Homeroom with Sal & David Sinclair, PhD - Tuesday, July 14

Hi everyone! Welcome to our homeroom livestream. Very excited about the conversation we're about to have. But I will start with my standard announcements, reminding everyone that we at Khan Academy we're a 501c3. We're a not-for-profit; we can only exist with donations from folks like yourself.

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So with that, I'm very excited to introduce our next guest, Dr. David Sinclair, professor at Harvard University. David, thanks for joining.

"Hey, Sal, good to see you again!"

"Likewise! You know, folks, I have talked about in the past, I have some fringe eating habits and so I'm definitely very in kind of the health world on certain things, but a lot of people don’t know that I've actually followed your work for many, many years. We will get into it, but it's probably best coming out of your own mouth. You know, what is the focus of your research, and also what got you into it? Why do you want to devote your life to this area of research?"

"Well, my passion is to extend healthy lifespan in people. I don't like people getting sick. And so, I'm a scientist, a medical doctor, and we research what I think is one of the biggest biological and medical problems of all time, which is why do we get sick especially as we get older? We all know that our bodies are capable of healing, especially when we're young. And the question is: why is that? Why is it when you're young you can heal from a wound or you don't get cancer or Alzheimer's, but as you get older you do? That's what we’re trying to figure out because if we can harness that energy of youth and even maybe even turn back the clock in our bodies, I think it'll be the biggest medical revolution of all time. So you ask me why do I do it? Well, you know, I think like a lot of people, I'd like to leave a legacy. I'd like to make an impact, make the world better than I found it. My grandmother instilled that in me especially, but I was also very curious. And I think that trying to tackle one of the hardest problems on the planet keeps me busy and very entertained with my lab."

"And there's a lot in what you just said. I mean, maybe the first thing that I've always found fascinating is, you know, we're always caught up with the diseases of the world, you know? The big ones: cancer, heart disease, diabetes. But you essentially just view those as side effects of another phenomenon, which is aging. And what I find fascinating about that is, you know, aging is such a part of what it means to be—not even human—but what it means to be a species as far as we know it, that we just don’t even question that as being the actual cause of all of these other things. When did it click in your mind that you could address aging itself? And at the same time, you know, there's all these other, you know, Ponce de Leon looking for the Fountain of Youth. How did you navigate that kind of fear that, like, wait, this does seem like something really important, but if I start talking about aging, people are going to think I'm Ponce de Leon or one of these folks looking for eternal life?"

"Well, it was like that when I first started. This is going back to the late 80s, early 90s. Aging research was the backwater of biology, and to go into it in a serious way was considered madness. I had a number of mentors saying, 'Why would you do such a thing?' Fortunately, during the 1990s, there were some real big breakthroughs. Geneticists, one of which I worked for, Lenny Guarente at MIT, they got into it and said, 'Okay, let's just throw out all these ideas of why we age. Let’s just look for what genes control aging.' What we, as a field, discovered is that there are individual genes that you can change that dramatically extend the lifespan of animals and yeast cells, which I was working on as a kid in my 20s. What that told me—and anyone who would listen—was that the control of aging is extremely simple. Now aging, of course, isn’t in the same way a car or work will wear out for many reasons, but if there's a way to slow that whole thing down by changing one gene, it means it's possible to have one day a medicine that would slow down and perhaps even reverse aspects of the aging process."

"And as you said, what's so important about this is that we throw away our preconceived ideas about what's natural. Now, getting heart disease and cancer 100 years ago were natural and very little could be done. And the same is going to be true for aging. Once we accept as a—you know, the medical profession and I'm a scientist and MD—but if we can accept that one of the main reasons, if not by far the biggest reason that we get these diseases as we get older is because of aging. And the reason we haven't made a lot of progress recently, or up until now, is because too many of us accepted it as an inevitability. Just to make a point, I'm not saying that I'm Ponce de Leon and I'm going to give everyone immortality. That's not the point at all. And fortunately, our field has gone ahead in leaps and bounds, and now we're one of the most respected areas of biology."

"Yeah, and give us a few key points. You mentioned some of that early research with Guarente's lab, with your case, the yeast. What are some, would you say, are the seminal data points over the last 20 or 30 years that have started to make people realize that wow, there's a lot here? And I'm familiar with some of it, but I'm guessing a lot of people don't realize what has already been done."

