Dr. Sinclair is an advisor to Levels. He is currently the professor of genetics and the co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School. He’s the author of the book Lifespan and was noted as one of Time Magazine’s 100 most influential people in the world.
Dr. Sinclair recently joined the Levels community on a video call for the Levels book club to answer questions inspired by Lifespan. Levels co-founder and chief medical officer Dr. Casey Means began with a few questions and then turned it over to Levels members. The following is an edited version of that session.
On shifting perspectives on death and aging
Dr. Sinclair: There are those who think about death a lot and those who don’t. I’ve met a lot of people who don’t get excitement out of life because they think about death; they get excitement out of life because they love life, and I’m one of those people. I don’t care if I’m going to live a hundred or a thousand or a million years; every day is exciting and new, and I just want to learn more and do more. There is a group—I would say, it’s more than half of people—that is not excited about life because they know they’re going to die. The other thing I would say is, I’ve been alive now for 52 years, which went by super quickly. That’s like a blink of an eye.
What would a hundred years be like? Well, it’d be two blinks. So what would be a thousand years? If we could live that long, that’d be 20 blinks of an eye, It’s still really short. Absent immortality, which I don’t believe will have any time within the next few thousand years, we’re all going to die, and I think we’re going to be just as excited about life. I mean, if you all thought you were going to live for a thousand years, would you be bored? Would you not show up to this? Would you not be listening to me? I don’t think so, I think we take every day as it comes and try to do our best, most of us do.
Imagine if I said to you, let’s all die at 40, like many of us used to. Would that make your life better? Because we can go back to those days if you want, we can take away antibiotics and vaccines and sanitation. Is life better then? I would guess that it would not be, and none of us, I don’t think, would want to go back 200 years and live [without] those medicines. If you extrapolate that the longer we live [and the healthier we are], it actually makes life better, and you want to live longer because the future looks even brighter.
Dr. Casey Means: That’s a beautiful way of putting it. It’s interesting hearing testaments of people in the Johns Hopkins studies and similar, who have done some of these very deep existential experiences that really relieved a lot of their anxiety around death. They don’t end up having this sort of fatalism where they say, “Oh, well, I’m fine with dying, and so I’m not going to try and live it.” It almost seems like the opposite, where being in awe of the cosmic journey makes people even more excited or in awe of the existence that we have here.
Dr. Sinclair: One other thing is that we tend to think that old age is going to be horrible—God forbid that we become old like that. When I say, “We can make people live longer,” people generally immediately jump to that image that I’m going to spend more time in a nursing home and be sick and depressed and suffer. It’s in fact, again, the opposite. By doing what Levels is doing for people and what I do, it’s about keeping people younger for longer, so that in your eighties and nineties, you can still be productive and have a life like you had when you were forty. My father’s 82. He lives life differently now than he did when he was in his thirties and forties—in fact, in some ways, many times better. It’s all about extending youth, not extending old age.
When I tell people that, they typically go from, “I don’t want to live beyond a hundred” to “I’ll keep living, I don’t have a real limit.” It turns out if you’re healthy and happy—let’s say you’ve got friends, you’ve got your health, you’ve got productivity, you’re doing something that you enjoy, it can be community service, whatever—nobody wants to die. I mean, can you imagine that you wake up one day, you’ve turned 80 and suddenly you’d say, “Okay, I want to die”? No, people want to die because they’re sick, they’re depressed, they don’t have any meaning in their lives, they’re lonely. We’re trying to make people avoid that.
On longevity treatment for youth
Dr. Casey Means: We have this epidemic of children who have severe metabolic disease, fatty liver disease, obesity, even Type 2 diabetes, atherosclerosis at young ages, presumably all from diet and lifestyle. Despite being young, we’re still seeing this morbidity. How do you think about the limits of longevity and aging treatments, given that the bodies that these future therapies are going into are highly dysfunctional, for the most part, due to our food and lifestyle norms in the US?
Dr. Sinclair: It is a tragedy that kids are being overfed and fed the wrong foods, largely due to marketing, and largely due to the saying that the biggest and most important meal of the day should be breakfast, which I don’t necessarily agree with. It sets kids up for a bad epigenetic clock and bad epigenetics for the rest of their life. We know that the clock is ticking from conception, and in fact, it goes very rapidly when you’re young and then becomes linear. What that means is that, if you say “It’s just puppy fat, Jimmy will lose it when he turns 18,” even if Jimmy does, it’s done permanent damage to the epigenome, and five, six, seven decades later, Jimmy’s body will feel it.
That’s something that most people don’t understand and most parents don’t get. I’m looking to write a book about that, about using these technologies earlier. Of course, not [to address] malnutrition or starvation, nothing like that. But the damage is not just temporary. That said, [with] these longevity treatments—let’s take the NAD boosters that we work on—when you slow down aging, you also improve metabolism and you tend to lose weight. In animal studies, and we’ll know in humans hopefully sometime within the next 12 months, you tend to lose weight as well. metformin does this for a variety of reasons, and it’s thought to be a longevity drug. What I think we can do for people is—not just for kids, but even when they’re older and for older obese people as well—we can give them added years but also improve their metabolism because they go hand in hand.
In the case of resveratrol, which is the old story from red wine, we were able to protect mice from a high-fat diet, even though they were still obese. There are ways to actually prevent some of the inflammation and damage that’s caused by obesity. But it’s far better to have a healthy diet, eat less often, and combine it with the interventions because there we find the biggest bang for the buck. In the case of the mouse study, when we gave resveratrol and food every other day, that’s when we got the extreme lifespan extension. But yeah, I’m with you. I really feel bad about what’s happening to the kids, and I would love to be able to help them all.
