There were big questions left, like, is it really safe in the long term?

26:43Dr. David Sinclair:How long does the effect last? Can you do it more than once? And these are questions we're now getting answers to. And in fact, a paper called Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of glaucoma adds a lot to that equation. Just what you're talking about here. That study followed many of the same steps as the 2020 paper, but the key word in that title is sustained. Right. It was a lot of work. I want to thank my colleague, Bruce Cassander, and Wan Cheng is also one of the key people there. And what we showed in this paper was that turning on this therapy for a long time had no negative side effects.

27:17Dr. David Sinclair:In the 2020 paper, we found that it worked well for six to eight weeks. Great. But we didn't know. Which was cool. That's great. I mean, curing blindness is no small thing. We were pretty excited. But people asked the question, well, gosh, if you're reversing aging in cells, won't they just turn into cancers? Won't you just get a big tumor in the eye? And the answer to that in this paper is no. It's seemingly perfectly safe in the mouse. And the effect lasts for many months after we switch it off. 11 months. For 11 months, yeah. Which might not sound a lot except for a lab mouse lives two to three years.

27:50So we're talking about essentially a third of the animal's life that translates into decades in human equivalents.

27:57Dr. David Sinclair:Yeah, well, we're excited because most drugs stop working once you stop taking them. But this one, it's a true reset. It's a semi-permanent reset. And of course, aging is still happening so that the eyes start aging out again, just as it would have. But the good news is that we have an inducible system. What that means is we can turn the treatment back on again whenever we want just by giving them an antibiotic. We engineered it that way. what i think will happen is that if it all goes well and hopefully we'll know in a couple of years or less patients will get their vision back glaucoma or just old age or macular degeneration patients and it'll last for a number of years and then they'll just take a course of antibiotics to regain their vision again and they'll turn it back on as they need to keep cycling and that is an important part of this study is that it showed that it didn't just stop the aging or send it on a reverse course into eternity.

28:46It reversed the aging and then reset it per the information theory of aging, and then it continued anew.

28:55Dr. David Sinclair:Right. Well, that's the other thing that's not obvious to most people who just hear about this theory. First of all, that we believe and have shown that there must be a backup copy of the software of youth in every cell that we've looked at. And we've looked at a lot of different types of cells. We've now rejuvenated the kidneys and the muscle, the brain, of course. Other labs have done the spleen and other tissues. So this seems to be a universal software that is in cells. Now, we don't know where that software is encoded. We think it's probably attached to the DNA somewhere, some chemical we're looking for.

29:26Yeah, you've been really cagey about this in our last couple of conversations.

29:29Dr. David Sinclair:We have some clues, but my student, Chris, would kill me if I divulge what he's finding. If you told people where to find it? Yeah, stay tuned. I mean, we'll divulge it here. There's a treasure map there somewhere. Exactly. There is. And we think that information is laid down when our eyes are very young, and it stays there until we trigger it to be reset. The other thing that's interesting is that now we know that it gets reset, but your age doesn't go back to zero, which would be cancer. What happens is that this program, which is set in motion by these three genes you mentioned, which we call O, S, and K, these three Yamanaka factors, age goes back about 80%, but stops.

30:05Dr. David Sinclair:There's a barrier to the cells getting too young, which we don't understand, but we're sure happy it exists. We don't understand, but thank God it exists, right? Because otherwise all this is for naught. Well, we'd have to be very, very careful with the technology. We'd have to turn it on for just the right time and turn it off again to be safe. But now we know it's not that dangerous. You can leave it on for whatever it is, third to half the lifespan. The eye just stays healthy. You've been increasingly willing to talk about like what's actually actively happening in your lab, save for the treasure map that you won't tell anybody about.

30:36Dr. David Sinclair:Yeah, well, I've always talked about research early because I believe that, first of all, the public has a right to know because they're paying for a lot of this research. And also, you know, unless I'm told by my student, please don't tell anyone because it's really competitive. I know I'll get scooped. You know, if I feel like that's not an issue and we're way ahead, then why not talk about it? Let the world know what's happening. Inspire young kids to start science. Inspire other labs to work on this. You mentioned Bruce Cassander earlier. He's a frequent collaborator of yours. He's also the co-director of the Ocular Oncology Center of Excellence at Harvard Medical School.

31:08And he is leading a study that helps bridge the gap between mice and men. It was described in an abstract presentation at the annual conference of the Association for Research in Vision and Ophthalmology, which was held in New Orleans in April of 2023. And that was the first time that it was publicly revealed that the process that was used to restore vision in mice was also working. in monkeys. Right.

31:35Dr. David Sinclair:Well, that was a big deal because mouse eyes are structurally slightly different than us. They have a membrane. They don't have the white. They also don't have the white, but monkey eyes are identical to our eyes. If it works in a monkey, it'd be shocking to me if it doesn't work in humans, now that it's working in the monkeys. And those mice that had bad vision, they had their vision returned again after just 28 days of treatment. And now with Bruce, we're doing some more studies to see how long we can leave it. If it gets better, the longer we leave it. So we're talking about African green monkeys here.