"I'm often shocked when I talk to people who are not paying attention because they've got their own lives to worry about, how far we've come, and most people don't realize so milestones. So we've known for well close to a hundred years that low-calorie diets can slow down aging in animals and seemingly in humans. Well, then I was skipping a meal, having a fast. It's always been considered healthy, and we didn’t really know why. And actually, you asked me why I was sure that studying aging might be helpful. Well, the main reason is when you give rats and mice 30% fewer calories in their life, they live longer. And they don’t live longer because they stay old; they live longer because they don’t get cancer! And these are the diseases of rat aging or mouse aging. So I knew that there was something to be had there, and if diet can do it, surely we can make a medicine to do that as well, and we've made a lot of progress towards that."

"So some of the milestones were, so the worm C. elegans, that's a nematode worm, there was a mutation in that called daf-2 that extended its lifespan twofold. And now, actually, you can extend the worm's lifespan by tenfold! So that's massive. You can extend a worm's lifespan by a factor of 10 by some gene editing. Is that how you do it, or is it some molecule, or both?"

"The best, the most careful ones are genetic, but there are molecules that now we can feed a worm. Even a drug that's on the market for transplant rejection called rapamycin, there are drugs that can do what fasting hunger used to only be able to do. And another milestone was we figured out that changes to how genes are turned on and off in yeast cells contribute to their aging as well. We learned how to control that in mice. We can now extend the lifespan of mice genetically and pharmacologically. And one of the things that—well, there are a couple of things I want to say. One is that these genes are found throughout life. They're found in yeast cells, they're found in worms, they're found in mice, they're found in us. So we have longevity genes in our body."

"And in fact, you can look at certain variants and see if you're more likely to live longer! And then the other big breakthrough was the realization that the way we live our lives, and the way animals in the lab live their lives—what they eat, whether they exercise—if they eat the right foods, they're actually turning on these longevity gene pathways. So we finally—I think we have a model where the reason that diet and exercise is so good for us isn't just because we stay lean and because our blood flow is, it’s actually because our bodies have protective genes. We call these longevity genes, and as we get older, if we're lazy and we eat a lot, they shut off. But there are ways we can turn them back on by living the right lifestyle."

"And hopefully one day having access to medicines that turn them on as well! And what— you know, I think the difficult thing about this research is, obviously, you can't study it. It takes too long to study a human’s lifespan. How do you do that? How do you translate the work on the worms and the mice and the rats to something that works in humans?"

"Well, there are business tricks to it. What we've done, and I've launched a number of companies to do this, certainly because a government grant won't give us enough money to do that. So the companies, we raise money, we have traditionally started companies where we see that these molecules that could extend lifespan in humans are also going to be useful for diseases that need cures. For instance, there’s a company called Metro Biotech. They work on raising a little molecule in the body called NAD, and it has potential applications in rare diseases such as Friedreich's ataxia, a genetic disease without a cure, as well as even potentially treating COVID-19. We have a study that's about to begin in that area, and we think that that will boost elderly people's ability to fight against infectious diseases as well."

"And so just to make sure we're all on the same page, the way you do this, obviously, it'd be very hard to run a randomized controlled trial to see if you can get some—if you can get an average lifespan from 80 to 83 years. That research would take forever, and none of us would be around maybe to see what happens. But instead, you look at some of these diseases that are associated with aging, and there you can see, hey, if this gets this type of therapy, this type of drug, or this type of lifestyle change, what happens to their—what happens to those disease conditions?"

"That's exactly right. These molecules that I work on and other scientists, they could be applied to probably a hundred different diseases that are related to aging and some not. Sometimes these are just the ability to boost the energy and the repair systems of even sick young people. So that's also important to realize that this research isn't just about keeping older people around; it's about boosting the body's natural defenses against disease and disability and promoting healing."

"And you're right, we can't do probably a million people over ten years—there's no country in the world that could even afford that. But the hope is that if we can get a drug on the market or even one that's already on the market and show that if you look at five, ten, or thousand people over a few years, we should be able to see that they have health improvements or at the very least slowing down of the rate of diseases that occur."

