Transcript: Harvard Scientist David Sinclair Interview: FO562 Raj Shamani

Aging will be declared a medical condition, or a disease. That’s what my book Lifespan talks about. And doctors will one day — probably for you, you’re still young, you probably won’t want to try it for another 5 to 10 years, I wouldn’t rush it — but for those people who are 80 or 90, what have they got to lose really? If it looks safe, their body’s deteriorating, they’ve got diseases, aches and pains, they’re going blind. There’s a lot to gain and not a lot to lose.

RAJ SHAMANI: (00:08:08 – 00:08:25) True. When you say aging, right, my passport has one age, which is my actual age, right? Then everything in my body, all my body organs, they have a different age than my passport age, than my actual age.

DAVID SINCLAIR: (00:08:26 – 00:08:26) That’s right.

RAJ SHAMANI: (00:08:26 – 00:08:32) And it’s like every organ has a different age, or are there just two ages, or are there multiple ages inside me?

DAVID SINCLAIR: (00:08:33 – 00:08:37) You’re made up of over 20 trillion cells, and each cell has a different age.

RAJ SHAMANI: (00:08:39 – 00:08:44) And it’s partly related to — so my brain, my heart, my immune system, everything is of a different age?

DAVID SINCLAIR: (00:08:44 – 00:09:06) Yes. And depending on how you treat your body, it can age at different rates. If you were to smoke and get obese and not exercise, parts of your body would age faster and be older than your actual age. And vice versa, you can age slower. Even identical twins with the same DNA can be 10 years apart in their actual biological age.

RAJ SHAMANI: (00:09:07 – 00:09:14) And so you’re saying even the biological age of every organ is different — it’s not one, right? So which one’s making me sicker?

DAVID SINCLAIR: (00:09:14 – 00:09:24) We’d have to analyze. I could do a blood test and have a look, or even a cheek swab, and have a look at how you’re doing — there’s a clock that’s in every cell that we can read now.

RAJ SHAMANI: (00:09:25 – 00:09:31) And is it possible that maybe my heart is older and my brain is younger?

DAVID SINCLAIR: (00:09:32 – 00:09:40) Absolutely. That’s almost certainly happening already. Even a baby will have organs that are different ages.

RAJ SHAMANI: (00:09:40 – 00:09:42) And is the oldest part making me sicker the most?

DAVID SINCLAIR: (00:09:45 – 00:10:05) It depends on the organ, right? If your heart is older, and you’re in your 20s, you’re probably not feeling anything yet. But in your 50s, you’ll feel it. And in your 60s, you could die from it if your heart is older. That’s one of the reasons we need to work on aging. If you have an old heart, or your mother does, we can target her heart and make her heart young.

RAJ SHAMANI: (00:10:07 – 00:10:07) Wow.

DAVID SINCLAIR: (00:10:07 – 00:10:07) How?

RAJ SHAMANI: (00:10:08 – 00:10:15) Okay, explain from the basics. Why do we age, and how is every body cell or every body organ aging differently?

The Information Theory of Aging and the Epigenome

DAVID SINCLAIR: (00:10:16 – 00:11:38) Well, there is a clock in every cell. We used to think it was the mutations, the defects in the DNA, but actually we learned that the DNA itself can be rejuvenated. The DNA from an old animal can be used to make a young animal. In fact, if you were to have children, they would be your age for the first week of conception, the first week of life — the same age as their parents’ cells. But then there’s a reset switch.

So the point is, we used to think it was DNA, and the mutations, the defects in your DNA. It’s almost certainly not that. It’s something else, but it’s related to your DNA. What I’ve proposed — and it’s not fully accepted, like all scientific theories, I have to say, but it has become one of the most prominent theories — is called the information theory of aging.

RAJ SHAMANI: So what is that?

DAVID SINCLAIR: I’m glad you asked, Raj. The information theory of aging says it’s not DNA, it’s not the genome, it’s something called the epigenome. The epigenome is the control system that reads the DNA. So a little bit of biology: in every cell you’ve got about 6 feet of DNA.

RAJ SHAMANI: (00:11:38 – 00:11:38) Okay.

DAVID SINCLAIR: (00:11:39 – 00:11:40) So it’s a lot of information.

RAJ SHAMANI: (00:11:40 – 00:11:41) Yeah.

DAVID SINCLAIR: (00:11:41 – 00:13:11) I have a little structure here that I brought to show you this, to explain it. So this is a piece of DNA. Six feet of this in every cell, but it’s wrapped up very tightly, microscopically. If you put all your cells end to end, it would go to the moon and back eight times. So it’s a lot of chemical, but it’s very thin, and you can wrap it up around proteins so it’s compact.

Each one of these steps in the ladder is a bit of information, and there are four letters in DNA. A matches with T, and G matches with C, and it’s double-stranded. So this looks like a spiral staircase — one strand running up, one running down. The way you copy your DNA is it splits apart. The stairs come apart, and then the cell puts one part of the stair there and another part of the stair there. Now you’ve got two stairs, and now you can split the cell — now you’ve got two cells.

So this is DNA. We used to think that changes to the steps were the cause of aging. What I’m saying, in my theory, is your DNA is largely intact. In fact, if you take a 100-year-old cell, you can make a young organism again. You can even make a young mouse out of a cancer cell. The DNA is not as big of a problem as we thought.

RAJ SHAMANI: (00:13:11 – 00:13:12) Okay.

DAVID SINCLAIR: (00:13:12 – 00:13:28) So what’s the epigenome? The epigenome are the control systems that package the DNA. DNA is not just floating around at 6 feet — it’s wrapped up tightly in little bundles. I have another model to show you this.

RAJ SHAMANI: (00:13:30 – 00:13:30) Okay.

DAVID SINCLAIR: (00:13:31 – 00:14:29) In this model, the DNA is blue and it’s wrapped around these tennis balls — these are proteins. So the DNA gets packaged, right? You can see that now the DNA, which is this blue Velcro, isn’t 6 feet — it’s much more tightly packaged.

Now there’s a problem once you’ve made the tight package in the cell: how do you read the gene? Because you have to get at it to read it. So what the cell does is say, alright, a gene that needs to be turned on — let’s say a gene for making a nerve cell — let’s turn that one on, but keep the liver cell closed because you don’t want the liver to be expressed. It unwraps these proteins so that now you’ll even take them off a bit, like this. Now the cell can read that gene.

RAJ SHAMANI: (00:14:30 – 00:14:30) Okay.

DAVID SINCLAIR: (00:14:31 – 00:16:11) That DNA is accessible, whereas these other ones are closed. This is open — what we call chromatin, open chromatin. And this over here is closed chromatin. Gene is on in the middle, gene is off on the left. That’s the epigenome. And every cell has a slightly different pattern of open and bundled — it’s about 20,000 genes, different patterns.

I think of it sometimes like a piano. We all have the same notes — every cell has the same keys — but the way they’re played, if each gene is a note, the cell plays beautiful music, but differently for each cell, though it’s the same instrument in every cell.

So what I’m telling you is the blue, the DNA, is not changing with aging. Your mother has essentially the same DNA that she had when she was a baby, but the way it’s packaged changes. Genes that were once open and working great and making the cell healthy start to get closed, like this. And genes that should stay closed start to open up.

Let’s see if I can open up this one. Alright, so let’s say this protein flies away, this tennis ball — here we go. Now your mother’s DNA has lost one of these proteins, and a gene that is for the liver is now coming on in her brain, and her brain cells are forgetting how to be brain cells. They’re starting to be a little bit more like liver cells. That’s what we see — this is what we call changes to the epigenome.

RAJ SHAMANI: (00:16:15 – 00:16:15) Okay.

DAVID SINCLAIR: (00:16:15 – 00:16:26) Another way to think of it is epigenetic noise. When you’re young, it’s perfect. When you’re old, this whole thing gets unraveled, tangled. It’s a huge mess.

Aging a Mouse on Purpose: Proving the Theory

RAJ SHAMANI: (00:16:27 – 00:16:27) Okay.

DAVID SINCLAIR: (00:16:27 – 00:16:54) So we discovered this and published it in 2023 in the journal Cell. It was 13 years of work. In the first 10 years of my lab, we tested it in human cells, and that wasn’t that difficult, but then we needed to test it in an animal. So how do you test whether this causes aging? We needed to do this in a mouse.

RAJ SHAMANI: (00:16:54 – 00:16:55) Yeah.

DAVID SINCLAIR: (00:16:55 – 00:16:56) In a young mouse.

RAJ SHAMANI: (00:16:56 – 00:16:56) Okay.

DAVID SINCLAIR: (00:16:57 – 00:17:01) We needed to do this in a young mouse. And if we’re right, and we do this in a young mouse, what’s going to happen to the mouse?

RAJ SHAMANI: (00:17:02 – 00:17:02) It’s going to age.

DAVID SINCLAIR: (00:17:02 – 00:17:16) It’s going to age. So we did that. The way we did it was we distracted the proteins that control the epigenome, because they don’t just wrap the DNA.

RAJ SHAMANI: (00:17:16 – 00:17:16) Okay.

DAVID SINCLAIR: (00:17:16 – 00:17:24) They actually repair DNA. So we created a few cuts in the DNA. Here’s a blow-up of the DNA.

RAJ SHAMANI: (00:17:24 – 00:17:25) Okay.

DAVID SINCLAIR: (00:17:25 – 00:18:17) We would cut it right through the yellow, and these proteins say, oh my goodness, we have to go repair the DNA. So they move, they go to the broken DNA, they help repair it, they wrap it up again. And then, if all goes well, they go back to where they came from.

But here’s the problem: we noticed that they don’t all go back. Sometimes they get lost — they’re gone. So now the gene that should be wrapped up is now exposed, and the cell is reading the wrong gene.

So we did this to a mouse. We cut the DNA for two weeks when they were young, and then we waited, because nothing happened immediately. The mice were happy, running around the cage — similar to if you got an X-ray. X-rays break your DNA, by the way.

RAJ SHAMANI: (00:18:17 – 00:18:17) Okay.

DAVID SINCLAIR: (00:18:18 – 00:18:18) Do you feel anything?

RAJ SHAMANI: (00:18:19 – 00:18:19) No.

DAVID SINCLAIR: (00:18:19 – 00:19:08) No. So broken DNA doesn’t hurt, but I can guarantee it’s aging you, because what we X-ray is aging me — absolutely, there’s no question. We did this to the mouse, not by X-rays, but we used a very precise cutting enzyme, and we did that for two weeks, a little bit more severe than an X-ray.