32:06How do we know that their eyesight is getting better? Because I know like some apes can do some sign language stuff. I don't think African green monkeys can. They can't communicate with us. So how's that work?

32:18Dr. David Sinclair:Yeah. Well, we did the same thing that we did in the mice. We did two things in the mice. We exposed them. We showed them a screen and they moved their head when the lines were moving. We didn't do that. They're following something. They follow them. It's called the optomotor response. Which they weren't doing when they had their damaged eyes. Yeah, or just old mice. They didn't turn their heads. And when I give talks, I show these videos of the mice turning their heads when they get their vision restored. We didn't do that with the monkeys because it just wasn't worth setting up. But what we did do that was fairly easy was to do the other test, which is called a PERG, which is like ECG that we do on our hearts.

32:54Dr. David Sinclair:We could do it on the eye. So the PERG measures the electrical activity in the optic nerve and you can measure it in response to changing patterns the p is stands for pattern and you show the monkeys in this case like a checkerboard like a chessboard and you can measure the changes when you show that light and the electrical activity was restored by the treatment just in 28 days wow david we mentioned earlier that we'd be talking about the macula that again it's a little tiny part in the back of the eye that's like really important to acute vision. And then that's where age-related macular degeneration happens, which has also been a subject that you and your collaborators in your lab are really, really interested and working on.

33:35Dr. David Sinclair:That's right. So this is a big disease and it's increasing all the time. And there are a couple of types of AMD. One is the blood vessels grow and you can treat that with an injection that stops blood vessel growth. There's another one that's untreatable at this point, and we'll talk about ways to slow it down. And that is you You accumulate lipofuscin clumps that block the ability of the nerves to work. And these are protein aggregates that have collections of damaged proteins and oxidized lipids. They're disgusting. These little chunks. And you can see them in the layers behind the... I'm sorry, I'm trying not to make you laugh, but like I can tell my face is getting like the disgusted look on it.

34:10Dr. David Sinclair:Yeah, I could see that. They are disgusting. And what we were asking with, again, Bruce Cassander is when we reverse the age of the retina, what happens? Maybe nothing, or maybe the nerves start working well, or maybe if we're lucky, the eye gets rid of those disgusting blobs of protein and fat. These junk boxes. Yeah, yeah. And guess what happened? The junk boxes went away. They went away. When you make the eye young again, it can cope, and it chews them up, and they're gone. And now all the layers of the retina that looked all messed up and expanded and cells growing in the wrong places, it went back to being young again.

34:47Dr. David Sinclair:Perfectly layered cells. And this is a major cause of AMD. Aging? No, the junk boxes. Of course, yeah. And people have tried to get rid of them, but they haven't been able to do that. And the problem is that they're buried within all these cells. And all you have to do is just make the cells young again. And they go, oh, what's this crap? Let's get rid of it. And actually, one of the things that we do with Bruce, again, is we can grow those cells in the lab and we can make them get old now. We have ways of aging cells. And these are the retinal epithelial cells, these RPEs that sit at the back of the retina.

35:18Dr. David Sinclair:And when they're old, they get all disgusting. They don't really grow very well. We treat them with sodium iodate, which gives them a lot of oxidative stress, which is an acceleration of aging. And then we can reverse their age and then they grow beautifully again. And the reason that's great is we want to use these cells as a screen, a screening to find new ways to reverse aging. And we're now at the point where we can see them go from crappy, disgusting to nice and beautiful young again. and we think we can find elixirs or little chemicals that can reverse aging using those cells and then we'll put them into the eye and then eventually into the whole mouse and then eventually into the whole human for age reversal.

35:56A lot of people might think okay well this is all nice sure it's going to be nice to have this sort of intervention available if I ever get a disease that results in this sort of destruction of my vision but I think we need to go back to this point when we're talking about macular degeneration there's a disease called macular degeneration at a certain state and rate of degeneration you can be diagnosed with macular degeneration but also literally we are all experiencing the degeneration of our macula not as fast as people with the designated disease but this is all of us this is happening to all of us all of the time just at a slower rate and really one of the problems with medicine is that

36:37Dr. David Sinclair:they have a cutoff right the doctors have to say this is a point where we're going to treat you versus not. My view is prevent the illness before it even strikes. That's probably the best way. Diabetes is a good example of that. We tend to have more glucose levels in our blood as we get older, but it has to reach a certain level before it becomes a disease. But does that mean when you're 0.999 % away from that number, you don't have the disease? No, of course not. You don't suddenly get a disease. It's happening throughout your whole adult life or most of it in the latter half. And vision is the same.

37:12Dr. David Sinclair:And that's why I was excited to treat not just glaucoma and macular degeneration and nerve damage, but actual aging in mice. Because aging is also a major cause of blindness. We just accept it because we think of it as natural. But being natural and common doesn't mean that it should be acceptable. Yeah. In fact, the American Optometric Association doesn't really meant words about this it says that if you're an adult aged 40 to 60 you will experience symptoms of age-related vision changes this happens to all of us not everybody's going to have the same symptoms but pretty much everybody's going to experience one or more symptoms it's like a need for more light or difficulty reading problems with glare changes in color perception cataracts cataracts all eventually we're all going to get there by the age of 50 about 60 percent of the population needs glasses, contacts, or surgery, and that shoots up to 94 % by the age of 75.