On the importance of continuously tracking personal health data
Dr. Sinclair: I helped start InsideTracker about 12 years ago. At the time, it was considered crazy that you would measure your body. That’s something that you do every year with your doctor. Now we know that’s a very medieval way of thinking and things change month to month, if not day to day, and you cannot optimize what you don’t measure. That’s why Levels is super important on a key parameter. Continuous is the way it has to go because measuring yourself three, four times a year is okay, but it’s not allowing you to change your lifestyle and see what happens with immediate feedback. Whereas, of course, I’ve got my levels monitored, and I do that every day. The future has to be like that.
The idea that you go to your doctor once a year is really quite scary, and very soon will certainly seem medieval. Not only that, what I find is that my doctor wants to have the data, but the insurance company won’t let him pay for it. When I show him my data, whether it’s the glucose or the InsideTracker, he loves it. There’s this unwillingness of insurance companies to pay, which I’m sure you’re thinking about. But yeah, if humanity doesn’t go in that direction, then we’re going to continue to fly in the dark, and we don’t know what’s working and what isn’t. It is really bad that for 99.9% of people, they might try a diet, they might try exercise, they might change other aspects of their lifestyle, take a supplement that they buy off the web with no real guarantee, and they have no idea if it’s damaging a liver, if it’s working, or if it’s contaminated. The only way to know that is to measure things.
On his own health dashboard
Dr. Sinclair: I still use InsideTracker and I just posted on Instagram and I think I broke the record at the company. They saw my post and they said, “Holy crap, you’re a decade younger”—more than a decade actually, so that was pretty cool. So, what have I done to achieve this? Well, it is in the book, and I think most of you have read it, but I have changed some things since 2019. What I’ve added are acid, I’m taking some spermidine now, a gram a day, and some senolytics—fisetin and quercetin—[which] we discovered back in 2003 were lifespan-extending molecules. Those appear to not just activate cells, like resveratrol does, but also kill off senescent cells at high doses.
I’m also monitoring myself epigenetically, to see if I’m actually reversing my epigenetic age, which you know from my book is one number that’s very important. I am going backward according to a number of those clocks, so that’s good news that you can send your age backward, not just slow it down. But actually, the biggest change since 2019 is my food intake. I have cut myself back to one and a half meals a day: a very small lunch; a snack, maybe late in the day; and then a healthy, regular dinner.
I’m a struggling vegan at the moment. I don’t eat meat, but occasionally I’ll take a slice of cheese or an oyster or something. Generally, I’m plant-based, and I’ve been doing that only for three months. One of my inspirations, and I think some of you have heard of her, is Serena, who I met a few months ago, and she’s been inspiring me with facts and knowledge. I’ve done that, and I’ve cut out alcohol to see what happens. There are social occasions where I miss it, and I think that you don’t have to cut it out, but I’m doing an experiment. That’s my life now, I’ve lost a fair amount of weight. I used to be 149 pounds, 150 at max, and I’m now 132, and I feel great. I look great. I have a lot better energy. My glucose levels, instead of doing this [gestures], are now stable through the day. I’ve gone down in age by a few years since I’ve started on this diet. I miss meat. I wish meat extended lifespan. I would eat meat all the time, but the data just says that’s not going to help. You will feel great in the short run.
There are a lot of carnivores who tell me I don’t know what I’m talking about because they feel great. If you feel great, that must mean it’s good for you. Well, that’s not true. What you have to think about is that there are two states of the body. Well, there are three. There’s homeostasis, and then there’s either adversity or abundance. Abundance will make you feel energetic and grow your body. So, make more muscle.
Then there are the adversity signals, which the supplements in my lifestyle are aimed at mimicking. You still have the energy because your body adjusts, but your body fights against aging because it’s worried that it might die in a couple of weeks’ time. That’s what fasting and exercise and the supplements and cold and heat are designed to do: get the body to be afraid of dying in the near future.
On the future of evidence-based medicine
Dr. Casey Means: Given the new era of personal tracking and monitoring, what is your model for thinking about future validation of therapies? What do you think the future should look like, in terms of the process for validating and regulating new therapies?
Dr. Sinclair: I don’t see the FDA changing in a hurry. That’s not where the innovation is going to come from. As much as they say they’d like to speed the process up, it’s still a few hundred million dollars per drug, at a minimum, because of all of the regulations, which are of course in place for good reason. There have been some terrible historical events where a drug has killed people. We don’t want that to ever happen again. But at the other end of the spectrum, we have a hundred thousand people dying every day from age-related diseases, that I think could be tackled, if we had better ways of getting drugs on the market that were more efficient. By more efficient, I mean less costly. It’s so expensive to make a drug. That’s the problem.
Sometimes people say, Dave, why don’t you just stick to your lab? Why do you have to start these companies? Well, that would be great if I could get 500 million dollars in my lab and run a clinical trial, but I just can’t and get a drug on the market. If I’m going to make drugs, I have to go out of the academic circuit. But I think we now live in an era where we are able to take our health into our own hands and see what works for us and what doesn’t, both as individuals buying products that are legal and available online or in shops. Of course, that’s a nutraceutical area. There are some cosmetics that are active as well. Then when you get into pharmaceuticals or regulated molecules, you can work with your doctor, such as it becoming more standard to ask your doctor for metformin before you have Type two diabetes. Those two models will continue to play out.
But the biggest innovation is going to be—at least until the FDA declares aging a true disease, which hopefully will happen in the next five to 10 years—is that people can look at what works for them. When the traditional medical establishment says we have to wait until it’s proven in a clinical trial, I would push back and I would say, nothing is proven in biology. Until you take it, we don’t know what’s going to happen. All drugs are unsafe, in fact. While it may be safe in a thousand people, there’s going to be one, and it could be you, that reacts badly. It’s all about individual personalized medicine at this point. But to do that, you need to measure things and be very careful about what you choose to put into your body and who’s supervising you.