We waited and we waited and we waited, and 10 months later we looked at the mice, and it’s now a very famous photo on the internet. The brother and the sister are next to each other. The brother was not treated — healthy, shiny coat, running around the cage, black coat. The other one — hunched back, wrinkled skin, gray, not moving around, couldn’t remember anything.

RAJ SHAMANI: (00:19:09 – 00:19:10) In just two weeks?

DAVID SINCLAIR: (00:19:11 – 00:19:51) No, it took months after, but the two-week treatment was enough to start this process of unraveling that led to aging, like dominoes. We got aging, and that was probably the hardest experiment we’ve ever done. It was 40 scientists, 13 years of work, but we got the result that the theory predicted — that unraveling the DNA leads to aging in an animal.

The reason it took 13 years was a lot of scientists said an old-looking mouse is not an old mouse. It could be gray for other reasons.

RAJ SHAMANI: (00:19:51 – 00:19:52) Yeah.

DAVID SINCLAIR: (00:19:53 – 00:20:44) So it took us about a decade to satisfy our peers, other scientists who are trying to disprove us, that these truly were old mice. We looked at their tissues. We did histology — we cut the tissue, we looked at it, we gave it to other scientists to analyze, experts in the eye, the liver, the brain — and they sent us back the results and said, this one’s an old mouse. And we said, no, it’s not — it’s the same age as the other one, it’s just been accelerated.

We also could use the clock. Remember how we talked about measuring your biological age by looking at cells? We could do that with mice too, and those mice that we did this unraveling to were 50% older than their twins born on the same day.

RAJ SHAMANI: (00:20:44 – 00:20:50) But you’d only tried it on mice, or did you try it on monkeys as well? Because monkeys are the closest to human beings, right?

Reversing Aging: The Yamanaka Genes

DAVID SINCLAIR: (00:20:51 – 00:21:01) Well, here was the question that I had about 10 years ago: do we keep studying age acceleration, or do we do what I really want to do with my life?

RAJ SHAMANI: (00:21:02 – 00:21:03) Hmm.

DAVID SINCLAIR: (00:21:04 – 00:23:55) Take it away. Because if you can give aging, maybe you can take it away. So we stopped working on age acceleration so much — we use it as a tool to make mice with gray hair, to study gray hair and skin aging. But at that point I said, alright, now let’s figure out if we can take an old epigenome that’s all messed up, and maybe there’s a way to get it to go back to being young again. Can you reverse aging?

That’s crazy — how would that be possible? Theoretically, it made no sense that it might be possible, but we know that embryos get young, they can reset. Remember I said after the first week of age, you can go back in time. My guess, my hunch, was that there’s a reset switch in the cell — we just needed to find the switch.

We didn’t want to repeat what was done in the early 2000s, but I do want to mention the guy’s name — I was just in Japan, actually, and he’s a legend there — Professor Shinya Yamanaka. He came up with four genes. You can use more genes — 10, 20 — but he needed at least 4 genes to make those cells go back to being stem cells.

So we had the idea: why don’t we try just a few of them? No one thought to do that, because the Nobel Committee and Yamanaka said you need all four for it to work. I said, well, let’s try three or two or one. Maybe that would help — maybe we could go partially back to being young, but not so much that we’d get cancer, and lose the identity. Remember, we want the cell to get their identity back, not to lose it — that was the trick. Yamanaka lost the identity; we wanted to do the opposite.

So how did we do that? We decided to take away one of the genes — a gene called c-Myc, which we call M for short. The reason we chose that one is that it’s a cancer-causing gene — c-Myc, we know, causes cancer, so we didn’t want that anyway.

Yuancheng Lu put three of the Yamanaka genes into old human cells — OSK for short, which are now legendary genes for this treatment. What he found in the next week was that those cells went back about 75–80% to being young, got their identity back. They remembered how to be skin cells, they grew better, they were more robust, healthier — but they never got to be stem cells, because we didn’t have the M, the Myc, to create the stem cells. That was in human cells, in the year 2017.

RAJ SHAMANI: (00:23:55 – 00:23:56) Yeah.

DAVID SINCLAIR: (00:23:56 – 00:24:41) But the next question that’s really interesting, that Lu decided to look into, was: what if we do this in an animal — will it heal it, or will it kill it or hurt it? We don’t want to hurt animals, but we wanted to test if it could help the animal. Lu decided to do the eye. I thought that was a crazy idea — I thought, let’s do the liver, the liver is easy. But the eye? Are you kidding me, that’s complicated.

He figured out how to do that. He put the genes — I have a model here to show you — inside a virus-like particle. It’s a capsule with a membrane, with proteins — like any virus.

RAJ SHAMANI: (00:24:41 – 00:24:41) Yeah.

DAVID SINCLAIR: (00:24:42 – 00:25:57) But inside is this protein pocket, and now you can put your OSK age reversal genes in there, and you can make trillions of these in the lab, put them in a syringe, and inject them anywhere you want, and the virus will infect the cells of the body. If you put it in the eye, it’ll go into the eye cells. If you put it into the vein, it’ll go to your liver and your lungs. When it gets inside the cell, it opens up and delivers the DNA — that’s how we get DNA into cells, that’s how we cure genetic diseases currently.

It’s called an AAV, and there are different flavors — ones that scientists use for the eye, some that are engineered for the liver, different flavors. We used one called AAV2, which is designed to hit the retina. Lu’s brilliant idea was, let’s see if we can make damaged optic nerves heal again. Why? Because old animals don’t heal their eye. If I hurt your eye, you would not regrow your optic nerve.

RAJ SHAMANI: (00:25:57 – 00:25:57) Yeah.

The Optic Nerve Breakthrough

DAVID SINCLAIR: (00:25:58 – 00:27:20) Same with your spine — if you break your back, you’re not going to walk again. But very young animals, even very young humans, can regrow their nerves. So Lu said, if we can take them back to being like a baby again, we’ll see that the animal can regrow the optic nerve.

He texted me a result — when was it, 2018. He sent me a photo of a nerve. The first one was dead — a little bit of color, but mostly black. He said, do you see that? I went, yeah. He goes, now look at this one. The next text was a beautiful regrown optic nerve, regrown within two weeks, back to being young and fresh again. It had regrown, and this had never been done before at this level.

Lu said, “Do you see what I see?” And I said, “I think I see it.” And he said, “What do you see?” And I said, “I see the future.”

That picture of that nerve is now flipped vertically and on the wall of the house at home, because that was a moment I’ll never forget. I get tingles in my body — I’m getting them now just thinking about that moment — because that was the first evidence that safe age reversal was possible, in mammals, in complex organisms, just in the eye. But we knew if it worked in the eye, it should work anywhere. We didn’t choose the eye because it would work better.

RAJ SHAMANI: (00:27:20 – 00:27:37) So you’re telling me a damaged eye, a damaged optic nerve, which got completely reversed and got back to the repaired version — so if this works, then what it possibly means is a blind person can see again.

DAVID SINCLAIR: (00:27:39 – 00:29:05) Well, what I can say as a scientist is we’ve cured blindness in mice. We’ve taken old mice that just can’t see, and then two weeks later they can see perfectly again, perfectly like a young mouse. So it works in mice, that’s a fact.

The other fact is if you have a monkey with a damaged optic nerve, we can improve their vision — in some cases, almost to normal, what they were before. And now we’re testing it in humans. I think theoretically — most likely, 80%, 90% — it will work in humans, because our eyes are the same as monkeys, just a little bit bigger. It worked really well in the monkey, and we can see that those nerves are getting younger — not just because they regrow from the damage, but we can measure their age, remember, with the clock, and the nerves got young again.

We didn’t just use damaged nerves — we tested glaucoma, which is a leading cause of blindness in India. There’s very prevalent pressure in the eye, 50 million people globally — it’s one of the largest causes of blindness. We’ve cured that in mice, and we hope, in these studies now in people, that we’ll be able to greatly improve the vision of glaucoma patients as well.

RAJ SHAMANI: (00:29:07 – 00:29:09) And wow, that’s—

DAVID SINCLAIR: (00:29:10 – 00:29:16) But this is just the beginning. We are just doing the eye because it’s a good place to start — a good place to put a virus.

RAJ SHAMANI: (00:29:16 – 00:29:21) And you did that in humans very recently, right? You did the first trial this year.

DAVID SINCLAIR: (00:29:21 – 00:29:21) Yeah.

RAJ SHAMANI: (00:29:21 – 00:29:22) How many months ago?

DAVID SINCLAIR: (00:29:24 – 00:29:25) A few months ago.

RAJ SHAMANI: (00:29:25 – 00:29:28) Okay. And till when do we have to wait for the results?

DAVID SINCLAIR: (00:29:28 – 00:30:44) So, this is where I have to get a little bit scientific, and FDA — under the regulation, it’s an FDA-approved study to test safety. The ultimate outcome of this study, in terms of the FDA, is: did it hurt the patient? Did it spread out of the eye — did it go anywhere else? Did it cause inflammation? Did it cause cancer? That’s why we’re doing this study, and we’re starting very carefully. The first patient that we saw dosed just got a very small dose, not a big one, and we waited for a month to see what would happen.

So now more people have been treated, and we’re waiting. But I know what you’re asking — will we know this year if it works? I could say, between friends, possibly, because every patient is their own experiment. You measure their eyesight before treatment, during, and actually for another 5 years. So if it works, even though it’s a small number of patients — only 18 people — we might see if it’s working this year.

Not Just Aging: A Treatment for (Almost) Every Disease

RAJ SHAMANI: (00:30:47 – 00:31:22) Wow. I hope it works out for everyone, because this is going to be one of the biggest impacts on human life, all around the world, because we could treat diseases, we could just make people more healthy — they don’t have to suffer through all these things while they’re alive. Forget coming back from 90 to being 50 again, but at 90, can this at least feel and live like a 40-year-old? That is going to be incredible, right?

DAVID SINCLAIR: (00:31:22 – 00:32:27) Yeah, it’s really worth pondering, because we have to throw away our misconceptions. The first misconception is that we’re treating aging, and that we’re just trying to make frail people look better or feel better. If this works, it could be a treatment for almost every disease known to humans. We can improve, in my lab: multiple sclerosis, wound healing, brain aging — so memory loss — the kidney, the heart, the muscles, the liver.

There’s no part of the body that could not theoretically be improved, treated, healed, repaired, rejuvenated, restored by this technology. It’s not just aging, it’s all diseases. Even young children, if they hurt themselves and need to rejuvenate and fix something that the body doesn’t normally heal — yes, lizards can regrow parts of their body, and salamanders can regrow a whole arm. Maybe we can do that for ourselves one day too.