38:08Dr. David Sinclair:Did you know that by 2050, it's estimated that half the world will need glasses for myopia? Yeah. And think about that. That's half the world, right? But that's not just half the old people. That's half the global population. I think already it's half, over 50 now. It's gone up sevenfold in prevalence in the last few decades. No one knows why. We can guess it's computer screens. It might even be a lack of sunlight. There's new evidence that says that violet light or the absence thereof in the eye causes the eye to become malformed and nerves don't function well. This actually reminds me a lot about the conversation that we had a few years ago now in the pilot season, the podcast, where we were talking about aging of the skin.

38:53This commonness of age-related loss of visual acuity is just accepted. Everybody knows it's going to happen. You just say, okay, that's just life. And this is right up there with like the idea that we are all going to get wrinkles, which yeah, is true, but also makes us more susceptible to other health problems as we age. And so I definitely encourage people to go back and listen to that episode because skin aging isn't just cosmetic, which is why it's smart to fight it. And the aging of the eye isn't just a thing that we need to accept, we should also fight it. So David, let's talk about what we can do to keep our eyes healthy because it's going to be a little bit of time before OSK-based age reversal or some other process is ready for prime time in humans.

39:44So in the meantime, as we often say, keeping your body as young as possible for as long as possible is the way to go.

39:53Dr. David Sinclair:Yeah, that's right. As we've discussed, our eyes can reveal a remarkable amount about our biological health and having accurate data about the rest of your body is just as valuable. Which brings me to a science-based wearable that I'm particularly fond of, partly because of its scientific foundation at Harvard where I work, but also the founder's own research and scientific rigor. Of course I'm talking about the Whoop band, the one that I rarely take off. As a scientist I like measuring things rather than guessing and WHOOP continuously tracks my sleep, my resting heart rate, my heart rate variability, respiratory rate, daily strain and recovery and other aspects of my health, giving me objective data about how my body is responding to the changes that I make.

40:37Dr. David Sinclair:On weekends, you'll usually find me on Cape Cod, in my workshop or outside on the property, planting fruit trees, repairing the house or hauling lumber in my old 1992 Ford F-150 pickup. Sometimes, however, I wake up eager to get outside but my WHOOP tells me a different story. My heart rate variability is lower than usual, my resting heart rate is elevated, and my recovery score is really poor. So on those days, I still head out but I pace myself. I found that listening to those signals helps me recover better and work harder over the long term. I appreciate that WHOOP is backed by great science.

41:12Dr. David Sinclair:For example, in 2022, Miller and colleagues published a study in the journal Sensors comparing six leading wearable devices against clinical grade measurements of sleep, heart rate, and heart rate variability. WHOOP was among the most accurate for measuring overnight heart rate and HRV. These are the two biomarkers that I pay close attention to because they provide valuable insights into recovery and physiological resilience. So if you don't already use WHOOP, I really encourage you to give them a try. So visit join.whoop.com slash lifespan, and you can use the code LIFESPAN to receive your free whoop and your first month of membership.

41:51Dr. David Sinclair:Actually, the things that are recommended for the eyes, most of them are procedures that you can use to keep your whole body to healthy as well. Yeah, this is a constant theme with us. So a lot of people are like, oh my God, they're going to talk about healthy eating and exercise and all that. We are, but there's some specific things that you should know about if in particular you really want to focus on eye health and eye aging. There's that. Well, let's start with vitamin C. Vitamin C. Classic vitamin C. It's one of the things at the top. If you want to keep your eyes nice and healthy, it's known to decrease glaucoma risk, protects the eye from oxidative damage and UV damage.

42:26Dr. David Sinclair:And that helps prevent cataracts as well. Exactly. So you don't want to have blurry lenses when you get older. But also we need to know that vitamin C supplements might be associated with an increased risk of age-related cataracts in women. You take extra vitamin C. I take a middle-of-the-road dose. So a regular dose is what, about 75 milligrams? Yeah. And the upper known safe limit for vitamin C is two grams a day. So I'm taking 1 ,000 milligrams, one gram a day, roughly. But I'm taking it for other reasons, not just to protect my eyes. In my lab, we've got some published results now that ascorbic acid, vitamin C, is helpful for slowing down epigenetic aging as well.