My approach has been, and I think this is the one that is becoming more popular, is to only change one thing at a time. Then take a reading and see what happens to your body. Do things get worse? Do they get better? Is your liver okay? Are your kidneys functioning okay? Is that product from that company okay? If it is, keep taking that and try something else. My regime, it wasn’t just made up yesterday. It’s taken over a decade to get to this point, even with the particular brands that I take. It’s not perfect, but it is all we have right now. We have to work within the law and technology. But I’m not one of those people that says, I’m going to wait another 20 years until it’s proven, because first of all, there’s going to be a lot of people who die tomorrow.
Second of all, I’m probably going to be fairly sick at that point. My father will be dead for sure if we don’t do something. It’s like people say, “I don’t know what’s going to happen if I take supplement X.” Okay, never mind the fact that it’s already been taken by a hundred thousand people for the last five years, that it’s been in clinical trials. It’s been in animals for years. There are still some people that say I need proof. But let’s face it, if you wait for that proof, it’s going to be too late for most people.
I think [it’s important to choose] molecules and vendors are very high quality and see what happens. You can escalate the dose carefully. That’s what’s done in clinical trials. I think that’s the way to go. That’s far better than taking a handful of pills and never measuring anything. You could really be doing yourself some harm. But I would say what’s important is, first of all, I’m not a physician, I don’t recommend anything. But you do want to tell your physician that you’ve taken these molecules so that they can make sure that if anything bad happens, they know what to do about it.
Dr. Casey Means: I’m certainly excited for a future world that bridges [this] with the standard way that we validate things through randomized control trials. What does that look like when all of the participants are wearing lots of monitoring technology and they’re totally hooked up? We start to be able to sub-stratify within these populations.
Dr. Sinclair: A hundred percent. If you have a million people hooked up with biomonitors, you’re going to learn within a matter of months what works and what doesn’t. You can have doctors who agree to do a trial off-label to see if a drug works or a supplement with a manufacturer that guarantees that it’s pure and the amount in the capsule is what you say. But a hundred percent that’s the way it needs to go. It’s just been slow. Fifteen years ago, I tried to do this and it’s just hard. I think the main barrier is that we don’t have good monitoring and we don’t want to just use questionnaires. Levels is the company that can do that for the population and not just help with an N-of-1.
On widespread adoption of continuous tracking technology
Dr. Casey Means: If one insurance company starts using some of this tracking stuff and realizes that it’s helping make people healthier, and costs are cut, it’s going to just be inevitable that the others [think], “We should get on board with this. We can have cost savings.” How do you see the domino effect happening, from direct to consumer into the system? Semi-relatedly, what are you seeing right now in your world that is most exciting and promising, in terms of biological observability?
Dr. Sinclair: The other areas are, obviously, these external biomonitors, and those are advancing really rapidly. There’s one company called BioIntelliSense. You may have spoken with them. I know the CEO well. They have made a couple of products. One’s a sticker on the chest. The other one is a double bigger sticker. They both do ECGs for the heart. They measure motion, coughing, breathing, and they have algorithms that are able to now, through machine learning, detect whether you have the flu or pneumonia or COVID. It was originally designed for the hearts. The other reason that they’re important to mention is that they’re FDA approved, and hospitals are starting to use them to send patients home early for monitoring.
That’ll just get better and better and better. There will be a point where doctors don’t just want to send people home with them but will send them a monitor to wear a couple of weeks before the annual checkup. At least they have some data to look at when they come in, rather than being blind. But where I see the tipping point is if a device can save a life. For instance, this bio sticker can predict a heart attack a week early, theoretically. Maybe it can, maybe can’t. Let’s say it can and someone dies from a heart attack, and a hospital did not provide it and it costs $20. Their family will sue the hospital and say, “For $20, you could have saved my father or mother’s life. Why didn’t you do it?” They’re going to get millions of dollars in compensation because their father is dead. From then on, of course, every patient will go home with a $20 monitor, because it’s too dangerous to risk somebody dying without it.
Dr. Casey Means: You can imagine a similar situation, even for something like a continuous glucose monitor. You can imagine people potentially developing diabetes down the road and saying to their doctor, “What the heck, you’re giving me a CGM now? This would’ve been really nice 15 years ago.” But we know how expensive it is for the healthcare system when someone has developed a chronic disease like diabetes, heart disease, et cetera. This is where I think some evidence in this space showing improved outcomes over time [when these are used] preventatively is going to, hopefully, move this forward even quicker.
On what happens when we eliminate aging as a disease
Tracy Stevens: If you talk about aging as a disease, as opposed to how we generally think of aging as the inevitable decline, what words do you use to describe advancing in years? In a future world where you can actually eliminate all of these negative physical aspects of aging, then what’s left? Is there an optimal chronological age that you would theoretically stay at forever?
Dr. Sinclair: There’s the chronological age and the biological age. Chronological age is simply the number of times the earth has gone around the sun. That’s hard to stop. That’s going to tick over no matter what we do. But the revelation and realization of scientists and revelation in the public is that our biological age is different from our chronological age and that we can change it backward and forwards. In my lab, we can drive aging forwards in a mouse and backward, at will. It’s easy. We have control over aging very precisely now. What does that mean? It means you can choose your own biological age. In the future, you can choose to be 30 and stay 30, choose to be 50, stay 50, but being 50 and biologically 40, which is basically what I am, doesn’t mean I have the wisdom of a 40-year-old. I have the wisdom of a 50-year-old. If you extrapolate, I could be a hundred, and still have a 40-year-old body and have the wisdom of a hundred years of living. That’s what’s exciting about me. You’ve got the biological clock you can control. Then the chronological age, in my view, just gets better and better with wisdom and experience. I don’t want to stick to any particular chronological age. I don’t mind that that advances, as long as my biological age is slow or even steady.
On making information about longevity accessible to the public
[Levels Head of Growth] Ben Grynol [paraphrasing April’s question]: Your book is very technical. How do you make this information more accessible and more digestible to people so that they can start to relay it back to the greater community?