RAJ SHAMANI: (00:32:29 – 00:32:52) But explain — while you’re explaining, I’ve written down a few words and I want to go deeper. The most basic thing is: this is there in every human being, right? And if you cut this yellow part, that’s damaging — and we are damaging ourselves on an everyday basis. We’re damaging 20 things, maybe 20,000 things, every day in our life, right?

DAVID SINCLAIR: (00:32:53 – 00:32:58) Every day you will get at least 20 trillion of those breaks in your body.

RAJ SHAMANI: (00:32:58 – 00:33:03) So the DNA is breaking in my body.

DAVID SINCLAIR: (00:33:04 – 00:33:04) Oh yes.

RAJ SHAMANI: (00:33:04 – 00:33:07) Right? And that is causing the aging. Why is it breaking?

DAVID SINCLAIR: (00:33:08 – 00:33:09) Oh well.

RAJ SHAMANI: (00:33:10 – 00:33:28) So why am I getting older, and why you versus me? Let’s say there are two different people, right — in your body this breakdown is happening probably in a different way, and in mine it’s happening faster or slower. Why? We’re all born the same, right?

Why You Age Faster (or Slower) Than Someone Else

DAVID SINCLAIR: (00:33:30 – 00:34:04) Well, partly it depends on our parents. If our parents had good genes to repair DNA and stop breaking, then we have an advantage. People that live a long time have less broken DNA and a much more stable epigenome — less epigenetic noise. Whales, which live the longest of all mammals, have low DNA damage, and their epigenome, those structures, stay stable.

But between you and me — let’s say I’m aging faster than you, let’s say we’re twins.

RAJ SHAMANI: (00:34:04 – 00:34:04) Okay.

DAVID SINCLAIR: (00:34:04 – 00:34:49) And I obviously don’t look as young as you. So what’s wrong with my body? Well, one thing that might be different is that the enzymes that mop up free radicals — I’m drinking coffee, right, it’s got free radicals, coffee has quite a lot of hydrogen peroxide in it — and you’re drinking, let’s say, water. Maybe I don’t repair my broken DNA as fast as you do, and that means these proteins that hold the DNA in place don’t get distracted as quickly. The other thing might be that these proteins that go away in your body find their way back better than in my body — for whatever reason, there’s a better signal to come back.

RAJ SHAMANI: (00:34:50 – 00:34:53) But why? Why mine are probably better and yours are not?

DAVID SINCLAIR: (00:34:54 – 00:35:26) Well, there are lots of different reasons. One is that there are signals that tell proteins where to go in the cell. I’ll give you an example — this is a tennis ball, but let’s imagine it’s a protein. Proteins get modified, they don’t just get folded — here’s a folded amino acid sequence. All of our proteins get modified, and I’ve got this little thing — this represents what we call acetylation.

RAJ SHAMANI: (00:35:26 – 00:35:26) Okay.

DAVID SINCLAIR: (00:35:27 – 00:35:54) It gets attached, typically, to an amino acid called lysine. Now that this has been acetylated, it will behave differently — it will be active, and will help repair the DNA, and it will go and fold up the DNA better because it’s got this attached. Maybe your body puts these on more frequently than mine does, to make this protein more active. That’s a difference between people.

RAJ SHAMANI: (00:35:55 – 00:35:57) But go ahead, you were saying something.

DAVID SINCLAIR: (00:35:57 – 00:37:25) Well, there’s another big difference that is not genetic — it’s actually as important as the genetic component, and this is the good news. The way you live your life impacts the pace of aging and how much DNA damage there is. If you don’t get a lot of X-rays, don’t fly a lot and get hit by cosmic rays, don’t get CT scans — that’s one thing that would give you an advantage.

If you eat a lot of colored plants — I call this xenohormesis, but basically Serena says eat colored food, eat the rainbow — colored food has chemicals that help repair DNA, that help proteins bind up the epigenome, and we get these chemicals from our food supply. If we eat a regular lettuce, mass-market grown, not colorful — like iceberg lettuce — that’s not going to have a lot of what we call polyphenol chemicals. But if you eat — what would be the best — green tea, matcha is full of it. There’s a bit in red wine, but we don’t like alcohol anymore. Another good one would be dark green leafy vegetables, spinach. Anything that’s got a lot of color will have these chemicals.

Xenohormesis: Why Colored Plants Are Good for You

RAJ SHAMANI: (00:37:25 – 00:37:26) Like bell peppers and stuff.

DAVID SINCLAIR: (00:37:27 – 00:38:15) Bell peppers are great. The other thing that helps plants become colorful is adversity, stress. If you eat a great, healthy, plant-based diet — not from meat, by the way — my diet and Serena’s is plant-focused for that reason. It’s healthier, and these chemicals come from plants, not from animals — that’s an advantage we can all have. Then there’s the usual things: running, moving, fasting — these also boost the activity of these proteins that help repair DNA and help bind up the epigenome and stabilize it. This is some of what my lab has done over the last 25 years — connecting how we live, what we eat, how we move, to this process of aging.

RAJ SHAMANI: (00:38:17 – 00:38:35) I’ll come to activities later, but before we go to colored plants — what is there in colored plants? Why are specific, very dark colored plants better, not the normal colored plants?

DAVID SINCLAIR: (00:38:36 – 00:38:36) So xenophyte—

RAJ SHAMANI: (00:38:36 – 00:38:45) Because when I look at two plants, they look the same to me — a lettuce looks like a lettuce, a spinach would look like a spinach. The darker spinach will be better for me, that’s what you’re trying to say.

DAVID SINCLAIR: (00:38:45 – 00:38:46) Yes. Yes.

RAJ SHAMANI: (00:38:46 – 00:38:47) And why?

DAVID SINCLAIR: (00:38:48 – 00:38:51) Why? This comes to my theory called xenohormesis.

RAJ SHAMANI: (00:38:52 – 00:38:52) Okay.

DAVID SINCLAIR: (00:38:52 – 00:40:13) It’s not just my theory — I came up with it with a colleague of mine who I want to mention, Konrad Howitz. In 2006, we published this theory, and the idea came from the observation that we couldn’t explain with current theory at the time.

In the pharmaceutical world, almost all drugs are based on plant molecules — aspirin, for example, a lot of cancer drugs, these are originally plant molecules. Even metformin, which is for diabetes, very popular in India, comes from a plant, which is goat’s rue, as it’s called in Europe. So why are these plant molecules so good for us? It makes no sense — the plants don’t care about us, do they? I don’t think so.

The xenohormesis hypothesis says that when plants need to survive too much shade, or not enough water — in the case of grapes, where they dry out — they try to survive, and the plants make these chemicals, many of which are colored. They make them to survive — these are plant stress survival molecules, polyphenols. A polyphenol, if you’re wondering — a phenol is a chemical ring.

RAJ SHAMANI: (00:40:14 – 00:40:14) Can you make it here?

DAVID SINCLAIR: (00:40:15 – 00:40:15) Yeah, sure.

RAJ SHAMANI: (00:40:16 – 00:40:17) Anything.

DAVID SINCLAIR: (00:40:17 – 00:40:19) Yeah, a bit of a chemistry lesson.

RAJ SHAMANI: (00:40:19 – 00:40:20) Yeah, please.

DAVID SINCLAIR: (00:40:21 – 00:40:24) So a phenolic ring looks like this.

RAJ SHAMANI: (00:40:26 – 00:40:26) Okay.

DAVID SINCLAIR: (00:40:28 – 00:42:25) And the “ol” stands for an OH, an alcohol, on there — well, just a polyphenol. So this is what’s called a phenolic ring, and you can make chemicals out of this structure. Plants make a lot of things out of it. The easiest one to draw is in grapes — called resveratrol. It looks like this. If you haven’t done chemistry, what’s at these joins here are carbons, and they all have a little hydrogen on there, but basically this is 2 phenols connected by a bridge — this is resveratrol.

Plants make this molecule, a polyphenol — 2 phenols — when they want to survive, when they get stressed. If there’s not enough light, not enough water, or even infection by a fungus, they make a lot of this, especially grapes, but most plants make this. When you drink red wine, you’re getting a lot of this — if there just wasn’t so much alcohol, it’d be even healthier.

But you can buy resveratrol. I’ve been taking resveratrol powder every morning for the last probably 20 years, because I truly believe that resveratrol is one of the polyphenols that can slow down aging. Why? Because one of the proteins that controls the epigenome, which we study, called SIRT1, gets activated by this molecule. So when I’m eating resveratrol in the morning — I eat about a gram, so it’s a lot — it floats through the body, gets inside the cell, and makes my epigenetic regulator more active, so I’m not going to age so quickly, is the theory. That’s why. But you can also eat stressed plants, which make these molecules.

RAJ SHAMANI: (00:42:25 – 00:42:26) Stressed plants.

DAVID SINCLAIR: (00:42:26 – 00:42:28) Stressed plants are good for you. Colored ones, yeah.

RAJ SHAMANI: (00:42:28 – 00:42:43) So because they’re stressed, they’re trying to survive, and the stuff that they’re making inside them, which helps them survive for longer — that is the stuff that we need. So it helps us survive as well.

DAVID SINCLAIR: (00:42:43 – 00:43:10) It does. And why is a good question. My theory is it’s because we get a signal when our food supply is going to run out — our bodies will hunker down and try to survive and be stronger. So these chemicals signal human adversity in the future, and by eating resveratrol every morning, I’m tricking my body into thinking that food supply might run out.

RAJ SHAMANI: (00:43:10 – 00:43:11) A big famine is coming.

DAVID SINCLAIR: (00:43:11 – 00:43:13) Exactly. Famine is coming.

RAJ SHAMANI: (00:43:17 – 00:43:44) Exactly. Yeah. I never knew science was going to be this interesting for me. Okay, so that’s why you want to eat colored plants, and that’s why it’s making us better. That was the first part. The second is, what’s happening inside my body as I sit here right now? I’m on this chair right now, and this is making me older, right? As I’m just sitting here.

DAVID SINCLAIR: (00:43:45 – 00:43:45) Yes.

What’s Happening Inside Your Body Right Now

RAJ SHAMANI: (00:43:46 – 00:43:52) Why? What’s happening inside my body, what’s happening inside each of my cells, which is making me older?

DAVID SINCLAIR: (00:43:53 – 00:44:03) Well, there are a few things that are happening. There are at least 12 major causes of aging. I just happen to think that what we’re talking about here, with the epigenome, is one of the primary major ones.

RAJ SHAMANI: (00:44:03 – 00:44:03) Yeah.