"And there's a lot of questions about NAD that we're even coming before you mentioned it, and for those super fans of Khan Academy videos or anyone who has been paying attention in their freshman biology classes or their high school biology classes, you might recognize NAD from respiration and ATP synthesis. So is that a coincidence that, for those who don’t remember, it shows up all the time in the whole Krebs cycle? So explain, is there a connection?"

"Yeah, so NAD is this little molecule that the cells used to carry out about 400 or more enzymatic reactions. It’s one of the most boring molecules—or at least it was up until the 2000s—but what my colleagues and I realized was that NAD levels also controlled the body's survival networks. And the lower your NAD levels, we believe the lower your defenses are. And actually, as we get older—and certainly we know for sure in animals as they get older—they have less NAD, or you can boost your energy levels somewhat back up by doing exercise and skipping a meal maybe once a day. That is fairly well accepted, but you can't expect someone who's in a hospital or who's elderly or sick to go for a run easily, right, or skip meals. So what we need are potentially NAD boosters. This is a group of drugs that I'm working on intensively, and we’re hopeful that the same kind of things that we see in mice in the lab, some of them will happen in people."

"And you know, we'll probably know in the next year or two or maybe sooner with the COVID-19 study. But the kind of things we see when we raise NAD levels back up in old mice, there's a lot of studies way beyond what my lab has done, but some of the things that I know of from my lab are increased endurance. Some old mice run further, they have much better blood flow. Better blood flow in the brain as well, not just in their skeletal muscle. They're resistant to heart attacks. They have less inflammation. Their respiration, their mitochondria, gets revved up like a young animal would. So there are lots of benefits that we can see in mice. We have a longevity study that's in progress that's looking promising. Now, I can't say much more just yet because people in my lab will kill me, but you know, these are the kinds of things that hold promise that we can use some of these changes in animals to treat patients."

"And ultimately, if a drug gets on the market for a particular disease, my hope, my personal hope, is that now that drug can be tested in many different areas, or many different disease areas by doctors, and do their own clinical trials in their own particular area. And eventually, if everything goes well, we could have millions or tens of millions of people being treated with these drugs for not just diseases, but eventually we'll see that those people on the drug hopefully will be less prone to diseases and may even live longer."

"Yeah, there's a ton of questions here from Twitter. AZ Latina please ask Dr. Sinclair regarding the status of his research on NAD and neurodegenerative diseases. I don’t know if that's the research that your staff would kill you for talking about! Other people are talking about NAD infusions, and I'll give a disclaimer here, this is not a place to get any medical advice. This is not a lesson for any of that; this is just—we're having a conversation—please consult doctors, etc. Standard. And then there are people talking about other molecules which I know you have done research on, things like resveratrol or, you know, people who've done research on resveratrol… I can never say it. I know the molecule Pterostilbene. However, you know how to pronounce it better than I do. So I'll just group all of those..."

"I mean, once again, I don’t want to make any recommendations of what people should or shouldn’t do with their lives. People should do their own research. But I mean, you mentioned NAD, how does, I guess, if you could talk about what you know about NAD and neurodegenerative diseases, and also, you know, how do you change NAD levels in say a mouse or potentially in human beings?"

"Well, in mice, there are a couple of ways that NAD seems to work. It will raise the levels of or activity of a set of genes which we call sirtuins, and many of those have been shown to be neuroprotective again in mice. Now, you know, it’s easy to criticize these mouse studies, but you know, in defense, we have to start somewhere. But yeah, there's a lot of data from other labs, in particular a little bit from mine, that you'll get your protection in a variety of diseases, from Parkinson's to Alzheimer's. The second thing that happens, which I mentioned earlier, is that the mice get more blood flow in their brain, and we track that down to the lining of blood vessels actually becoming more useful and growing in a healthy way—not nothing dangerous that we can tell—and that makes me think that there might be a chance to use these so-called NAD-boosting molecules to treat vascular dementia, which is a very, you know, pernicious and common disease actually with not much you can do."

"So I think that there's a lot of reason to go and explore NAD boosters in neurodegenerative diseases. I haven't done any myself in humans; I'm aware that there are some studies. There was one in Parkinson's, and there's one, I believe it was also in ALS, which I know is not neurodegenerative central but peripheral. But yeah, I think that that's one area. The area that I particularly worked on are muscle wasting diseases and also immunity. And what is, how do you adjust the NAD levels in a mouse or human? Is it an injection? Is it a pill? Is it genetic G, or whatever, how do you do that?"