Dr. Sinclair: The first comment is, I didn’t want to dumb it down, because I believe in the intelligence of humanity and that’s been borne out. It was not dumbed down and it still became a bestseller, which to me is just great news. I’m writing my second book. I’m not making it as technical, but I’m certainly not going to talk down to anybody. I am very pleased to hear that many people read multiple times and get more out of it every time. I still read it and get stuff out of it, believe it or not. That’s the good news. The way to reach more people is to get to the people who don’t read books. I don’t know what percentage of people read books. It’s at most, it’s got to be 10% at this point.
What about the rest of the people? You can reach them through podcasts, which I’ve been doing. I’ve recorded my own podcast, which is coming out in January, and you’ll hear me every episode reading an advertisement for Levels Health. I can recite for you all the good things about Levels and why I use it. Then I’m going to see if I can venture into more mass media without ruining my reputation. I haven’t decided yet how to do that, but it might be a documentary or some sort of series on TV. That’s really the only way to truly reach tens of millions of people, and that’s really the goal here. But people digest information differently, and we are all in the top 1% at measuring ourselves, reading a book about aging. There are still a lot more people to reach and we’ll just keep going down the various levels of medium.
I didn’t mention social media, but that’s probably the best way. That’s why I have built up a following on social media. Not because I care about the numbers and for my ego, it’s because it’s a platform to reach people that you normally wouldn’t be able to reach. That has been a real revolution in my ability and scientists’ ability to talk to the public directly. You know what it was like 10 years ago to be a scientist. It was a nightmare. We would talk to a newspaper. They would have an agenda. They’d write a stupid title, especially with aging. “Harvard researcher says we’re all going to live to 200.” It would just be embarrassing to my colleagues, to me. It’s different now. I barely ever talk to a newspaper. I talk directly to the public through social media and through podcasts. That’s the best way.
On his personal thought leaders
Lisa: Who is your H.G. Wells or Gene Roddenberry of the day? What are they saying? What are you finding intriguing or interesting?
Dr. Sinclair: My answer is going to shock some of you and for the rest of you, it’s going to disappoint you. I go around the world giving talks, and often I’m told you should read this book, or you should watch this movie, it’s exactly what you’re talking about. I went to the Pentagon many times and they said, ‘This is just like this movie.” My answer is I haven’t read the book and I haven’t seen the movie, but it sounds great.
The closest I’ve seen, probably, is Gattaca. But here’s the sad thing; I used to have a lot of time to read fiction and a lot of science fiction, but I don’t do that anymore. It’s probably because of time, but it’s also because I like imagining my own future. I’m very good at imagining things. I’d rather, to be honest, not be contaminated by other people’s visions of the future. I might get locked into something that is someone else’s idea. It’s the same for science. I like going to conferences. It’s great. But I try not to get distracted by too much other stuff and get locked into the dogma because dogma’s typically wrong and I’d rather be this free-flowing mind and just let it expand.
Usually, when I’m talking about the future it’s with people, guys like Brian Greene, and Lex Fridman, George Church who’s in my department. We talk and dream about the future together, and that’s my main inspiration. The rest is just what I dream up when I’m lying in bed at night, thinking about what the future would be like if it was a perfect world. Speaking of a perfect world, I got to chat with William Shatner last night, which was a real thrill for me because as a kid, I was inspired by that somewhat perfect world, and I still feel like we are aiming to get there. That may be what drives me each day, that knowledge that humans just can do better, and I just want us to get there as fast as possible.
On longevity and humanity’s impact on the world
Eva: You talked a bit about this in the second part of your book, [where you were] answering the question of, “If we live longer, what happens to our planet and can it sustain us, so many people at once?” It’ll be awesome to see your great-great-great-grandkids, but are we perpetuating the decline of our planet in that process as well?
Dr. Sinclair: I do think about this every day. Since I published the book, somebody said something that stuck in my mind, which I want to repeat. They said, “When you hear about the news for a cure for childhood leukemia, the reaction isn’t, ‘Oh, that’s going to ruin the planet with all these kids staying alive.’ Why do we have that reaction when we are trying to keep middle-aged and older people alive?” That’s one. The second thing is I’ve put some numbers where my mouth was, or my head was, and published a Nature Aging article on the cost savings of extending lifespan by a year or ten years in the US. The value to the economy over, say, 30 years after that discovery would be in the trillions of dollars.
The numbers are actually 86 trillion for a year and 365 for 10 years. Now that’s a lot of money that’s currently wasted on what I call “sick care,” not healthcare. That money can be put towards education or developing new technologies to treat or prevent climate change. That’s a lot of money. It really is all about the allocation of resources and money. Now humans can achieve anything, and they can either be making widgets or repairing crash cars or, I don’t know, pumping oil out of the ground. But if you have money to spend on other things, you can put people to work on really productive things, rather than things that are just currently perhaps too expensive. If we save this money, we can use that wisely.
In terms of population growth, a lot of people worry that we’re going to be overpopulated. The numbers just don’t pan out. We’re already, in most of the world, approaching levels of replacement. Actually, in the US and Europe, we’re actually declining. Japan’s already in that process. That’s a disaster for the economy if we don’t do something about it. Our kids and our grandkids are going to suffer badly economically if we don’t do something to keep people productive for longer. That’s what we’re talking about here today.
On taking NMN later in life
Dolf: I thought it was a really compelling story in the book and a bitter pill to swallow, and you talked about your dad and his experimentation with NMN (nicotinamide mononucleotide). When he told you that he was going to go down that road, what scared you about that?
Dr. Sinclair: If I was worried about it, I would advise him not to do it. All of the things that I do are based on the knowledge that it’s extremely, extremely unlikely that it’s going to do any harm. I typically take molecules that have been in the body already for millions of years. NMN has been in the body for billions of years. What we are doing by giving NMN is replacing what’s lost with age. Speaking just generally, tissues decline in their NAD production, NMN being a precursor, by about 50% by the time you’re my age. I can raise those back up. I actually know a lot more than the public thinks about the effects of NMN on the human body. I’ve been helping do clinical trials for about three years now.