DAVID SINCLAIR: (00:44:04 – 00:44:50) But some of the things that are happening are at the ends of your chromosomes — the DNA. If this is the end of a chromosome, it’s getting chewed away slowly. Every time the cell divides, it gets shorter — these are like fuses that get shorter. That happens particularly in cells that divide a lot, like your blood cells, your liver. That’s one thing. Your stem cells are getting older.

The one thing though that you can’t stop is this DNA breakage. This is happening even if I put you in a lead box at the bottom of the ocean with no X-rays, no cosmic rays — DNA still breaks. Why? Because during the copying process — remember how I said DNA copies by unzipping down the middle — you cut it down the middle.

RAJ SHAMANI: (00:44:51 – 00:44:51) Yeah.

DAVID SINCLAIR: (00:44:51 – 00:44:52) Now you get two strands.

RAJ SHAMANI: (00:44:52 – 00:44:52) Yeah.

DAVID SINCLAIR: (00:44:53 – 00:45:10) As you do that to the 6-foot-long piece, inevitably it’s going to break once or twice every time — it’s weak, you can’t stop it. So the process of being alive is causing DNA breaks. You cannot stop that.

RAJ SHAMANI: (00:45:10 – 00:45:11) But can I slow that down?

DAVID SINCLAIR: (00:45:12 – 00:45:20) Yes. Eating the right foods, exercising, fasting — doing all those good things will slow down that process.

RAJ SHAMANI: (00:45:21 – 00:45:37) Okay. You said slowing down comes with eating colorful plants — that’s one way of doing it. What’s there in meat? Because meat has a lot of protein, meat has a lot of good things — a lot of people will argue that you should start eating liver and whatever.

DAVID SINCLAIR: (00:45:38 – 00:46:52) Yeah, but that’s not going to give you longevity. It’s going to give you some strength, and you’re going to build muscle a bit faster — not a lot faster, but a bit. But that’s not longevity.

Here’s one way to think of it: there’s adversity mode, right — the body thinks it’s stressed — and then there’s abundance mode: lots of meat, just killed a mammoth, lots of food, energy, fat, protein. Abundance mode accelerates aging, and adversity mode, as we’ve talked about, slows this down, protects the body.

So if you want to be in abundance mode and grow big and be Mr. Universe, live this lifestyle. If you want to live a long time, be in adversity — fast, eat plants, run. That signals adversity to the body, to preserve the body.

Or what I think is probably the best, especially for someone young like you — do both. A few days a week, eat protein, work out, be abundant. But have some adversity too — sauna, running, fasting, that’s also good.

RAJ SHAMANI: (00:46:53 – 00:47:04) So this applies in every aspect of life — if I am making myself and my body stressed and trying to signal that I’m in adversity, then it’s going to help me live longer?

DAVID SINCLAIR: (00:47:05 – 00:48:31) Yes. Now, we haven’t done a human trial, so “yes” is based on all the evidence in animals pointing to it being true in humans as well. If you take a mouse and feed it resveratrol, or other polyphenols, yes, it will live longer and be healthier in general — it can even be resistant to obesity. We published, in 2006, that resveratrol given to fat mice makes them as healthy and long-lived as thin, lean mice.

So you can eat these molecules and get the benefits of adversity without actually having to be hungry. But you might say, well, then why do I have to fast if just eating plants is good enough? I don’t think it’s good enough. What we found in my lab, looking at these animals, is if you do both — if you don’t eat 3 meals a day, and you take these molecules as well in the diet — you get double the effect. That’s why, in my lifestyle, I focus on plants, I exercise, I try to do hot-cold as much as I can, and I’m taking polyphenols every day. That’s my belief — it’s not proven yet, but all the science points to doing all of these things together. They’re additive.

Fasting: The Specific Protocols

RAJ SHAMANI: (00:48:32 – 00:48:51) Give me specifics — the way you gave me specifics of how colorful plants will make you better. What other protocols will make me better, will help me age slower? You said running — how much running? You said sauna or cold — how much of that? There’s so many things right now.

DAVID SINCLAIR: (00:48:51 – 00:48:56) This is why I restarted my podcast — this is a shameless plug for my podcast.

RAJ SHAMANI: (00:48:56 – 00:48:56) Okay.

DAVID SINCLAIR: (00:48:56 – 00:49:05) It’s called Lifespan, because I get these questions every day — what are the details, how much should I fast, what should I eat, if I’m a woman is it different than being a man.

RAJ SHAMANI: (00:49:05 – 00:49:05) Yeah.

DAVID SINCLAIR: (00:49:06 – 00:49:07) So my podcast has a lot of that.

RAJ SHAMANI: (00:49:08 – 00:49:08) Okay.

DAVID SINCLAIR: (00:49:08 – 00:49:24) If you have a little bit of time — what I know, you’ve watched some of it, so I appreciate that — but we can cover some of it today. It really takes many days of listening to know all the details, but there are some general rules. Let’s start with fasting. Is that okay?

RAJ SHAMANI: (00:49:24 – 00:49:24) Yep.

DAVID SINCLAIR: (00:49:24 – 00:49:38) Okay. So fasting — if you’re not a young child, let’s say in your 20s, three main meals a day is too much. How many meals a day do you eat?

RAJ SHAMANI: (00:49:39 – 00:49:39) Three.

DAVID SINCLAIR: (00:49:39 – 00:49:43) Three. Do you think you could get away with two?

RAJ SHAMANI: (00:49:44 – 00:49:44) Easily.

DAVID SINCLAIR: (00:49:45 – 00:49:55) Because you can eat the same calories, just reduce the window of eating. That’s been shown, in many clinical trials, even in humans, to have vast health benefits.

RAJ SHAMANI: (00:49:56 – 00:50:02) I read that you need to eat 6 small meals in order to grow and get better.

DAVID SINCLAIR: (00:50:02 – 00:50:03) Yeah, who told you that?

RAJ SHAMANI: (00:50:03 – 00:50:06) So much internet chatter just gave me that.

DAVID SINCLAIR: (00:50:06 – 00:50:11) It’s wrong. That’s old-school nutritional advice.

RAJ SHAMANI: (00:50:11 – 00:50:11) Okay.

DAVID SINCLAIR: (00:50:11 – 00:50:19) That didn’t understand longevity science. The idea was don’t stress your pancreas, have a little bit of food, a snack.

RAJ SHAMANI: (00:50:19 – 00:50:19) Yeah.

DAVID SINCLAIR: (00:50:19 – 00:50:33) A lot of that, I hate to admit, when you do the research, is marketing from food companies. Breakfast is not the most important meal of the day — that’s a cereal company marketing breakfast cereal.

RAJ SHAMANI: (00:50:33 – 00:50:33) No way.

DAVID SINCLAIR: (00:50:34 – 00:50:34) It is.

RAJ SHAMANI: (00:50:34 – 00:50:47) All my life I’ve believed breakfast is — in fact, I’ve made certain changes in the last 4 or 5 years to make sure that I eat breakfast no matter what, because breakfast is going to help me do so many things.

DAVID SINCLAIR: (00:50:49 – 00:51:02) Well, if you love breakfast, that’s fine, but you should have almost no dinner in that case. What you want to do is have a period of fasting — no food so you can sleep, you’re not eating while you’re sleeping.

RAJ SHAMANI: (00:51:02 – 00:51:02) Yeah.

DAVID SINCLAIR: (00:51:03 – 00:51:29) But if you’re eating first thing in the morning, then you’ll want to finish eating in the early afternoon, so that you get that big stretch of no food. Why? Because it’s going to turn on our anti-aging natural defenses against DNA damage and epigenetic change. If your body always has sugar and protein, it’s going to be in abundance mode, not adversity mode. And we know what abundance mode does — it speeds it up.

RAJ SHAMANI: (00:51:30 – 00:51:31) What’s the most important meal then?

DAVID SINCLAIR: (00:51:32 – 00:52:09) It depends on the person — we have different chronotypes. Some of us like to eat in the morning, some like to exercise. I’m not a morning person, I don’t need food in the morning, so I’ve been skipping breakfast most of my life, and my father, who’s now 87 in perfect health, same — that’s the Sinclairs. But you might love breakfast, you wake up hungry, you want to eat, you want to exercise. But you may not feel hungry at night, so you can choose. I do want everyone to consider that this old idea of eating constantly through the day and snacking is actually a marketing ploy.

RAJ SHAMANI: (00:52:11 – 00:52:25) You know, you’ve just ruined my belief right now — I eat a very heavy breakfast and a very heavy dinner. Lunch, I’ll probably skip or maybe have a small thing, that’s it.

DAVID SINCLAIR: (00:52:25 – 00:52:30) Raj, we’re going to have to measure your biological age. Now I’m worried.

RAJ SHAMANI: (00:52:30 – 00:52:34) The two things that you told me, those are the two things which I’m doing very—

DAVID SINCLAIR: (00:52:34 – 00:52:36) Man, you might be 35 for all we know.

RAJ SHAMANI: (00:52:37 – 00:52:38) No, don’t worry. Don’t tell me.

DAVID SINCLAIR: (00:52:38 – 00:55:08) We can fix you. Here’s a good point I want to make for everybody: if you’re nervous — and I can tell, I just hit a nerve — it’s never too late. We have really good protocols now to slow down aging, and soon to be reversing it, I believe. So don’t worry, it’s never too late, and you’re very young, so you’ll be fine.

I do want to stress something that a lot of people don’t think about: we mentioned that we’re getting DNA damage all the time. There are other things that can accelerate aging as well, besides DNA damage. Since we published our work in 2023, we and others have shown that any major damage to a cell can accelerate its age, not just DNA damage.

For example, if you pinch the nerves, like we did for the eye, those nerves got old very quickly, by years — within days they went years old, in a mouse. That’s like 20, 30 years in a human. I think that every time we go to a rock concert and we’re blasting our ears, we go home with older ears than when we went to the concert. It makes sense, right — because now when you get to 60, you’re losing your hearing. Why? Because your ears have gotten older faster than someone who lives in the countryside.

What I think is happening is every time we stress a cell beyond what it’s capable of handling, these proteins that control the epigenome, the genetic readers, move around to help repair the problem, and they don’t all go back to where they came from. If you could make sure that this structure here stays stable and doesn’t unravel, you could live hundreds of years, in fact — that’s why whales live hundreds of years, we think, is that they stabilize this structure, whereas we humans are damaging ourselves and they fly away.