"Well, yeah, I have to be careful because I'm not prescribing anything. I'm just a PhD talking about science. But let's make that clear. But there are molecules you can give to a mouse. They’re called NAD precursors. These are the building blocks of NAD, and we know from mouse and some human studies that I've been involved in that they will raise NAD levels in the body. And the hope is that by doing that, we'll get those sirtuin defenses back up to where they used to be when you were young. So you can take pills; that’s sufficient. Some people do injections; I don’t know if they work or not, but I hear about them. But based on the literature, you know we're right on the cusp of learning what these NAD boosters are capable of doing in people, and many of them are natural molecules, so you know that piques people’s interest as well."

"Yeah, and there's that—you could imagine there's a lot of questions about this. Well, actually, there're some philosophical, there're some medical questions, so let's go the medical ones first! So, you know, Madonna Checotah from Facebook, she's 60 years old; she's saying, 'How many years before we see a cocktail of drugs that extend lives?' So obviously, you know, no one can predict the future, but you're really at the forefront of where this research is. What do you think things are going to look like in five or ten years? When do you think this is going to become very relevant to you know, the average person watching us right now?"

"There are—I lost estimate—20 companies who are either close to or running clinical trials that came out of aging research. I'm hopeful that one or more of them will be successful in the coming years. How long till we have a cocktail? It's probably more than that. You know the drug development, as I've learned in my career, is extremely tough and plenty of things can stop you, so I'm always a bit cautious about making predictions for the future. There are drugs actually that are on the market—one I mentioned, which is reclamation, which is not something you take lightly because it has some toxicity—but there's another one for example called metformin, which almost anybody who has type 2 or age-associated diabetes will know of. It's also called glucophage, which lowers, and tends to lower, blood sugar. It's one of the safer drugs that you can get anywhere, and it's also on the WHO's list of essential medicines for humanity."

"Why do I mention that? Because if you feed it to animals, they are healthier and can live longer. And also, in studies that have looked at tens of thousands of people on this drug, those people on average tend to be not just resistant or are doing better for type two diabetes but other diseases like cancer, heart disease, Alzheimer’s, needing frailty. It seems that those people on the drug actually have less chance than somebody who never takes the drug. So the reason I mentioned that is that there may be drugs already out there that are going to be part of a future cocktail that people can go on in their midlife, you know, under doctor's supervision to make sure it's all safe."

"But you know, I don’t think we're that far away in terms of the science; we're pretty much there. And I know, I know you’re not a futurist, but given your area of research, I’m sure people ask you questions. So I will ask you a little bit more about that, Wendy. I mean, do you think that in 30 years we could be talking about a human lifespan that is appreciably longer? Five, ten, fifteen years longer?"

"You might be surprised if there wasn't! Again, you know, we live in a time where the average lifespan is going down, so that's tragic and difficult. But in 30 years, when we're over this current crisis, and this research that I'm talking about and new areas that are emerging have blossomed and give nice medicines, yeah, I think five years is not that challenging. Making it to fifty years is, you know, another fifty is much harder, but there are some new technologies that are exciting that are complementary to this NAD work. There's a way to delete old cells and harmful cells in the body; these are called senescent cells. There are some human trials that look promising out of Mayo Clinic, for example."

"And how do they do that? How do you delete the senescent cells? I've read about the issue with senescent cells, and I know things like fasting can help with the autophagy, but how do you do that in a trial?"

"Well, scientists have looked for molecules that either singly or typically in combination will kill those senescent cells but not hurt the natural or healthy cells. The problem is that those senescent cells are just stuck in a zombie-like state, and you need to trigger their death process. So that's what those molecules do. When you do that in a mouse at least, there are a lot healthier, and you don’t need a lot of senescent cells to cause havoc. Jim Kirkland from Mayo Clinic put just a dab of senescent cells into a mouse, and it had more signs of aging. So that's one way. The other area that's of interest is actual reprogramming of the body to be young again—not just slowing down aging but literally turning back the clock of the body."