43:07Dr. David Sinclair:But that's a whole separate topic. But yeah, vitamin C now is a staple. I've added that to my daily regimen. So in addition to vitamin C supplementation, we're talking about fruits, oranges, watermelon. Yeah, sources of vitamin C are good ones. I have berries, dark berries. I eat blueberries with a small amount of yogurt in the morning. That's a good source. There's another vitamin that everybody or many people associate with better vision. That's related to an old thing that we've all heard that beta carotene, which we get from carrots, is good for eyesight. turns out carrots are good for eyesight because beta carotene converts into vitamin a and vitamin a is good for our eyes yeah yeah so we can put retinol on our skin for wrinkles retinol is also important because it gets converted to retinol al not ol and that little chemical is used by the opsins these proteins in the rods and cones those are the light detecting proteins yeah so retinol is a chemical that has this strange property that when it gets hit by a photon it'll go from a cysts to a trans closed to an open flat structure and that triggers what's called a g protein coupled cascade that allows the cells to now signal to the the optic nerve the retinal ganglial cells that there's a signal but those cells they die pretty quickly because they're really going hard at it there's a lot of oxidative stress they need to be recycled and so you need vitamin a to rebuild that you got to keep feeding them essentially you do and those rpe cells that are defective in macular degeneration.

44:38Dr. David Sinclair:They actually sit next to the rods and cones to gobble up the membranes that are now defective because of all of this activity. And in some forms of macular degeneration, it's this RPE65 protein that recycles the retinal back to its closed detection form. And you've got to keep this cycle going all the time to be able to see. Let's tick off a couple of other vitamins here. Vitamin E. Vitamin E is good. Another antioxidant. Remember, the eyes are constantly getting hit by oxidants and they're dying, need to be recycled. So vitamin E is good. Zinc is also very important. It interacts with taurine, which is thought to extend lifespan, which we'll cover in another episode.

45:17Dr. David Sinclair:And it also interacts with vitamin A. It helps with the plasma membranes, helps with this reaction of the rhodopsins, and it also helps the neurons signal. So it's all good. So keep the zinc levels up. Not too high, but just at the right levels. And then vitamin B1, thiamine? Yeah, vitamin B1, it decreases inflammation. Healthy nerves require vitamin B1. So that a B vitamin blend is what I take, which includes B1, B6, B9, B12. These are all good, especially for people like me who don't eat much meat. So B1 for eyes. What else, Matt? Omega-3s. So omega-3s are good for all inflammation in the body.

45:55Dr. David Sinclair:I take mine mainly to stop cardiovascular disease, but they're also good for the eyes. They promote the development of retinal function. And it's been shown in a study that high intraocular pressure that gives rise to glaucoma is improved if you take omega-3 supplements. Finally in this list, although this is a big list, this is non-exhaustive and we should also say if you're having trouble keeping track of all of these, show notes, show notes, show notes, right? Yeah, oh there's one thing before you go there. Show notes are good and Andrew who's here with us, I'm calling him the boy wonder these days, he will make sure that all these references there.

46:27Dr. David Sinclair:But I want to talk about something you reminded me on omega-3 fatty acids in the eye. A lot of people, even when they're young, have dry eye. You blink, it hurts, it's scratchy, particularly when it's winter, the air is dry. One of the ways to treat that is taking this fish oil supplement. And another way is to take an NAD booster. It's been shown in a Japanese study. NMN can actually help dry eye. And there's a third thing that's interesting. There's a drug on the market. It's low-dose rapamycin. Now, those who've listened to this podcast before know that rapamycin is a longevity drug in animals and probably in people as well.

47:03Dr. David Sinclair:It was designed to suppress the immune system, but it also in low doses, in eye drops can prevent dry eye. Wow. All of these things come back around. Yeah. What's actually happening, I think, is that these longevity genes, they protect the body and just like they're protecting the liver and the kidney, they also can protect and rejuvenate the eye. Before we get away from nutrients and we start talking about other things that we can do to protect our eyes from aging. There was one more that I wanted to mention, which is lutein. There's a few. There's one called lutein. There's one called lycopene.

47:35Dr. David Sinclair:Lutein I actually take every day. It's a little red capsule. Lutein is one of those antioxidants that's been shown in clinical trials to slow down eye aging, particularly as it relates to macular degeneration. This is one that I put my father on or suggested to him and he started taking it. Let's put it that way. So yeah, lutein is great. I take that every day. Lycopene I don't take, but I eat enough of these reddish vegetables and fruits. So tomatoes have a lot of lycopene in them. And so that's if you eat for amount of tomato products, tomato paste, for example, loads of lycopene. I actually have the numbers here that in one large raw tomato, you've got five milligrams, which is a big, big serving.

48:17Dr. David Sinclair:But if you eat a quarter of a cup of tomato paste, maybe you put it on a pizza, 19 milligrams. So this is all good. But I did find a paper that said that lycopene, when fed at high doses during pregnancy to women, children that were born had low birth weight. So if you're pregnant, don't take high doses of lycopene. Don't eat tons of tomatoes. But if you're an adult, it's good for your eyesight. Yeah, that's true. Plus, tomatoes are high in vitamin C, right? That's true. There's another one called astaxanthin, A-S-T-A-X-A-N-T-H-I-N, and it's a carotenoid. You can find it also in trout, algae, yeast, shrimp.

48:51Dr. David Sinclair:and it actually gives fish like trout the pink color and that's also been found to protect the eye from oxidative stress and macular degeneration and aging itself okay a lot of people might say oh my god that's a lot right that's a lot of supplements which remind people the best way to get nutrients is through food if they possibly can a lot of times we can't get probably the doses that you're talking about through food but that's sort of the first and primary way to get bring these nutrients into your body there are several diet types that have been shown to be holistically good for eyesight and general ocular health.