Some animals only live a couple of years, some only for a few days. And if anyone has seen me at a rock concert, I’ve got earplugs in. If I’m walking down the street and a loud noise happens, I now have my fingers in my ears — I know it looks silly, like why is this guy, it’s just an ambulance — but I truly believe that these loud noises age you, particularly your ears. And you know what you get if you drink a lot of alcohol or smoke — you get cancer and other issues.

RAJ SHAMANI: (00:55:09 – 00:55:11) I don’t smoke or drink, so that’s — I’m safe there.

DAVID SINCLAIR: (00:55:12 – 00:55:12) I love that.

RAJ SHAMANI: (00:55:13 – 00:55:14) Well, I’ve never tried any of that.

DAVID SINCLAIR: (00:55:14 – 00:55:27) Then you’re probably younger than your actual chronological age, we call it. That’s good, you’re doing all the right things. Now we just need to reduce your number of meals down to 2 and you’ll be good.

RAJ SHAMANI: (00:55:27 – 00:55:32) Okay, let’s go back to fasting — actually, we deviated. You were telling me about fasting.

DAVID SINCLAIR: (00:55:32 – 00:55:43) Yeah. So what I talk about on my podcast is how to practice fasting and not have it be a real problem. What most people do is say, I’m going to stop eating for a day and see what happens.

RAJ SHAMANI: (00:55:44 – 00:55:44) Yeah.

DAVID SINCLAIR: (00:55:44 – 00:57:33) Then they say, this is too hard, I’m hungry, I can’t think, I’ve got brain fog — that’s the wrong way to do it. The way you would do it is, let’s say you love dinner but you want to stop eating dinner, or just eat early — don’t stop eating immediately. Just have a smaller meal each day, or eat something that’s filling, a lot of vegetables, and fill your stomach up with tea instead. If it’s at night, not caffeinated, but perhaps some hot water. Serena and I are always with hot water — we just got off a plane from Tokyo, and we were saying we need hot water. It’s not just healthy to drink and it cleans out your blood, but it also fills you up, you don’t feel hungry.

So that’s one hack for fasting — fill yourself up with liquids. Another hack is to do it slowly. And another hack is to just get over it — you might feel a little bit hungry, but so what, it’s not going to kill you. I’ve been able to fast for — I went without a meal really for 2 and a half weeks, fairly recently, last month.

There were times where I thought I should just go to the cupboard and eat everything that’s in there. I wanted to, but your mind is very strong, right — everybody has the power to resist going into the fridge. It’s not easy, we all want to do it. But you have to think, do I really want to achieve this, or am I going to give in to my animal instincts? That’s one of the keys to fasting — don’t give in to that quick fix. It’s worth it.

If you fast for over 3 days, you start to get into this new phase called chaperone-mediated autophagy. Have you ever heard of that?

RAJ SHAMANI: (00:57:33 – 00:57:34) Never.

DAVID SINCLAIR: (00:57:34 – 00:58:27) Alright, so autophagy is self-eating. Our cells are always eating themselves. When there’s a damaged protein — let’s say this thing unfolds, or gets too many of these attached in the wrong place — the cell can detect it and send it to be destroyed and recycled. Proteins get turned into amino acids, amino acids rebuilt into protein. That’s autophagy — it happens all the time, but happens much more when we’re hungry, and even deeper cleansing after 3 days of not eating. That will get rid of the really old, worn-out proteins. So these days I try to do a 3-day or 5-day fast probably once every few months, partly for autophagy, partly because it helps me drink water, stay the same weight, and live life well.

RAJ SHAMANI: (00:58:28 – 00:58:30) So for 3 days you drink only water?

DAVID SINCLAIR: (00:58:30 – 00:58:56) I’m definitely drinking all the time. If it’s a strict fast, I won’t eat anything. If I’m going for a few weeks, I will eat some vegetables, small amounts, like a carrot, some celery, but not a lot — just enough food to fill my little tummy up. But I feel great actually. Once you get past 3 days, you don’t feel hungry anymore. What happens is remarkable.

RAJ SHAMANI: (00:58:57 – 00:58:57) I highly—

DAVID SINCLAIR: (00:58:57 – 00:58:58) Have you ever fasted?

RAJ SHAMANI: (00:58:58 – 00:58:58) No.

DAVID SINCLAIR: (00:58:59 – 01:00:24) It’s really amazing. I can tell you, I’m not good at fasting — I don’t have a lot of willpower. If I can do it, most people can do it. I decided to try it — I was actually doing it before a podcast so I could say on the podcast that I did it.

After the third day, something remarkable happened. I went from feeling a little bit hungry, a little bit tired, to, wow, my brain turned on. My body was making what are called ketones, and the brain loves them — they fuel the brain. I was super awake, like taking a few shots of caffeine. I was also more energetic, I wasn’t tired at all, I woke up every morning feeling great. So I love that feeling — when I fast, I’m actually looking forward to getting into that state again. But most people don’t get there — after the second day they’re like, oh, I can’t do this anymore, or I’m going out to dinner, I have to eat with my friends.

That’s also the hardest problem with fasting — we’re social animals. I do find that. When I’m with Serena traveling — she’s a trained chef, actually — we do like to eat really well. Every time we go to a new city, we eat at one of the top restaurants. But when I come home, that’s my recovery fasting period, and the clean-out autophagy process.

Fasting Culture, Vegetarianism, and NAD

RAJ SHAMANI: (01:00:24 – 01:00:36) You know, in India, a lot of small communities and cultures have a practice around fasting, and it’s deep-rooted in religion.

DAVID SINCLAIR: (01:00:36 – 01:01:17) It’s wisdom, it’s so wise — they knew it was healthy. The problem that I’ve seen, perhaps not in India, but in the Middle East, is because there’s so much food, they eat late at night after the daily fast, but they eat so much — probably twice as much as normal. That counteracts probably any good that they get. But if you fast and don’t overeat, I think the health benefits are really huge. There have been studies of caloric restriction and fasting in humans, and I think actually the best way to rejuvenate yourself and feel better and even get younger is to fast.

RAJ SHAMANI: (01:01:18 – 01:01:18) Once a month?

DAVID SINCLAIR: (01:01:20 – 01:01:25) I would say at least once a month. I would say every day you could skip a meal.

RAJ SHAMANI: (01:01:25 – 01:01:28) And fast for how long? What should be the break between meals?

DAVID SINCLAIR: (01:01:29 – 01:02:16) There’s a few different versions — on the podcast I get into it. There’s one that’s very popular in Australia called the 5:2 — you fast for 2 days and eat for 5. Depends what you can do. In terms of a daily window, try to fast for 14 hours. If you can do 16, it’s great. I try to go for 18, but it’s not that hard if you sleep for 7 or 8 of those hours. Then it’s really just skipping a meal and having a late lunch, skipping breakfast, or having a late lunch and not eating till breakfast. That’s the way I think is the healthiest — to do it every day, not just once a month.

RAJ SHAMANI: (01:02:16 – 01:02:23) And would you consider a morning smoothie, or morning protein, or morning whatever, a breakfast as well?

DAVID SINCLAIR: (01:02:25 – 01:03:01) Yeah, but I’m not as strict as most people. I’ve measured myself over the years — this is all scientific, I’m not just making stuff up. I’ve found that having small amounts of food, particularly if it’s not carbohydrates, doesn’t break my fast. I’ve been having resveratrol mixed with a bit of yogurt — vegan yogurt now, I used to have Greek yogurt. That doesn’t break my fast. A little bit of olive oil, that’s okay. But a real smoothie — that’s loads of calories, that could be 600 calories right there if you put a banana in there. That’s a meal.

RAJ SHAMANI: (01:03:02 – 01:03:20) Interesting. I’m vegetarian, so I think I’m not very concerned about my meals because I eat vegetables all the time. Only once a day would I eat bread or rice, and other meals it’s just vegetables or protein.

DAVID SINCLAIR: (01:03:21 – 01:04:10) Now I’m going to get a lot of people hating on me, because people love the carnivore diet. I just want to say the carnivore diet can work great — it has seemingly improved the health of a lot of people, helped them lose weight. What I’m saying, though, is long-term, by the time you’re 90, I think it’s not as beneficial as a vegetarian or vegan diet. If you’re going to do something, you don’t need to do it every day — do it for a couple of days, then have a rest, do it again. That way you can get the benefits of exercise and protein, but also this adversity, hunkering-down survival mode. I think that actually works the best, because your body gets the chance not just to hunker down and slow down, but gets some time to heal and grow fast and fix things.

RAJ SHAMANI: (01:04:11 – 01:04:14) Got it. Have you heard about water fasting?

DAVID SINCLAIR: (01:04:15 – 01:04:15) Yes.

RAJ SHAMANI: (01:04:15 – 01:04:20) Like 7-day water fasting actually repairs a lot of stuff, stuff like that.

DAVID SINCLAIR: (01:04:21 – 01:04:22) There’s a lot of good evidence. I believe in it.

RAJ SHAMANI: (01:04:23 – 01:04:25) Yeah. What does a 7-day water fast do?

DAVID SINCLAIR: (01:04:26 – 01:04:26) What would it do?

RAJ SHAMANI: (01:04:27 – 01:04:27) What would it do?

DAVID SINCLAIR: (01:04:28 – 01:04:57) Well, it activates chaperone-mediated autophagy, CMA. It’ll also activate these repair systems, probably rebuild your epigenome. It also raises the level of a molecule called NAD, which the proteins we study, called sirtuins, need. So by being hungry, you raise your NAD levels, and these become super active. So that’s another hack — get your NAD levels higher.

RAJ SHAMANI: (01:04:57 – 01:04:58) What is NAD?

DAVID SINCLAIR: (01:04:58 – 01:07:08) I’m glad you asked. NAD is one of the most important molecules for life. There are 2 molecules we cannot survive without for 10 seconds, and we’re full of these 2 chemicals. One is called ATP, which is chemical energy — if you take cyanide, you stop making ATP and you’re dead. You need ATP.

The other, which is more of a machinery reaction, a mediator, is called NAD. The full name, if listeners want to know it, is nicotinamide, which is vitamin B3, fused to adenine, actually part of DNA — dinucleotide. NAD is in our bodies, and when we exercise, or if we’re fasting, we get more of it.

For the last 10 years I’ve been working with teams to test if boosting NAD levels in humans gives health benefits, as the theory would predict — it should use these proteins to repair DNA and do other cool stuff. And the answer is yes — my colleagues have published, and I’ve been fortunate to be part of that group, a number of Harvard studies people could check out online. Raising NAD levels reduces blood pressure, lipids, cholesterol. And — what was the latest — oh, it’s not published yet, but there are some benefits to cognition as well. This molecule, NAD, is being tested around the world in different studies — Alzheimer’s, kidney disease, heart failure — and those studies are just finishing up this year. That’s another reason why I’m optimistic that something big is going to happen this year.