We know its safety, to some extent; we know how much it raises NAD in the body, in which tissues, and we’ll even have some efficacy results to tell you about next year. In mice, it extends their lifespan, it appears. We’re doing more mice, but it looks really good, especially in females. It reduces obesity, improves lean mass, improves their metabolic flexibility, and delays their frailty, which is based on 20 measures of health including hearing and eyesight. Based on all of that, I’ve had no issue with my father choosing to take it. I couldn’t stop him. He’s a grown man; he’s a scientist himself. But I don’t have any concerns. There is something on the internet; unfortunately, like a lot of stuff on the internet, it’s just hype. It’s in the same realm as “metformin prevents you from building muscle.” This one is that NMN will make your cancer grow more.
It comes from a study from Washington University where they depleted NAD from brain cancer cells, and they grew slower. The PR department of Washington put out a press release saying NAD makes cancer cells grow. Well yeah, right. That’s kind of a misreading of the data, especially when you need NAD for life. Having less of it, of course, is going to make cancer cells grow slower, but giving them more doesn’t seem to do that in our hands. We’ve tested it in a couple of cancer models.
In an abundance of caution, if you had a tumor, I wouldn’t take NMNs because we don’t know. But if you’re healthy right now, there’s no evidence that it should have any negative side effects. The biggest side effect that we’ve seen anecdotally is in perimenopausal women. It might improve the health of the ovaries and put out more hormones. They tend to have shorter menstrual cycles and heavier ones. That’s consistent with our mice studies showing you can reverse infertility in old mice. But other than that, I don’t know of any downsides of taking NMN. We haven’t seen anything in the clinical trials either.
On extending lifespan and mental health
Maria: I have a brother with severe mental health challenges and daily life is really a struggle for him. In all of your research or thinking about this, it’s really exciting when you’re really healthy and you have everything going for you, but if daily life is a struggle in that respect—it’s probably environmental, probably—what are your thoughts in that area?
Dr. Sinclair: We talk a lot about aging, but actually what we’ve discovered are the body’s defenses against disease. That’s not just age-related diseases. It can be applied to enhance the resilience and defenses of the body. Even in children, NMN or at least a version of NMN is being tested now in a disease called Friedreich ataxia as part of a company that I started out of my lab, and that’s just an example. That disease affects kids in their teens through to their thirties. They end up in wheelchairs.
What gives me hope is that these molecules should be able to help people of any age with potentially, I wouldn’t say any disability, but it’s pretty broad from reducing inflammation. We’ve seen results in humans already. We see improvements in blood-brain flow in animals, and we’re testing this in people now. Perhaps even our changes in mood. We see some evidence that it improves our positivity as well. But yeah, I would say that we talk a lot about helping healthy people stay healthier, but that’s really just one part of what we’re hoping to do with the science.
On ethnicity in lifespan longevity research
Dr. Sinclair: We’re still in the dark ages there. As a field, we’ve only just started using females in our studies, let alone people from different races. We live in a time where that’s very much in the forefront of our conversations, but because it takes a while to get results from clinical trials, we’re still in the dark about that. Now I’d be surprised if there are no ethnic differences, racial differences in mice, even inbred strains of mice have different effects when it comes to calorie restrictions. Some calorie restriction protocols will hurt certain strains of mice and others will live longer.
Until we have the data on the effects of different ethnicities, it’s even more important that individuals measure them themselves to make sure that what works for a white male will also work for an African American female, for example. We also look at data typically at Levels and at InsideTracker, from the wealthier part of society, and they skew ethnically as well. So there’s a whole other group of people that are not typically being equally measured. My goal would be hopefully yours too, to democratize this and get it out to everybody as fast as we can and as cheap as we can.
On rapidly evolving research
Ben [paraphrasing Tina’s question]: Is there anything that you wrote in the book that your outlook has drastically changed on just because research is evolving so quickly?
Dr. Sinclair: The good news is that the basic scientific principles, if anything, are much stronger than in 2019. Many of you will have seen that the field of epigenetic reprogramming and age reversal, since our paper came out in nature a year ago, has exploded, with the likes of Jeff Bezos and Brian Cunningham from Coinbase getting involved with lots of money. There’s been at least 20 billion invested since our paper came out. I can’t take credit for it all, [though] that certainly didn’t hurt. That’s been a big change since the book, but the fundamental science is the same. That’s great because I wrote the book when epigenetics and aging were not even on the radar for most people.
That’s held up. The interesting thing though was that the science that’s in the book was, was written and published in the book before the scientific paper came out in Nature, which I think doesn’t happen very often. Luckily, I didn’t get destroyed there by my colleagues for doing that—talk about scooping yourself. But if you ask me what’s the big change, well, I predicted that there was going to be a pandemic at the end of 2019. Three months later, it came out, or four months later. I wish I was wrong about that. My thinking about that was that this was going to be some time in the future. Maybe 10 years. I was wrong, it came months later.
Actually, I think I was too conservative. I didn’t realize that the amount of attention on money would come into this field, and you can achieve a lot with $20 billion. That’s like putting the whole NIH on one topic. I think my timelines might have been out. I thought I was already optimistic. Matt LaPlante was pushing me to be super optimistic and I did, but I really think that it’s possible now that we will be able to reset many parts of our bodies within our lifetime.
I think I’m much more optimistic. I now believe that with this infusion of research dollars and the development of drugs, that’s going to happen. We might within the next 10 years have the ability to reverse the age of certain organs. Perhaps within 20 years, the whole body. Already there are people, doctors, that are claiming to have sent their age back by 10 years, based on the blood methylation clock. I’ve seen it in myself that I’ve gone back, according to those clocks, by at least a couple of years. That’s all you need to do every year to have a big effect on lifespan.