"And the reason I bring up that one in particular, beside that we work on it, is that that to me is a game changer. If that works and it's safe in humans, you could potentially roll back the clock a decade in the body. And what does that mean? Is that— I know decades ago people talked a lot about telomeres, which are kind of those, what we thought were nonsense DNA at the end of chromosomes. What mechanisms are you talking about when you talk about actually turning back the clock?"

"Yeah, so I wrote a book about this. If anyone wants to follow what I'm talking about, essentially it's the idea that I have a copy at all right there! Yeah, so this was 20 years of my thinking all rolled into one book. The idea, besides tips on how to live longer, is that aging is primarily a loss of information in the body, and that our old cells just lose the ability to read the right genes at the right time. And we've known this occurs, but very few people have thought that that's what's driving all these other problems. So we've done experiments in my lab, some of which we're about to publish, which say that you can cause aging to go forwards by disrupting that information. And then we can also reprogram cells to get that information back again, and that's the BET’s of game-changer."

"How is it possible to restore the age of a cell? Isn’t that information gone forever? If you break a compact disc or a DVD, how are you possibly going to put that back together?"

"But what we're seeing in the lab is that if you just turn on some very specific genes that are normally only on when you're very, very young—in the womb—the cells have the ability to reset their age—not back to zero but far enough that the cells now are behaving like they're young again. And literally, when you measure their age—and we have a way of doing that now—there's a clock we can measure—they are literally young again! I mean, that is, to put it lightly, mind-blowing."

"And I know like you, you want to speak about it in very tempered ways because it leads to very big possibilities or questions—many of which people have been asking on social media. You know, let's put our science fiction hat on. Let's say that that works—that you know, in 10-15 years there are therapies that go along the lines that you are saying. I think I'm almost afraid to say what it could imply because people would think that I'm dreaming! But in a world where you could, I mean, I guess, you know, keep someone who is 90 years old looking like a 30-year-old type of sin, and then therefore could live much, much longer, you know, there are all these philosophical questions people ask about, you know, from YouTube the best speaker says if nobody aged, what will happen to the earth? Will we have to build more land? Samara from Facebook is saying, 'I would be so worried about medication that increases longevity; we'd be tampering with the circle of life.' What I'm sure you get a lot of that. What how do you view it? What do you think this creates problems, or does this create solutions, or we don’t know?!"

"Well, yet the last part of my book talks about this—about the good and the bad that may come of this. Now, the good I think is to me obvious. We're hoping to do our first clinical trial in under two years from now to turn back the age of the eye. In my suit, it's pretty easy. We can turn back the age of an old eye in a mouse and restore its vision. We can treat glaucomatous pressure in the eye. We can create even optic nerve damage. So there are parts of the body that I think it will initially benefit, and if it's your sister or your child or your parent who’s been injured or has a disease, I think you'd be hard-pressed to say, 'Oh, don’t give them a medicine; it's the circle of life. Let them suffer.' You know, that’s the easy part."

"But if you want to, you know, get into the ethics, if we really are able to turn back the clock 10, 20, 30 years in people? What does the world look like? And that's a very important question. So some of the work that I've been doing is with economists to see what happens as you know people live longer. The important thing about the economy, I should mention, is that when people are old and sick, it's a huge drain. You know, in the U.S., we're spending 17 percent of GDP on healthcare, and that's mostly because of the elderly."

"If older people are still productive and healthy and then die fairly rapidly, that’s a massive saving in the trillions of dollars. So for the U.S., within even just the first decade, the global economy would thrive. So that, economically, it’s not going to be the big issue that you might think. And actually also you mentioned the population; if you do the numbers, I'm sure... if we—if nobody ever dies that’s a problem and I wouldn’t even say that’s something we’re trying to do. But am I trying to give people more health and prevent suffering? Absolutely! And actually, even if we stopped anyone dying today, the rate of population growth would be less than immigration in the U.S., so it’s not going to ruin the world anytime soon. We have bigger problems to worry about than that. And I think by saving these trillions of dollars, that’s money that can be put towards solving the, you know, the problems that we really need to solve right now in housing, unemployment, and climate change."