So to summarize what I’ve said: we’ve got ER-100 to reverse aging, but we’ve also got this other molecule which we call MIB-626, which boosts NAD and can slow aging. Slowing aging is important until we get the age reversal worked out.

RAJ SHAMANI: (01:07:10 – 01:07:15) And this is the supplement, or the thing that you told me you take after a long flight?

DAVID SINCLAIR: (01:07:16 – 01:07:33) Exactly. Well, we don’t take NAD, because NAD is a big molecule — I told you all the components — if you eat it, it’s not going to get absorbed easily. So we take a piece of NAD called NMN.

RAJ SHAMANI: (01:07:34 – 01:07:34) Okay.

DAVID SINCLAIR: (01:07:34 – 01:08:02) NMN, which is nicotinamide mononucleotide, not dinucleotide, one mononucleotide — it can be swallowed, it’s absorbed. We know it raises blood levels of NAD by twofold in most people. That’s what I’ve been doing for at least 13 years, in the hopes, in the science, that we would see slower aging because of that.

Why Can’t Adults Repair Themselves Like a Child?

RAJ SHAMANI: (01:08:04 – 01:08:15) We’re talking about aging, we’re talking about damage, but I was reading that a child’s repair system is much better than an adult’s, right?

DAVID SINCLAIR: (01:08:15 – 01:08:16) For sure, yeah.

RAJ SHAMANI: (01:08:16 – 01:08:35) So what happens — why is a kid able to repair themselves with all these damages, even if a kid doesn’t fast, doesn’t run, doesn’t do anything, they’re still able to repair all these damages. But I’m not, or, as we age, we are not.

DAVID SINCLAIR: (01:08:35 – 01:08:45) That’s such a good question, and the best questions are the obvious ones that we don’t talk about. Why is a child so good at repairing?

RAJ SHAMANI: (01:08:46 – 01:08:46) Yeah.

DAVID SINCLAIR: (01:08:46 – 01:08:52) Why doesn’t a child get Alzheimer’s disease? Why don’t they get heart disease? You know why?

RAJ SHAMANI: (01:08:52 – 01:08:59) Yeah, even kids have lower rates of cancer as well. Why? These are the same things that happen to all of us.

DAVID SINCLAIR: (01:08:59 – 01:09:42) Okay, here’s what I believe to be the truth: their epigenome, which controls the genes, is optimal — every cell knows what it is, what it should do, and can do it. But starting even before birth, this process of aging starts to happen, and cells eventually forget how to be optimal. That’s what we see as aging — it’s what we see as diseases of aging. We start out optimal, and ER-100, the drug we’re testing, is designed to get us to go back to that optimal point where we can heal pretty much anything.

RAJ SHAMANI: (01:09:45 – 01:09:56) So as I’m getting older, these things in my body are forgetting, and because there are too many, they don’t know where to go, what was the original place to go?

DAVID SINCLAIR: (01:09:57 – 01:10:25) Yes — your cells are forgetting which piano keys to play, or which genes to turn on, because these are the piano players. They’re getting lost and not hitting the right keys anymore, and the beautiful music of our youth becomes a terrible noise, a cacophony. But then the question is, can you play it again beautifully, and heal like a baby again?

Which of Your Organs Is Aging Fastest?

RAJ SHAMANI: (01:10:26 – 01:10:37) And this is there in every organ, right? So every organ is now operating in a different system. Can I find out which organ, or which specific place, is being damaged more?

DAVID SINCLAIR: (01:10:39 – 01:10:39) In your body?

RAJ SHAMANI: (01:10:39 – 01:10:40) Yeah.

DAVID SINCLAIR: (01:10:40 – 01:10:42) Yeah, we can read it. We can see—

RAJ SHAMANI: (01:10:42 – 01:10:48) Like specifically, you can find out whether my heart is older, or my brain is older, or my immune system? I don’t know.

DAVID SINCLAIR: (01:10:48 – 01:10:48) Yeah.

RAJ SHAMANI: (01:10:49 – 01:10:51) What all is possible, and what all is not possible?

DAVID SINCLAIR: (01:10:52 – 01:11:25) For sure, we could do what we do to the mice to you, but it would just require a sample. If you give me a tissue sample, I can tell you how old your tissue is — that’s easy. I can take your skin, from your mouth, I can take your blood. Taking your heart tissue is a little harder, but from a cheek swab we’ve actually found — and it’s been published — that using a test we developed partially in my lab, the signature of the cells in your cheek also has a signature of how well your heart is aging. It’s crazy, right?

RAJ SHAMANI: (01:11:25 – 01:11:26) Yeah, I don’t — why?

DAVID SINCLAIR: (01:11:26 – 01:12:27) We don’t know, but there is that signature of different organs in the mouth, and it might be because there’s a memory of how you’ve been living. If you’ve been fasting your whole life — which you haven’t — your cheek cells would have a memory of that. If you’ve been smoking — which, thank God, you haven’t — there is a memory of smoking in every one of these cells that we measure. My friend Steve Horvath, who invented this clock, said that the clock is much more accurate than people’s memory of smoking — most people are in denial, but that’s an aside.

There are surrogates for different tissues in the mouth. So what I think will happen in the future is you’ll give a sample of your cheek or your blood to your doctor, and you’ll get back a picture of yourself saying, this part of your body is old, this part is young, we need to target this part.

RAJ SHAMANI: (01:12:28 – 01:12:37) Interesting. Wow, pretty fascinating. And if I get to know, let’s say, my heart is old, and it has aged—

DAVID SINCLAIR: (01:12:37 – 01:12:38) Yeah.

RAJ SHAMANI: (01:12:39 – 01:12:46) Is it because of some disease which is why it’s aging? Or is it because it’s aging, that’s why I’m getting a lot of diseases?

DAVID SINCLAIR: (01:12:46 – 01:13:35) It’s mostly the second one — because you’re aging, you get diseases. If we could reverse the age of that diseased tissue, the disease goes away. We know this from studies in my lab and others. If you give a mouse Alzheimer’s disease dementia and you make the brain young, the disease goes away. The body can cure Alzheimer’s if it’s young. That’s why young people don’t get Alzheimer’s — we have to think about that.

But yes, you are right also that diseases can accelerate aging — if you genetically have a problem with your heart, it can age faster. Some people have diseases that accelerate aging in all tissues. Have you heard of progeria?

RAJ SHAMANI: (01:13:35 – 01:13:35) No.

DAVID SINCLAIR: (01:13:36 – 01:14:11) There are progeria diseases which accelerate aging in essentially the whole body of a child, and a teenage kid can look 80 years old. We actually made the same mice in the lab — mice that look old rapidly, like the ones we cut the DNA in, but with the same mutation as in the human patient. Now what we’re testing is, can we reverse the age of those mice to make them young again? And if that works, then there’s hope for these children.

RAJ SHAMANI: (01:14:12 – 01:14:23) Can one organ that’s getting older in my body make my entire body older, or make all the other organs in my body old?

How Old Fat and an Old Brain Can Age Your Whole Body

DAVID SINCLAIR: (01:14:23 – 01:15:52) That’s so fascinating. I wouldn’t say all, but most of the tissues and organs are talking to each other, and one old tissue can accelerate aging in other tissues. I’ll give you a couple of examples. One: if you implant old fat into a mouse, or a rat, it will make the rest of the body old — the age spreads from this one old part of the body, the fat. All of us in our 50s have old fat — we can actually stain it, there’s a color we can stain it. Your fat is probably light blue, a 90-year-old would be super dark blue, almost black. We can measure that. Those cells are secreting inflammation molecules called inflammatory cytokines, and they age the rest of the body.

The second example: if you accelerate aging of part of the brain called the hypothalamus, which is at the base here, that’s a part of the brain that communicates to the body with lots of different hormones — if you accelerate the aging of that tissue, the body gets older. But here’s the cool thing — if you keep it young, it makes the whole mouse young, and the mouse lives longer.

RAJ SHAMANI: (01:15:52 – 01:15:54) And how do I keep them young? Adversity.

DAVID SINCLAIR: (01:15:55 – 01:16:11) Well, yeah, like I said — don’t eat as much, exercise, all that. I think polyphenols are a very good way to keep your brain young. The other thing that I do, which I don’t talk about a lot — let’s talk about it now.

RAJ SHAMANI: (01:16:11 – 01:16:11) Okay.

DAVID SINCLAIR: (01:16:11 – 01:17:18) Between friends, no one else is listening, right? Blood flow — by the time you get to my age, there’s always a loss of blood vessels. I’ve got an aorta that’s still flowing well, or I’d be dead. I measure it, not all the time, but every few years, with an ultrasound of my carotid.

What we forget is that all the tissues are filled with microscopic capillaries — those become less numerous as we get older. When we’re young, blood’s flowing easily; when we’re older, it’s pushing hard through, there’s not a lot of gaps. That’s one of the reasons we’re not fit when we’re older — the blood just can’t get through.

One of the things I do, besides trying to exercise aerobically — which I should do a lot more of, but I’m on planes a lot of the time — is take a small dose of an erectile dysfunction drug. I won’t say the name, but you know what I’m talking about.

RAJ SHAMANI: (01:17:18 – 01:17:18) Yeah.

DAVID SINCLAIR: (01:17:19 – 01:17:37) An ED drug. I’m not taking it because I have problems with erections — I don’t have any dysfunction — but it does open up blood vessels, makes them more flexible, and you get better blood flow. It’s the reason that it works down there, but it doesn’t just work there.

RAJ SHAMANI: (01:17:37 – 01:17:38) Blood vessels, yeah.

DAVID SINCLAIR: (01:17:38 – 01:17:48) And it allows my tissues to be filled with more oxygen. The reason I mention that is a lot of the problems in the brain, especially, are caused by a lack of blood flow.

RAJ SHAMANI: (01:17:49 – 01:17:54) Do you think tracking blood flow can actually be helpful for anybody?

DAVID SINCLAIR: (01:17:55 – 01:17:55) Yes.

RAJ SHAMANI: (01:17:55 – 01:17:56) Brain blood flow?

DAVID SINCLAIR: (01:17:56 – 01:18:21) If you can track it, it’s not easy, but yes, I think it’s worth doing. I’ve had it done with an MRI — you can measure that. It’s very important to maintain healthy blood flow, and one of the things I attribute my father’s mental health to is that he’s done everything he can to maintain a healthy cardiovascular system.