On telomere length and aging
Dr. Sinclair: Telomeres were the old way of measuring aging, and they’re still somewhat relevant. Some aspects of aging do seem to be important for the health of the body, the immune system, and the liver, but what the scientific field has found is that telomeres actually do grow and shrink. You can lengthen them. They do bounce around a lot more than the epigenome does. I think ultimately if we’re going to live for hundreds of years, we have to address telomere length. But I think that the best path to this is to work out how to reprogram the epigenome and that’ll actually take care of things. We find that we can regrow telomeres.
When we reprogram cells to get younger, the telomeres will grow longer. The gene expression gets set back to 80% of what it was or at least 80% of age. There are some drugs and some supplements that are in clinical trials that look somewhat promising as well. I know that that’s not a perfect single binary answer, but the summary would be that we have to address those at some point. I think that what we’re working on in the reprogramming space can take care of that and the other eight hallmarks of aging.
On researching aging after it’s designated as a disease
[Levels Head of Research and Development] Taylor Sittler: Let’s zoom ahead a couple of years. Medical societies and the FDA are finally accepting that aging is a disease. We now have that designation. Now we need to establish what the biomarkers are. Then we need to have diagnostics and therapeutics that are going to be given over that course. What’s the process?
Dr. Sinclair: I can think of at least a few stages. The first stage is what we’re doing now, which is n-of-1 studies showing, at least in some individuals, that with your own self as your negative control starting point, measuring blood biomarkers including glucose, but also and including epigenetic age and telomere length, that’s still part of the determinant of your ultimate longevity. Learn that way very quickly. Already in the last year, we’ve seen some successes. We’ve actually seen some published papers where changing lifestyle, Mediterranean diet, exercise and supplements, [are] seemingly reversing—[or] slowing, if not reversing—age. That’s stage one. That’s self-experimentation or a small clinical trial with each person being their own control. The next stage would be to have hundreds. Perhaps millions of people who are being monitored and then you give them intervention A and no intervention, or [have] a group that has no intervention.
Then you can learn that way from lots of people. That would be done perhaps in [or] by the public rather than in a hospital setting. That would be a lot quicker and cheaper, of course. Then the third way would be the traditional way, but that’s expensive. A trial would be 30 to 50 million, but the standard way would be a double-blind, placebo-controlled intervention. People come into the hospital, get measured, and you have to do multiple hospitals and run it for four or five years and have a look at their frailty and, of course, all the biomarkers that we’d want to measure in the previous studies I mentioned. Then if you do enough people, you can actually also do lifespan, but that’s a lot of people. That’s thousands of people over age 70, that you’ll need to do that. But at a minimum, through all of those three steps, we’ll have a good idea as to whether aging can be slowed in humans.
Will it be proof that you can extend lifespan? No, there you really need a lot of people and done under double-blind placebo controls, which is tough, right? If you’re doing it for a decade, it’s not easy. That would be stage four, but I think we’ll get there in our lifetimes. We’ll be able to say that this molecule extends lifespan. In the meantime, we are relying on these epidemiological studies, such as metformin, where tens of thousands of people have been looked at and Type 2 diabetics live longer on metformin than people who don’t even have Type 2 diabetes and don’t take the drug. Which is an astounding observation, but the real proof, if you want to call it proof, has to come from prospective studies, not retrospective.
Taylor Sittler: I think there comes a point in time with many diseases where biomarkers can be synonymous with the progression of the diseases. Like you were saying, it’s very difficult to get to the point where we could definitively show that we’re improving lifespan, right? How long do you think it will be before we can take certain biomarkers of aging, e.g., the epigenetic clocks that you’re doing, and have enough confidence that those will actually be reducing or extending healthspan?
Dr. Sinclair: Right well, we already know from Horvath’s work and others that certain lifestyles will accelerate the clock and others will reduce it. That’s looking at thousands of people. Unless you’re a total skeptic and you’re just a glass-half-empty kind of person, you’ve got to look at that data and say—and, by the way, Horvath’s clock. like GrimAge, predicts your longevity that way and even how long you’re going to live from that point—so you’ve got to look at that data and say, “Okay, the clock is valid.” It’s got 5% error, but still, you’ve got to believe that it’s measuring something related to your actual aging and your future health. I think we’re already there. [But] I think that these clocks need a bit more development.
We need them in more people, but I have no doubt that we’re going to be able to use these clocks to predict someone’s future health and longevity. It’s already done in various studies. This means that if you reverse the clock and in multiple clocks—I don’t just mean a blood test because your blood might improve, but your brain might not. We need a way to actually test multiple tissues. It could be a cheek swab, spit, might be a muscle biopsy in some people, and also blood. But at least you need to see it happening in multiple parts of the body to be more convinced that this is true. But with that, I think that, at least if you’re not skeptical, in the next five years, we’ll have a number of interventions that are well-established and well-accepted to slow down, and if not also reverse aging. Including alpha-ketoglutarate, which looks promising. Senolytic molecules look promising for true age reversal.
That’s different than saying, “Oh, the mainstream medical establishment and the FDA agree.” That will take many more years. We know from the TAME study, the metformin study that Nir Barzilai’s heading, that while the FDA is open to the idea of calling aging a disease, they need to see that you can reduce markers that are agreed upon that represent age. Which includes frailty, cognition, and some blood biomarkers as well. That’s a lot of work. It’s very expensive. It’s different, I think. Acceptance within our community is pretty much going to happen in the next few years. Doctors will probably take maybe seven to ten years, and then the FDA could be even longer. But I hope I’m wrong about that.
Taylor Sittler: I think it’s a question of how quickly we can get the medical societies engaged.
Dr. Sinclair: I sounded a little bit conservative there. I think with the pace that we’re learning to educate people, with the books, with the podcast, with just people talking about this, it’s a lot of buzz, I hope that we can accelerate this. But so far, it’s happening at a grassroots level rather than the top down.