"Right! And you mentioned in the book that, you know, the kind of crowding issue is much more of a, not only just lifespan, but there’s reproduction. And there’s a good argument that is people become wealthier and more productive and more economically productive. Those are the countries that are actually having shrinking populations. And so, so ya know—they're—it's fascinating! What is your—"

"Well, I’m sure people—I don't know if you mind me saying this. For those who don’t know, my wife and I—my wife, O’Mame, and I met David at a conference a couple of years ago, and I had been following his work for a long time, so I was very excited to meet him! We started chatting, and we were—and I know this is kind of a flip dimension of all of this—you’re a serious researcher, but you're clearly doing something right. Anyone looking at this screen right now would assume that I'm like 10 years older than you, but I think you're ten years older than me! Eighty-one, but I haven’t shaved in a while, and I haven't had a haircut in a while. But thank you for saying that! Yeah, I mean, we’ll see. I think the proof is in the pudding, and I’m trying to live the life that I think is the healthiest as a role model."

"You know, if I didn’t do what I'm telling all this to do, it’d be hypocritical. So I try to exercise; I try to eat well. I try to— If I can skip breakfast and even have a late lunch, my father does something very similar. And you know, we’ll see. Neither of us is sick at all. My father is eighty, close to81, and is as vibrant as ever! I think he’s even stronger than me last time we checked. But you know, I’m not trying to prove anything; I’m not worried about myself. I’m just curious to see what happens, and I’m measuring things in myself to try and gain insights into what works and what doesn't."

"And this is a look—yeah, I’ll give the same disclaimer I’ve given several times; you know neither of us are doctors, neither of us are trying to give advice or sell pharmaceuticals, etc. But I am curious. I mean you mentioned you do a few things actually and we have that in common. I also do intermittent fasting; I, you know, as we speak I haven’t eaten for about 20 hours. So, you know, I do that. I’ve actually recently become pescetarian; I like fish a lot, so that's taking a little bit harder to let go of. And so I try to do a lot of these things than you’re right! Regardless of what it does to lifespan, I just feel better; I feel healthier! I have much more mental clarity during the day and actually in a fasted state. Once again, not medical advice! Don't do it while you're growing kids! But when you're an adult, you can think about it, read the research, decide for yourself what other things do you—I mean, or at least would you recommend people research and make a decision for themselves? If it makes sense? Or, you know, other people in the field think, 'Yeah, this is probably a good idea; it might make sense.'"

"Well, yeah! Exercise is the other thing besides eating less. And again, you know, we’re not talking about malnutrition or starvation. No, you need a healthy diet, and you can make up for it with your other meals. But what we find in animals and in humans is that being hungry for a little part of the day turns on these defenses! But exercise—let's turn to that! So right in front of me, no, you can't see this, anybody—but I have a gym which is attached to my bedroom. You know, I'm sure that's hard for you to have a gym attached to your bedroom."

"I do! I sure you took more often, but yeah, I do! I really try to work out! I've got a treadmill, I've got weights, and looking at my father, he’s been doing this for many more years than I have. It’s essential for helping in your old age. And it’s not just about maintaining your muscle mass, which of course you lose that as you get older. It’s also flexibility! So if you fall over, you'll bounce! And you also—you know, you won’t tear anything, and that's just as important. So keep that flexibility, keep the muscle strength up! But also, if you exercise just for—it’s been shown just for 10 minutes a day, lose your breath—that’ll also activate these longevity pathways, these genes that I talked about."

"And so it doesn’t take that much. You don't need to be a marathon runner to get a lot of the benefits. We’re talking about—and I've read about that as well. And actually, a lot of trainers these days advocate with these high-intensity training. What you just said was interesting: you said, 'Lose your breath,' that’s kind of what you see is one of the key factors there. Is there some evidence that when you get winded, that that stimulates some of these pathways?"

"Right, that seems to be the case. Just walking will be good for you! But yeah, if you can just get hypoxia going—the lack of oxygen—then you stimulate all sorts of things like boosting those energy-producing mitochondria, and it's borne out in studies of people—particularly elderly people get studied. You know, there's a great place down at the University of Florida where they test what’s good for older people, and it is very clear that losing your breath is the best thing. I don’t find it pleasant losing my breath; you know, some people do, but I'm not in that camp. So I push sleds when I’m at the gym, and I try to run a little bit, and that—that’s the least you should do actually."