49:21And these aren't going to come as any surprise to anybody who's listened to the show either. Fruits and vegetables.

49:26Dr. David Sinclair:But go for the colored vegetables. So my partner Serena says, eat the rainbow. You and I call it xenohormesis. What doesn't kill you makes you stronger. These are plants that have been stressed and produce these chemicals, and they're full of color. Anything that's colorful, so dark green, bright orange, red, these are all good for you. And in general, they're good for the eye as well. Again, I recommended to my father to go into these kinds of foods. And he also went on the lutein. He's on metformin, which has also been shown to slow down macular degeneration. And he was starting to get macular degeneration, AMD as it's called.

49:56Dr. David Sinclair:And it's now completely stopped in its tracks. It's not getting any worse. It may even be better. And he doesn't even need glasses to drive at night. Also, good diet. Keto has been shown to increase optic nerve mitochondrial biogenesis, which is important because our mitochondria deplenish with aging, but that apparently helps with cell survival in glaucoma in mice. Yeah, it does. Calorie restriction has been good in plant-based diets. Mediterranean diets are all good for slowing down the aging of the eye. There was a study I want to point out in 2012 that showed that eating a lot of greens, kale, carrots, peaches, I don't like collard greens, but they were in the study.

50:38Dr. David Sinclair:People that ate that kind of food had much lower glaucoma risk in women, probably because they have a lot of vitamin A and vitamin C and these other xenohromatic compounds that we talk about a lot that activate these defenses against aging. You just brushed over caloric restriction there, but there's a lot of evidence that caloric restriction, for instance, decreases retinal ganglion cell death in mice. It delays age-related cataracts and rodents. It attenuates inherent age-related loss of RGCs and is neuroprotective against ischemia. There's a lot of data that suggests that caloric restriction is good for eye health.

51:18What do you think is going on there in the context of the survival circuit, the information theory of aging?

51:24Dr. David Sinclair:Well, if you've listened to this podcast before or read our book, you'll know that caloric restriction slows aging across the entire body. So the eyes, of course, are no exception. And what we believe is happening is that choleric restriction is turning on the cell's defense against the aging process. And a major cause of aging, we believe, is the loss of epigenetic information, the ability of cells to read the right genes at the right time and maintain their function and their identity. So what we've seen and published is that during aging, cells such as the nerve cells in the eye, they lose their ability to read the right genes to maintain their nerveness and that that leads to dysfunction and these diseases or even just bad eyesight as we get older.

52:03Dr. David Sinclair:What do we need to do about that? We need to put the body in a state of hormesis, tricking them into thinking that times are tough and they respond in defensive ways, turning on the sirtuin genes. We've shown that happens with caloric restriction. And now these sirtuins, they go on to the DNA, they help wrap it up and maintain that epigenetic information for much longer. And so what we're trying to do is to find ways to slow that progress down, reset the system. Even though we're not there yet in humans to reset the system, there are ways, as we're talking about now, through diet, even exercise, certain foods that you can eat, supplements that activate these defenses and slow that process.

52:40And caloric restriction is one of those ways. But what I hear you saying is that this has a whole body effect. Our eyes are part of our body. It's sort of part and parcel.

52:47Dr. David Sinclair:Yeah. Protects our brain, protects our eyes, liver, kidneys. But I want to make one thing clear. It doesn't mean you have to be hungry all the time. Right. We've never said starve yourself. No, but skip breakfast or have a late lunch or even have dinner and have it early and don't eat till maybe 11 o 'clock the next day. These are ways to put your body in a state of perceived adversity, at least part of the day. And that has huge benefits long term. Yeah. Feeling a little bit hungry is not a bad thing. Right. And actually your body gets used to it. When you start out first, I will admit if you're used to eating three meals a day, you'll feel starving.

53:19Dr. David Sinclair:You won't be able to think. It's happened to me. But what happens after a couple of weeks of this lifestyle, your body gets used to it. So I don't get hungry in the morning now. And I've skipped breakfast for many years. We've spent a lot of time so far talking about diets and nutrients that we need in order to allow our eyes to do what our eyes are designed to do. There's something else that we need. And this comes out of the work of one of your friends, Dr. Zubata, violet light. Not to be confused with ultraviolet light, which we'll get into in a moment here, but can we talk about violet light and how important it is for our eyes?

53:54Dr. David Sinclair:Yeah, so Kazuo is a friend of mine in Japan, and he's made some really great discoveries. One of the best ones, probably the most important one was just a few years ago, he discovered that violet light. Now, this is not ultraviolet light. This is, we can actually see very dark purple light. That is essential for maintaining the shape and the activity of the eye. and that without it, you get short-sightedness or myopia. And he thinks, and I do too, that that's responsible for this sevenfold increase in the amount of short-sightedness across the planet because we don't go out into sunlight and LED screens like our computers don't produce enough violet light for our eyes to respond to.