Taylor Sittler: Do you see any signs yet, from the traditional medical community, of movement?
Dr. Sinclair: Well, talking to my circle of advisors and friends, there’s been a paradigm shift in the way they think, but of course, my circle is not representative. I haven’t taken a survey. That would be the thing to tweet today to see what happens. If you’re a doctor, what do you think? I have faced the opposite. I faced criticism in particular from one doctor through direct messaging that nobody should be allowed to use a glucose monitor unless they have Type two diabetes. To which I replied and then tweeted, that’d be like saying, “People shouldn’t have bathroom scales in their bathroom to monitor their body weight.” Who’s to tell us what we can measure and what we cannot?
But anyway, there certainly are these really strict opponents. Even with calling aging a disease. I’m going to be publishing in the Lancet a letter saying, “Please don’t reverse the decision to call aging a disease at the World Health Organization.” Because there are some vehemently opposed doctors that say aging should never be considered a disease and I don’t even know why it hurts. I don’t know why they’re offended. I think just people don’t like change and this is an example of that. But I couldn’t tell you. You probably have a much better idea of what percentage of doctors are on board with home monitoring of blood glucose versus those that are not.
Taylor Sittler: I have to say it’s been a slow shift, but the numbers are increasing. I think part of it is that these services that incorporate glucose monitoring are now getting traction across the board. They’re now publishing studies. I feel like the key to shifting doctors’ minds is, you just have to have this formula for producing the output and creating studies in a way that they can understand. Then it becomes part of medical education. It will be slow, but it’s coming.
On aging and COVID
Dr. Sinclair: First of all, COVID very likely accelerates aging. It accelerates cellular senescence. We see that in my lab, we can counteract that by deleting the senescence cells. There are two possible ways, at least in the supplement world. That’s one issue. The other thing that the virus does is it depletes NAD massively. If you Google it, you’ll see a lot of papers on this. There are some case studies at hospitals where patients have been given NMN and they’ve recovered rapidly. Metro Biotech is doing a COVID-19 NMN trial right now and also to protect kidneys as well, which is a problem for some patients. Those are the two things I think NMN might help with. Certainly, recovery and cellular senescence is a problem.
Senolytics might address long COVID. I think it’s important that people know—tell your family and friends—that if you get a bad case of COVID, it might accelerate aging. If they haven’t had the vaccine, they’ll probably go get one after they hear that.
On longevity and “blue zones”
Dr. Sinclair: I totally agree that the science says that the environment is important; your social environment, your stress levels. Cortisol, I measure in my body. I try to keep that log. Now it’s very clear that the data says it. You need a social environment to live really long. Now it can mean having a great partner you can rely on, or if not, having a pet that you come home to. These are all shown to be great for longevity.
There’s a study that’s worth noting, which is that at Harvard, they followed men after World War I, I think, maybe it was World War II. Anyway, it was for their whole lifespan and looked at their health. The one thing that was in common with the people that lived a long time was to have a reliable partner. To me that’s striking. It wasn’t just what they ate or how much they exercised. The partner was important. So yeah, I think being lonely really will accelerate aging, so big emphasis on that, big emphasis on the mind, meditation, peacefulness, mindfulness, calming yourself, not stressing about life too much. That’s a quick way to accelerate aging.
On reducing food intake
Dr. Sinclair: Plant-based, yep. Definitely a fan of eating at least one fewer meal a day. I skip breakfast. I’ve done most of my life. In the last year, I’ve started skipping lunch. If I can, most days I do that. I’ll have some nuts or supplement drink, Athletic Greens or something like that, or just add water as another product. Then I get through to dinner and I have a nice dinner. That’s hopefully vegan, if not vegetarian. Then the stacking. I think that taking multiple supplements and doing multiple things such as exercise and all that has an added benefit. Now, do I have proof of that? No, because trying to do that clinical trial is never going to be possible. You need a billion dollars to do all of that, and individually. But what I’ve done is I’ve added things sequentially. I’ve been slowly stacking these things over my adult life, to a point where I’ve gotten to where I probably take 10 supplements a day and my health has never been better.
Literally never been better since I was in my thirties, and my age is calculated to be much younger. I doubt that would be possible by taking one thing. In fact, I know that it’s not true because when I only took one thing, resveratrol, I wasn’t this healthy. Then I added NMN and metformin. It was great, but I didn’t get down to these levels. All of these things, including my diet and my exercise, have gradually been getting me younger and younger over the last decade. Cutting meals.
On how athletes should approach treatment
Dr. Sinclair: There’s a real question around athletes, I don’t agree that metformin should be cut out of any plan unless maybe you want to be Mr. Universe or Miss Universe. Actually, Mr. is the only way—that’s an issue. If you dig into the data, metformin only reduces the size of muscles by about 5%. It’s probably only because you feel a bit weaker on that day because it interferes with your mitochondria. But other than that, you can take metformin on days you don’t exercise. It seems to be fine. It’s only a 5% difference. Unless you’re Mr. Universe or extremely vain, 5% you won’t even notice. Those muscles on metformin were healthier, just as strong, and had less inflammation. I’m a proponent of actually reading the data and not going on these rumors that are on the internet.
Cutting meals as an athlete? Well, I think that you can still do it, [but] you don’t want to do it on the day that you’re running, probably. But it’s amazing what the liver can put out in terms of glucose. You see those levels are very steady; that’s because of gluconeogenesis in my liver. But on days that you run, you want to have more energy than just in your liver, especially if it’s a long-distance one. I would say you don’t want to skip meals on super training days or competing days, but I would encourage you to look at the documentary, Game Changers. You’ll see that a lot of athletes do just as well, if not better, on a plant-based diet.