RAJ SHAMANI: (01:18:22 – 01:18:28) Interesting. So the friend I was talking to you about, the entrepreneur friend in India who’s trying to solve this—

DAVID SINCLAIR: (01:18:28 – 01:18:29) Yeah.

RAJ SHAMANI: (01:18:29 – 01:18:39) Right, I ended up meeting him, and he’s built this device called Tempil, and they’re now trying to measure brain blood flow.

DAVID SINCLAIR: (01:18:39 – 01:18:49) That would be very useful — I would love to try that. We could even see if fasting helps, if polyphenols help, if ED drugs help.

RAJ SHAMANI: (01:18:49 – 01:18:50) Yes.

DAVID SINCLAIR: (01:18:50 – 01:19:01) All of that’s great, and we could see, using this Tempil device, if the brain is aging faster or not, because it’s a good indicator.

RAJ SHAMANI: (01:19:02 – 01:19:24) That’s the whole bet, right? It’s fascinating — every time I do these exercises, which you were telling me right now on the app, I can see my brain blood flow going up. Every time I’m in the sauna, or every time I’m running like crazy, it just grows — it just goes up. And then when I’m lying down doing my breathwork, doing nothing, and it just—

DAVID SINCLAIR: (01:19:25 – 01:19:25) Like, it’s—

RAJ SHAMANI: (01:19:26 – 01:19:31) You can see all the things that you were talking about — you can see your brain blood flow actually increasing.

DAVID SINCLAIR: (01:19:31 – 01:19:42) Amazing. That’d be very helpful, because right now it’s an expensive MRI. Most people can’t do that or afford it, but if there was a cheap way to measure it, I’d walk around with it all the time.

Entropy and the “Backup Copy” of Youth

RAJ SHAMANI: (01:19:43 – 01:19:45) We were talking about this, you also told me about entropy.

DAVID SINCLAIR: (01:19:46 – 01:19:46) Yes.

RAJ SHAMANI: (01:19:47 – 01:19:54) What is entropy? Why is it becoming such an important conversation all around the world?

DAVID SINCLAIR: (01:19:56 – 01:19:58) Well, there are different types of entropy.

RAJ SHAMANI: (01:19:59 – 01:20:00) What is entropy?

DAVID SINCLAIR: (01:20:00 – 01:21:46) Well, people even disagree on what entropy is. At its fundamental level, it’s information. But what most people are taught in college is that it’s disorder — the more entropy, the more disorder. Real professionals disagree with that description — fundamentally it’s information and informational noise.

The reason that’s important in my field, and in many fields including AI, is: a young cell is ordered, has pristine information — all the information is there. Now we’re aging — now we’re 57 years old, unfortunately — this is loss of information. It doesn’t remember how to be like it was when it was young. This is increased entropy, disorder — a loss of information.

But the question I had in 2014 was: is there a backup copy of this information? Is it possible to reverse entropy? Of course it requires energy — you don’t circumvent the second law of thermodynamics for free — but we can eat, we can get energy, and maybe there’s a system, a memory of how the cell was put together, the DNA wrapped up, from 30, 40, or in my case 50 years ago. That was Yuancheng Lu’s PhD thesis — can he find a way to get this to go back, is there a memory of that? And I think we found it — that it exists. There’s a backup copy of the original state of the cell.

RAJ SHAMANI: (01:21:46 – 01:21:46) Where?

DAVID SINCLAIR: (01:21:47 – 01:21:54) Now that’s the question we’re trying to answer in my lab right now — where is that information stored?

RAJ SHAMANI: (01:21:54 – 01:21:59) But every piece of information from 30, 40, 50 years is stored somewhere there.

DAVID SINCLAIR: (01:21:59 – 01:22:29) We believe so — it’s new biology, we’re looking at it. We think we’ve found evidence that there are new structures on this original molecule that tell the cell this gene should be wrapped up tightly, and this other one should be opened up, like when we were young. That’s sitting in every old person. So now when I see an old person who’s frail, can’t cross the street well, I don’t see an old person — I just see someone who needs to be reset.

RAJ SHAMANI: (01:22:30 – 01:22:33) Someone who’s just forgotten how to be young again.

DAVID SINCLAIR: (01:22:33 – 01:22:37) Yes, but inside is a young person, who just needs to be switched on again.

RAJ SHAMANI: (01:22:38 – 01:22:40) Can you do that? Can you switch it on?

DAVID SINCLAIR: (01:22:40 – 01:22:41) We do it in my lab every day.

RAJ SHAMANI: (01:22:43 – 01:22:46) But if someone’s been switched on for a long time, is it bad for them then?

DAVID SINCLAIR: (01:22:47 – 01:24:17) We don’t think so — that’s why the FDA gave us permission. We did a lot of safety studies in monkeys and mice for years. We haven’t seen any negative issues so far. Cross your fingers. We have to be very careful because we’re playing with very powerful technology, but we wouldn’t have started the clinical trial if we thought there was any risk to the patient.

I’ll give you an example. We’ve published that if you turn on those three genes in the eye at high levels — not just for 2 weeks, 3 weeks, we did it for 6 weeks — if you leave it on for a year, even up to 21 months, there’s no negative effects. In fact, the longer you leave it on in the eye, the better the effect — the vision gets better and better.

And here’s the thing I love, in that paper we published on glaucoma: if you turn it off — and we have the ability to turn it on and off, we actually just give the patient a pill, it turns it on, they stop taking the pill, it turns off — it’s the world’s first regulatable gene therapy, by the way. We did this in mice: turn it on, cured or at least improved vision, turn it off. What happens? The disease comes back, aging happens, they lose their vision now for the second time. Now we do a cool experiment — we turn on the genes again. What do you think happened?

RAJ SHAMANI: (01:24:20 – 01:24:22) You saw positive results?

DAVID SINCLAIR: (01:24:23 – 01:24:48) We can do it multiple times. Now, I would have wanted to turn it on 3, 4, or 5 times, but the mice got old and they died — but they died with very good eyesight. So this tells me that this can be turned on many times. Imagine a future where we have these genes in our body that we can turn on with a pill, and we just take a pill for a few weeks every few years, and we just go back in time.

Reversing Spine Damage and Joint Degeneration

RAJ SHAMANI: (01:24:50 – 01:25:24) That would be so cool, so amazing. Essentially, you’re telling me that most old people aren’t old, they’ve just forgotten that they’re a young person inside, and you just need to switch that thing on. Does that mean for every part — like, you said spine, right, spine is very difficult to do that. Spine degeneration is one of the biggest problems in the world right now because we’re all sitting. I have it — my L4, L5, S1 is just gone.

DAVID SINCLAIR: (01:25:25 – 01:25:47) There was a recent study that came out of China, done very well — they injected these three Yamanaka age restoration genes into a joint of an animal, a mouse that had osteoarthritis.

RAJ SHAMANI: (01:25:47 – 01:25:47) Okay, alright.

DAVID SINCLAIR: (01:25:49 – 01:26:12) I think it was the leg, not the spine, but still, it’s a good model — the cartilage regrew. I’m excited about testing this in human patients — back injury, sports injury, or just old age wearing out. Wouldn’t that be good — instead of putting stem cells in there to try and fix a little bit, we just give you a young new joint, it grows again.

RAJ SHAMANI: (01:26:14 – 01:26:21) True. But with your thing, can those pills switch on and stop my degeneration as well?

DAVID SINCLAIR: (01:26:22 – 01:26:56) I would be optimistic, given this study we’ve just talked about — we’d have to test it. The way we would do it, theoretically, we’d need FDA approval, but we could take ER-100 and put it into your spine, give you the pill, and do an MRI to see if your spine regrew. That’s what we’re doing with the eye right now — if it works in the eye, it’s going to start — we should talk.

RAJ SHAMANI: (01:26:58 – 01:27:07) Absolutely. You tell me when the eye thing starts up. Another thing is about the immune system.

DAVID SINCLAIR: (01:27:07 – 01:27:07) Yeah.

The Immune System and Senescent “Zombie” Cells

RAJ SHAMANI: (01:27:08 – 01:27:22) People who have a weak immune system age faster — is it because I’m doing all the bad things that my immunity is weak? Or my immunity is weak, and that’s why — what’s the correlation?

DAVID SINCLAIR: (01:27:24 – 01:28:01) There are a few possibilities — it’s not fully agreed upon by scientists, but one is the immune system can be overactive and secrete inflammation factors, and having a lot of inflammation, like IL-6, IL-1 beta, these can accelerate aging because the inflammation is just bad overall.

The other thing that can happen is if your immune system is not very active, it’s the opposite — it can actually fail to destroy old cells, so that some old cells, like the blue ones in my fat, stick around. They’re called senescent cells.

RAJ SHAMANI: (01:28:01 – 01:28:02) Okay.

DAVID SINCLAIR: (01:28:02 – 01:28:03) Have you heard of senescent cells?

RAJ SHAMANI: (01:28:03 – 01:28:03) No.

DAVID SINCLAIR: (01:28:04 – 01:28:06) Some people call them zombie cells.

RAJ SHAMANI: (01:28:06 – 01:28:06) Okay.

DAVID SINCLAIR: (01:28:07 – 01:29:03) The reason they’re called zombie cells is when cells divide, they’re young and healthy, but when they get really old — either because their epigenome is unraveled and they’re confused, or the ends of their DNA get too short and run out — the cell gets a signal to stop dividing. Then they just become a useless zombie cell — actually, they’re worse than useless, they start putting out inflammation factors, it’s called SASP.

We know that if you put senescent cells into the fat, like I was saying before, it makes you age faster, and your immune system is what clears out these senescent cells. There are companies now working on vaccines that will help the body kill them — so that might be another reason why, if your body’s not good at killing these senescent cells, you would age faster.

RAJ SHAMANI: (01:29:04 – 01:29:47) Coming back to the aging part — when you were explaining the immune system and these things, I had this very basic question: what determines whether in my future I’m going to age faster or slower? Is it the pace of my aging, is it my current scenario, what’s already there in my body, or is it my psychological or physiological resistance — my whole body fighting against that aging? What’s the biggest determinant, the biggest contributor?

How Much of Aging Is Genetics vs. Lifestyle?

DAVID SINCLAIR: (01:29:48 – 01:31:26) The biggest contributor to your rate of aging is your environment and how you live your life. It’s debated somewhere between 50 and 80% of your future health and rate of aging is how you live, and your body composition — if you’re lean, in good shape with lots of strength, you’re going to age slower than someone who has let themselves gain weight and sit around. Some of it, between 20 and 50%, is you’re just born with that — there’s not much you can do about the part you get from your parents.