54:31So the kind of light that we're getting doesn't include this part of the spectrum and ergo the options that are evolved to receive this light and to incorporate it into our biochemistry aren't getting it.

54:43Dr. David Sinclair:That's exactly right. And there was a study that, first of all, he did it in mice, and he could show that mice responded well to this violet light. But he also looked at children who had glasses that either blocked or let this violet light through. There was a much greater incidence in short-sightedness in the kids that didn't let violet light in. And Kazuo did a very kind thing. He sent me a little USB stick that shines violet light into the kitchen, wherever you plug it in. And so these days, especially during winter when I'm not outside a lot, and let's face it, I'm barely outside ever, ever, I use this violet light in the hopes that it's going to slow down my short-decidedness.

55:19Dr. David Sinclair:And I still don't need glasses, so so far, so good. But the easy answer there is go outside and get some violet light, right? Because that's part of the spectrum that we get from the sun. Yeah, just a little bit. UV is still very damaging to the skin and the eyes in high doses, but a little bit goes a long way, yeah. Yeah, so let's talk about that now. Now let's talk about the things that can damage our eyes. UV is the obvious one. This doesn't just mean don't stare at the sun. That should be obvious. But we also want to avoid UV rays, which can modify our lens proteins and cause cataracts and blurry and hazy vision.

55:55And also UV rays increase the incidence of eyelid cancers.

56:00Dr. David Sinclair:Yeah, in fact, UV can cause a lot of cancers, of course, on the skin being the most prevalent one. And what's happening is that the UV radiation will actually go into the cell and damage the DNA. You know how there's four bases of DNA, which we call A, C, T, and G. The T's actually with some UV will link together. So two T's together in a string will become a dimer, chemically linked together. And now you're screwed because now the cell can't read the DNA. And there are special enzymes that remove those. But if they don't work well, you can actually have a mutation. And that is really the reason that UV causes cancer.

56:35Whoa, so like UV melts the teas together, basically?

56:38Dr. David Sinclair:Fuses them together, yeah. Wow. Yeah, it's pretty horrible. And I remember that when I go out and spend too long. So when you're getting sunburned, that's what's happening is your cells detect that your DNA is being damaged. And they have an inflammatory response. So your cells are trying to protect the cells, but also kill off those cells that have been damaged so much that they might cause cancer. Okay, so that's sunlight. It bears mentioning because it is in the research. Don't look at lasers. Lasers are bad for your eyesight. They are. It's particularly dangerous if you have pet sharks with laser beams attached.

57:09Dr. David Sinclair:So don't get those as pets. Like Dr. Evil? Dr. Evil, yeah. For the young people that haven't seen Austin Powers movies. God, there are people out there who haven't seen Austin Powers. No, we're old, dude. Man. One thing I've learned after decades of studying aging is that you simply can't consistently improve anything that you don't measure. Speaking of which, a few months ago, after a lot of travel and speaking engagements and probably too many dinners out, I realized I'd put on a few extra pounds and I could see the graph on my Withings scale and I needed to shed a few. My goal, however, was not to simply lose weight.

57:44Dr. David Sinclair:I wanted to get back to my usual body composition. Had I lost muscle? Was my visceral fat creeping up? What did I need to focus on? That's why I like the Withings Body Scan Scale. It tells me much more than my weight. It measures body fat, muscle mass, visceral fat, and even includes an FDA-cleared ECG. As I made a few changes to my diet and got back into my normal routine, I could actually watch my body fat come down while preserving my muscle. And that's far more useful than watching a single number on a scale. I've actually been using Withings products for well over 10 years, and lately I've become a big fan of their watches as well.

58:23Dr. David Sinclair:They continuously track heart rate, sleep activity, temperature trends, and even blood oxygen. I wear the Withings Silver ScanWatch Nova, which looks a lot like an expensive diving watch. And my partner Serena wears one of the slim gold models. She loves that it looks like an elegant watch first and a health tracker second. Withings also makes one of my favorite blood pressure monitors for home use. Also a sleep analyzer that can help identify sleep issues and have a smart thermometer as well. To me, that's what longevity is all about. measuring what matters, making small improvements, and letting those improvements compound over the years.

59:00Dr. David Sinclair:Withings makes it easy to build your own health home lab. So whether you're tracking your body composition, blood pressure, sleep, heart health, or activity, you'll have the data you need to understand whether the choices you're making are actually improving your health or even harming them. If you'd like to build your own health home lab like I have, visit withings.com slash lifespan and use the code lifespan to receive 10 % off. The other thing that you want to make sure is that if you get that damage, you want to take some NAD or at least an NAD booster because it was shown by Raj Abda, who's one of the leading surgeons in the eye.

59:41Dr. David Sinclair:He's at WashU, Washington University in St. Louis, that if you get damage to the retina, either by lasers or by other other stresses on the eye raising your nad levels really does protect the eye and that was a lot of interest to pilots especially military pilots who can have lasers shun straight in their eyes by the by the enemy so they're like carrying around some like nad in their pocket just in case they take the laser in the eye they can shove that down they might be if they've been reading papers they they probably do there's two more big ones that i want to talk about uh again these should at this point, I feel like sort of be in the category of no-duh information.