On the impact of C60 fullerenes
Dr. Sinclair: I’m open to the possibility. I know the lead author, Ian. I’ve talked to him about it. No one knows this but I’m currently trying his product, which has oleic acid fused to C60. I’m going to see if it helps or not. If it doesn’t, I’ll stop; if it does, I’ll keep doing it. But the effects were dramatic. There was, I think, close to 30, 40% life span extension, it was crazy Oh, 90%—there you go. That is truly insane if it’s true. What’s the mechanism? Well, Ion thinks that it’s also mitohormesis in the same way exercise, hyperbaric oxygen, and metformin create a disruption in the electron transport chain that leads to free radicals that creates mitohormesis and you get help that way. He could be right about that. I really don’t know if that’s true, but that’s his theory. Just to give something that is useful: More and more mechanisms point to mitohormesis as a productive way to boost longevity. That’s why I’m bullish on exercise and metformin as ways to do that.
On the impacts of media consumption
Ben: Let’s make an assumption that [in the Blue Zones] most people they’re very laid back, they consume different food, it’s a very different lifestyle. But in these smaller communities, there might not be the same media consumption that we have in North America or in Europe, which is raising cortisol levels and you become consumed by it. How much of what goes on in the blue zones do you think has to do with the societal obsession with always consuming the news? When you’re in that mindset you’re elevating your cortisol and you become wrapped up in the negative of the immediate versus having a 10,000-foot-view of this world.
Dr. Sinclair: I think there’s a lot to that, that your cortisol levels and possibly other molecules we haven’t discovered yet are circulating in your body when in this heightened fight-or-flight state, which, based on my surveys of people that I meet, reached its height during the Trump administration and the election. Since then, a lot of us, including myself, have gone cold turkey on consumption of the news. Just speaking for myself, [I’m] much healthier, my cortisol levels are down, and my mental state is so much better. I even talk slower than I used to. I’m in a more Zen-like state. Before it was, “Oh my goodness, how many people have died today? What’s going to happen? The world’s going to blow up.” That’s not healthy at all, and I can easily imagine it to be true that that reduces the longevity of an entire country [or communities] watching it versus those that don’t. What we also hear from people who live a long time is that they don’t worry about things and they don’t consume huge amounts of media. Often they say it’s their sense of humor that has gotten them through. That’s a common theme with these centenarians. Actually, it’s one of the few things that are common. Often they smoke, they drink, they do bad things, but being relaxed and brushing off problems, and not worrying is one of the things that they all share.
On the reversibility of aging
Dr. Casey Means: I went to this talk this weekend at a longevity conference about this Grim Reaper clock in the pineal hypothalamus. Pineal calcification, which can happen from long-term exposure to melatonin, is upstream. The theory in this talk was it was upstream of everything else with cellular aging. I’m just curious how structural, maybe irreversible, changes like that, relate to what’s happening more on the cellular and epigenetic level. If we can bypass central changes with more downstream therapeutics that affect the epigenome and whatnot.
Dr. Sinclair: There’s a bunch of problems with melatonin and I’m guilty as anyone of taking melatonin. I probably do that three, four times a week, but I also am paying attention to this new data that looks like calcification is a major problem, not just for Alzheimer’s disease, but for normal aging as well. You get calcification, reduced volume of the pineal gland, and then you get decreased melatonin, and then you take more melatonin. It just makes things worse. You’re going to reduce neurogenesis in the brain, increase inflammation. It’s just not good feedback at all. In some countries, they don’t allow you to have melatonin. I’m Australian originally, and you just can’t buy melatonin. It’s funny that it’s available over here and it’s a hormone.
I’m cutting back my melatonin consumption and using other methods to go to sleep. I now am mostly using GABA and altheine and some magnesium if needed. I’ve taken myself off alcohol and Ambien that I used to need to get to sleep, which of course are extremely toxic and addictive substances. That’s the overall theme, which is to get away from the things that we know about and replace them with things that are at least apparently safe. I’ll tell you from my experience, I was in my late thirties, and I was suicidal because I couldn’t sleep. It was really a bad thing. Through calming thoughts—I didn’t meditate, but I’m trying now—but just by reducing my levels of stress and taking these supplements nowadays, I have no trouble sleeping. It’s really quite something to have gone from that state to this. I think it’s entirely due to that shift.
Dr. Casey Means: The main focus was endogenous melatonin. We’re producing it throughout our lifetime. It naturally causes, in theory, calcification. It’s almost like this is our way of nature, controlling our lifespan by naturally producing something that then calcifies a part of our body that then leads us to essentially no longer have hypothalamic dysfunction, and then aging. If this is happening, is that a block towards some of this stuff working, or is it a different mechanism that we can bypass? If there are irreversible changes that happen with aging like that, can we?
Dr. Sinclair: First of all, what I’d say is there’s nothing that’s irreversible in aging. At least, there’s no reason to believe that it’s irreversible. There are three things that we’ve proven are not irreversible: blindness, dementia, and protein aggregations in tissues—they can get eaten up. Of course, we’ve reversed vascular aging as well. That was pretty easy, did that a few years ago. Is pineal calcification reversible? I don’t know. We can try it. I think that, probably, if we just make the tissue younger, that’d be something to try. I do know melatonin will impact calcification even in the cardiovascular system, which you can try to slow down using vitamin K2, which will keep the calcium out of the arteries and put it into the bones. But do we know if K2 will help the pineal gland?
Dr. Casey Means: I don’t know, that’s a really interesting question. Not sure. Future directions.
Dr. Sinclair: We should [see] mouse pineal glands. We throw them away, but do you remember if mouse pineal glands get old and calcified as well? Because we can easily check that.
Dr. Casey Means: I think so. I think some of this work was in mice. But I think that the point you make that is so hopeful is that our paradigm of irreversibility may need to be updated and modernized. I think that’s a really good point for us to end on: the body has a remarkable adaptive capability when it has the right conditions.
Dr. Sinclair: One more thing that we reversed that I forgot to say is the ultimate irreversible aspect of aging, which is senescence. Once you know the trick, it’s easier to make a senescent cell healthy again.