"And just find these conversations! I'm sorry; we're already over time! But I have one last question, because obviously we're having this conversation about health and aging in a time where there's a global pandemic. And you touched on it a little bit that, you know, molecules like NAD might have a benefit in COVID. And COVID is an example that has clear age correlations where, as far as I know, there's zero or a handful of cases of children being seriously sick from COVID, and the risks just go up exponentially as you get older. What do you understand? You know, how much have you directly studied COVID? What do you understand about why do you think it has such a strong age correlation? Essentially kids don’t get it, or they get it but they don’t have any of the real bad symptoms?"

"So I wrote a review on this which I think is fairly available to anybody. So if you Google my name, you should be able to read about it. There are lots of explanations or potential explanations; I don’t think anybody really knows. There’s everything from changes to how proteins are modified through to exhaustion of our immune system as we get older. Even having lots of viral infections during our lifetime can exhaust that part. A possible explanation does include NAD, and you know, a lot of people, you know, probably roll their eyes, you know, 'Can Sinclair talk about anything else?' But during the beginning of the pandemic, I resisted really trying to figure out if NAD happened to roll. But more and more evidence came up."

"So we've had a study in my lab for the last few years that shows that NAD depletion occurs when—or lack of NAD occurs—when there’s an infection, you know? That’s one bit of evidence. But then there was another study Charlie Brenner, professor, showed that patient samples actually have low NAD if they have bad COVID infections, and then there are some are case studies coming out of Cedars-Sinai Hospital. Patients that did remarkably well were given an NAD booster cocktail."

"So all of that led me to look more into it, and it turns out, but my lab and now our Charlie's lab was also shown that the virus is depleting NAD in the body. It does that for reasons we're not really sure but it might be part of the pathogenesis, as we call it, part of the problem that the virus causes. The hope—and we're testing this now, and hopefully soon in patients—is that by getting that NAD depletion back up to normal, elderly people will have the energy and the immune system to be able to fight the virus."

"And there's another thing that’s interesting, is that hyper inflammation where these severe cases actually succumb to over-inflammation, the cytokine storm that we know. If you have less NAD, you get this hyper activation. So that's another possible way that NAD boosting could actually help people with a very extreme late-stage form of COVID-19."

"So that’s interesting. There’s this—because you know, when you see the cytokine storm, as you mentioned, that’s for the—you know, when inflammation—that’s your immune system is kind of going in attacking a bunch of stuff. Cytokines are our cells and you’re in your immune system and that’s one of the causes of severe illness or even death of COVID. It’s actually because of her—it's correlated with when people have low NAD, they're more likely to have a cytokine storm. That seems counterintuitive because I was associated NAD with ATP production and metabolism but that you can be overactive? Is my intuition off, or...?"

"Well, the critical determinant of this is called the inflammasome, and there's a protein called NLRP3. A couple of labs have shown that the NAD levels directly control the activity of that protein, and that if you don’t have enough NAD, that inflammasome complex goes berserk. And then, you know, one thing leads to another and you can switch it off. So it hasn’t been proven in humans, of course, but in cells and in mice, it has been shown that low NAD in those older animals leads to this hyperactivation."

"Wow! Wow! Well, I could, as you know, I—you probably had trouble getting away from me when I met you a couple of years ago! We could talk for hours, but we’re already well over the scheduled time. But thank you so much, David, for joining and having this conversation, which I clearly am deeply intrigued by!"

"Well, Sal, it's great to see you again, and thanks for having me on!"

"Yeah, well, thanks everyone for joining today! As always, fascinating conversation! I wasn't joking when I said I've called David's work for many decades and have his book right over there! I recommend folks to take a look at it if you've been intrigued by this conversation! It's called Lifespan. But I look forward to seeing you, and I think—is it day after tomorrow or tomorrow? Let me see, I have it on the—Oh, there you go, tomorrow, Felipe's all right there for me! So I'll be tomorrow with an Ask Me Anything, and then on Thursday, we're gonna have Jacqueline Fuller, the vice president and president—vice president—vice president of Google and president of google.org to talk about all of the work they do around the world, including some of which is actually helping us do our work at Khan Academy. So thanks everyone for joining, and I will see you tomorrow and then on Thursday!"