1:00:19Smoking damages retinal cells. It increases the risk of AMD. And drinking, we know that alcohol consumption increases the risk of age-related macular degeneration as well.

1:00:31Dr. David Sinclair:Yeah, smoking and drinking, especially smoking, that's the fastest way to get older and you'll look older as well. But drinking, that's also very common. I used to drink probably one or two glasses a day. I now don't drink. barely ever a few times a year. One of the reasons is that it damages tissues, including the eye, and particularly the brain, which of course we now know is an extension of your eye. And so for instance, total alcohol consumption does accelerate aging. You can look at the blood, you can look at the eye. And even one episode of binge drinking, which is more than five or more drinks on the same occasion, was associated with a month and a half acceleration of biological aging.

1:01:10I wish I thinking about a visit I had to the University of Illinois, which is this enormous campus of 40 ,000 students. And I arrived there on the last weekend of finals week. And the binge drinking that was happening before my eyes was horrific.

1:01:28Dr. David Sinclair:Well, we think that when we're young, we're immune to everything. And it is true that if you drink a lot of alcohol when you're younger, it's less damaging than when you're older, but it's still damaging. We were always aging, even from conception and drinking when you're young will accelerate the biological clock so try not to binge drink if you're going to drink drink in moderation and try to drink you know not every day because it is known that it does damage your body and even your brain will be smaller at the end of the the day so two other things to talk about here vegetable oils and animal fats animal fats that contain omega-6 fatty acids red and processed meat do it in moderation but it's bad for your eyes right like over time that's going to contribute to age-related vision loss right and so you know there are some people that they eat a lot of meat they love meat and it will make you feel better initially you'll get a fair amount of muscle you may even lose a lot of weight being in ketosis long term though there's no evidence that that's a healthy diet when it comes to overall health including your eyes one more thing that comes up a lot particularly in relationship to glaucoma is ocular pressure and there are some age-related findings about this as well well there are i mean glaucoma is a disease we also know that you can change the pressure of your eye in many ways if you go bungee jumping even if you sleep on the pillow with face down it can change the pressure okay so bungee jumping because you're suddenly going from like really high to really low or because when you get to the end of the bungee cord like your eyes pop out of your head like a cartoon.

1:02:59Dr. David Sinclair:Yeah, the second one. Okay. Yeah. And so what we want to do is reduce the amount of pressure in the eye. Sometimes it occurs naturally. This is glaucoma, but the way we live can also affect it. And there was one study out of South Korea I was looking at. It was only admittedly only 20 people in the study, but they found that people who slipped face down and on a certain side could increase the pressure of the eye, which has been shown in rodents. When you increase the pressure, it actually ages the nerve cells in your eye, consistent with the information theory of aging and that's going to lead to eventual loss of vision.

1:03:29Dr. David Sinclair:So I sleep face down and I never thought that that might be hurting my eye, but maybe it does. So there are lots of things we can do to try to avoid getting older eyes as we get older and things you can take, things you can do even the way you sleep. Okay. And then some things that we can't do, but I still think in the realm of interesting things, for instance, this is my favorite one, mice in spaceflight decelerated the retinal epigenetic clock really yeah it was like they put these mice up in the international space station they leave them up there for a while they bring them down they check the retinal epigenetic clock and lo and behold their eyes are younger well that's interesting maybe do they look at the methylation clock yeah according to the study the mouse retinas were isolated and both dna methylome and transcriptone were determined by deep sequencing, there's less methylation.

1:04:21Dr. David Sinclair:I wonder why that would be. Okay, this is not necessarily news we can use. Very few of us will ever go to space probably and even fewer of us will stay up there for a long enough time to observe like a long time period of less pressure on our eyeballs. But if you're friends with Jeff Bezos, maybe. Yeah, but it does bring up a theme which is protect your eyes from radiation, pressure, chemicals. the more damage you do your eyes the faster they will age even goggles like swimming goggles yeah yeah that's been shown to increase the risk of glaucoma so you want to wear a face mask yeah yeah it's similar to the ears we should do an episode on on ear aging because a lot of people have loss of hearing as they get older it's rarely appreciated how bad it is and one of the things that accelerates hearing loss is damage to the ears like a rock concert and we think go to rock concert my ears will ring a bit next day i'll be fine not true your your ears will be older because of that damage same for the eye so you think we should do a show on yours as well i'm listening we're gonna do one but your jokes have to be better next time all of this is really important for everyone i want to i just really want to emphasize this this is not just information for people who are genetically predisposed to diseases of the eyes if you are susceptible though these principles are doubly important so as we also often say on this program it really is important to understand your genome, get sequenced, and then consider testing for the early signs of these conditions.

1:05:51Because if you are susceptible to them, it's even more important to do all of these things to be protective and not to do things that are damaging your eyes.

1:05:59Dr. David Sinclair:Yeah, we live in an age where you can get your genome analyzed, either for a few hundred bucks or a few thousand, you can do it shallow or deep sequencing. And it can tell you if you have susceptibility to retinal damage, or you might get an AMD, macular degeneration, or even retinitis pigmentosa. The good news about those diseases now, particularly retinitis pigmentosa, is that you can get a drug that cures your genetic defect. In the case of the RPE65 mutation that runs in families, Luxturna is a drug. It's actually gene therapy from Spark Therapeutics. Jean Bennett and her colleagues, I think it was just a few years ago, got permission to sell a drug that cures that genetic disease that's lexterna in 2017 yep and it's the same technology actually we're working with genes advice with the aav with the av to deliver the yamanaka factors this is the domesticated virus right yeah so you inject it into the igis once and we've engineered our virus to turn on and off with an antibiotic doxycycline well let's explain the lexterna thing because they're not delivering the OSK genes.

1:07:02They're delivering basically the healthy variant of the gene that people with this disease do not have. Right.

1:07:10Dr. David Sinclair:So that's stage one gene therapy, right? Replace what's missing. The next stage is to knock out or change the composition of genes. Treatment for sickle cell anemia was approved by the FDA using CRISPR technology, the technology that allows us to go in and change individual bases and chemical letters on the DNA. That's stage two. Stage three will be what we're doing, which is going in and changing actually the behavior of the cells. And that seems to be very effective, not just in one particular disease, but across many. Yeah. And that's really the gold standard. The gold standard is ultimately going to be reprogramming.

1:07:48Yeah.

1:07:49Dr. David Sinclair:And what we're doing now, which we've published one paper on, is chemical reprogramming. So instead of gene therapy, which is what's going to be our first clinical trial, we hope that with just a pill, take it for a month, you'll get your eyesight back. And that's likely because of the trajectory of the research and stuff that's come out of your lab and decisions that were made by your people in your lab. It's likely that what we're going to see is reprogramming of the eye first and then ultimately the entire body. So if you're watching the trajectory of how this is going to come into human lives, eye is probably ahead of most other things, right?

1:08:26Right.

1:08:26Dr. David Sinclair:Because eyes are a very good place to start. They're a little sack of liquid, right? If you were to choose a place that's safe to inject something like gene therapy, a sack of liquid is pretty good. And that's what your eye is. And that's why we started with the eye. But it doesn't mean that the same therapy won't work for the brain, for the liver, the kidney, and eventually the whole body. There's a study that showed that this age reversal technology that we co-developed reverses aging in the whole body of a mouse. And now those mice that were very old when they were treated, 25 months, the remaining lifespan was an additional 109%.

1:08:59Dr. David Sinclair:So reversal of aging isn't just for the eye, it seems to work across the entire body of animals too. Oh, we should keep an eye out for that. Oh, Matt. We should look for it. Yeah, yeah. I guess we'll see. Matt, I think that's enough. You and your puns. good conversation today thank you so much i feel like when we started talking about this subject you and i a few weeks ago said hey let's do an episode on aging of the eye and this has happened to us a few times now we go like oh is there enough to have a conversation about and then there's almost too much to have a conversation about yeah i thought today was really good we got a lot of take-home messages about what people can do now even if they're young to make sure that they are able to see later in life.

1:09:44Dr. David Sinclair:And I wish I had this information when I was young because I probably have even better eyesight now. So even if you're in your 70s, maybe in 80s, you should start now. It's never too early to start protecting your eye, turning on longevity genes, eating the right foods and taking these supplements that we believe can protect the eye long term. It's been great to have you with us. This is a show where science and evidence come first. The team works hundreds of hours to bring you only the facts. To learn more and to join our community, visit lifespan.com and you'll get early access to future episodes, to the Lifespan magazine, and to detailed episode show notes.

1:10:21Dr. David Sinclair:You'll also get transcripts and links to the papers that we talked about today. As a member, you'll actually be helping us support medical research to extend all of our healthy lives. If you found this episode valuable, do consider subscribing and also turn on your notifications so you don't miss new episodes. It'll also help us make a better show for you. And feel free to share this episode with any family or friends who you think might enjoy it and learn from it. Finally, for the latest discoveries in longevity science, consider following us on Instagram at Lifespan and on X at Join Lifespan.

1:10:58Dr. David Sinclair:From all of us at Lifespan, thank you for being part of this growing community. And remember, life's short, So let's change that together. Lifespan is produced by Andrew, the Wonder Man Ying, Rajiv, Geek Me Out Ramesh, Marissa, who's on First Volgamore, Kathleen, TLDR Fitzgerald, and our researchers, Shivani, Just One More Thing, Sethi, and Adiv, Meet Me in the Year 3000, Johnson. Also, I want to mention our new recruit, Daniel Rocketman Salazar, who's our new producer. And of course, Serena, my honeypoo. I also want to thank Inspiro Studio and Create Ape for making this show possible. And finally, thanks to our partners for helping us support longevity research.

1:11:40Dr. David Sinclair:We'll see you next time.

1:12:01Dr. David Sinclair:and not those of Harvard University or Harvard Medical School. Full disclaimer is in the show notes.