But the good news is at least half, maybe more, we can change, and we can slow it down by living the right life. Now, some changes take decades — taking resveratrol, you’re not going to suddenly get younger tomorrow, despite what some cosmetic companies say. So there are long-term things, and you have to have some faith. But some things are quite quick — you see them quickly.

I switched to a vegan diet when I met Serena, about 5 years ago. I gave up wine, gave up most meat, didn’t eat as many calories, and I noticed really within days I felt better. After a month I did my blood work again, and my inflammation levels went way down — I was already healthy. There’s an inflammation marker everybody should get measured called CRP.

RAJ SHAMANI: (01:31:26 – 01:31:27) Okay, what is it?

DAVID SINCLAIR: (01:31:27 – 01:31:45) C-reactive protein. Doctors usually measure it as a predictor of heart disease, but it’s a good measure of overall inflammation. My CRP levels went way down — the lower, the better, actually — with this change. That was quite a quick effect, it didn’t take decades to see the benefits.

Cardio vs. Strength Training

RAJ SHAMANI: (01:31:46 – 01:32:01) So we spoke about fasting, and we spoke about exercise but delved into other things. In exercise, is running better or is strength training better?

DAVID SINCLAIR: (01:32:02 – 01:32:21) Oh gee, well, I would say both, unfortunately — there isn’t one that’s better, they do different things. But if I could only do one thing for health, it would be aerobic exercise — losing my breath for 10 minutes, 3 times a week minimum. How much do you do?

RAJ SHAMANI: (01:32:24 – 01:32:26) Very little. Let’s just not go there.

DAVID SINCLAIR: (01:32:26 – 01:32:35) Well, I can sympathize, because it is tough when you’re as busy as you are — it’s hard to fit it in.

RAJ SHAMANI: (01:32:36 – 01:32:37) I do it once a week for sure.

DAVID SINCLAIR: (01:32:37 – 01:32:39) Oh, good. You lose your breath, you’re running hard?

RAJ SHAMANI: (01:32:39 – 01:32:46) Yeah, I lose my breath at least once a week, but I lift weights, or do some of that, 2 to 3 times a week.

DAVID SINCLAIR: (01:32:46 – 01:33:01) Good. Well, lifting weights is important for other reasons — it’s not going to massively change your blood flow, but it is going to help you with a few things. Strength, which is super important, even at your age, for your back.

RAJ SHAMANI: (01:33:01 – 01:33:01) Yeah.

DAVID SINCLAIR: (01:33:01 – 01:33:06) And limbs. Most people my age have a shoulder issue.

RAJ SHAMANI: (01:33:06 – 01:33:06) Yeah, right.

DAVID SINCLAIR: (01:33:07 – 01:33:36) And if you’re older than me, let’s say in your 70s or 80s, if you don’t have muscle strength, you can fall, you can break bones, you can even die from falling. So you do want muscles. At your age, in your 20s and 30s, the biggest effect, besides looking better, is that you’ll have a better metabolism — you’ll be burning more energy, so you can eat a little more, enjoy life a little more. It’s also very good for maintaining hormone levels.

Sugar, Glycation, and Blood Flow

RAJ SHAMANI: (01:33:36 – 01:33:49) When you were talking about improving brain blood flow, and the supplement that would expand your vessels — do you think L-arginine helps with that?

DAVID SINCLAIR: (01:33:49 – 01:33:50) I don’t know.

RAJ SHAMANI: (01:33:50 – 01:33:56) A lot of people take L-arginine for improving vascularity in the blood.

DAVID SINCLAIR: (01:33:57 – 01:34:50) Yeah, I don’t, off the top of my head, know how that works. It’s an amino acid, it may be involved in the production of nitric oxide, which is how erectile dysfunction drugs work. It’s a gas produced by what are called the endothelial cells that line the blood vessels. As you get older, you don’t make as much nitric oxide gas, and parts of your body fail because of that.

It may be that L-arginine, the amino acid, is helpful for the production of that gas, though I’m not an expert, so I have to speculate. But there are other things you can do — you can take nitric oxide boosters, for instance beets have nitric oxide. You’ve heard about beets?

RAJ SHAMANI: (01:34:50 – 01:34:50) Yeah.

DAVID SINCLAIR: (01:34:50 – 01:35:04) Now, I don’t take that, because typically it comes with a lot of sugar. I regard sugar as like a poison. Occasionally I’ll eat some candy, but I don’t eat a lot of carbs and sugar — I try to avoid it as much as possible.

RAJ SHAMANI: (01:35:04 – 01:35:28) Why is everybody so anti-sugar? I understand what’s going on and I understand it’s a poison, absolutely — the days when I’m not taking sugar are tremendously better. But demonizing everything around it, I feel we’re doing so much injustice. At least once a month is fine, or once in 15 days is okay.

DAVID SINCLAIR: (01:35:28 – 01:37:11) Yeah, everything in moderation. It’s just that the world, especially the United States food supply — I don’t know, India is probably the same — everything has sugar in it, even hidden sugar. Even the Chinese soups that I order — I thought, oh, healthy Chinese soups with vegetables — grams of sugar in there. The sauces, you have to be really careful, it’s the hidden sugars. Eating a candy once in a while is not going to hurt — it’s taking in all this sugar every day.

So why is sugar bad? A couple of main reasons. One is sugar attaches to proteins — this protein, and every protein in the body, can have sugar stuck to it, and that makes it an old protein. Actually, just a few days ago, a company announced they found a way to remove the sugar off proteins, which is great — one day we can get rid of it. Glucose on the proteins is called glycation. The problem is a lot of proteins in the body cannot be easily recycled — the ones that make up part of the skin, the collagen that’s in the skin, you don’t recycle that easily, so when it gets sugar attached it’s almost permanently damaged. So you don’t want high levels of sugar — try to keep your sugar levels low, because it’s the high concentrations that are bad. That’s one thing.

The second is you don’t want to be susceptible to diabetes, and diabetes is pretty prevalent in India and globally. So it is demonized, but sometimes I say it’s a poison to make the point, because I’m trying to counteract the other group of people that are making billions of dollars off sugar.

RAJ SHAMANI: (01:37:12 – 01:37:12) Yeah.

DAVID SINCLAIR: (01:37:13 – 01:37:20) And high-fructose corn syrup is up there — in America they use it in most foods, especially the sauces.

A Family History of Diabetes

RAJ SHAMANI: (01:37:21 – 01:37:55) True. Diabetes is one of the biggest reasons why I started getting healthier in my life, because my dad has diabetes, my grandmother has diabetes — it runs in my family. I remember when I was 15 or 16, I went to a clinic with my dad and was eating a sandwich, and the doctor there just looked at me and said, you should stop that, or you’re going to be diabetic before you even turn 25, because everyone in your family has it.

DAVID SINCLAIR: (01:37:55 – 01:37:56) Oh yeah.

RAJ SHAMANI: (01:37:56 – 01:38:14) And that just stuck with me. So you can call that doctor a devil or a blessing, because since that day my only challenge in life became: I want to beat diabetes by 25. I don’t want to have diabetes at the age of 25.

DAVID SINCLAIR: (01:38:14 – 01:38:15) Yeah.

RAJ SHAMANI: (01:38:15 – 01:38:23) And I just kept at it — that’s why I measure my sugar levels to the T. Everything I do is just to defeat diabetes in my life.

DAVID SINCLAIR: (01:38:23 – 01:38:26) What’s your fasting blood sugar level right now?

RAJ SHAMANI: (01:38:26 – 01:38:28) I don’t remember, but it’s way below.

DAVID SINCLAIR: (01:38:29 – 01:38:29) That’s okay.

RAJ SHAMANI: (01:38:29 – 01:38:32) Yeah, it’s much better, and my HbA1c is also good.

DAVID SINCLAIR: (01:38:32 – 01:38:34) I was going to mention that — yeah, HbA1c is good.

RAJ SHAMANI: (01:38:34 – 01:38:35) Yeah.

DAVID SINCLAIR: (01:38:35 – 01:38:35) Alright.

RAJ SHAMANI: (01:38:35 – 01:38:40) Everything is great — it’s better than most people in the world.

DAVID SINCLAIR: (01:38:40 – 01:39:22) I’m pleased. Obviously, if you’re eating a vegetarian diet, that’s going to help. For listeners and viewers who don’t know what HbA1c is, it’s worth speaking about — it’s when sugar gets attached to your hemoglobin in your blood. The red blood cells get sugar attached, and doctors can measure the percentage of your hemoglobin that has sugar on it — that’s your HbA1c, and the higher the percentage, the more sugar you’ve had over a period of a month in your blood. If you’re above 7, that’s bad.

RAJ SHAMANI: (01:39:22 – 01:39:23) Bad, yeah, that’s diabetic already.

DAVID SINCLAIR: (01:39:23 – 01:39:45) Diabetic. I like mine to be around 5, 5.2 — that’s a healthy level for someone my age. I have the same problem, my family is diabetic if they don’t watch out — my father, my grandmother had a stroke in her 30s, it’s that bad. So I have terrible genetics, I’ve had to also be very careful.

RAJ SHAMANI: (01:39:45 – 01:39:59) Same, that makes two of us. That’s why I keep my blood markers checked every 3 months, testing a lot of things, and keeping everything in check. That’s why I’m around 5. Good news.

DAVID SINCLAIR: (01:39:59 – 01:40:07) You have to stay alive, or healthy, for as long as possible, because the breakthroughs are coming. There are companies now that have figured out how to replace a pancreas to make insulin.

RAJ SHAMANI: (01:40:10 – 01:40:10) Really?

DAVID SINCLAIR: (01:40:10 – 01:40:10) Yeah.

RAJ SHAMANI: (01:40:10 – 01:40:11) Is it out there already?

DAVID SINCLAIR: (01:40:11 – 01:40:17) It’s not on the market yet, but they’re able to do it, and I think they’ve had success in the clinic now.

RAJ SHAMANI: (01:40:18 – 01:40:23) But my intention and my goal is to not have it in the first place.

DAVID SINCLAIR: (01:40:23 – 01:40:23) Ever, yeah.

RAJ SHAMANI: (01:40:24 – 01:40:32) Just live such a healthy life that at least I can delay it for as long as I can.

A World Without Disease, and the Role of AI

DAVID SINCLAIR: (01:40:33 – 01:41:03) Yeah. There will be a time in your lifespan where you won’t have to worry about getting cancer, diabetes, heart disease. We’re already almost there — you can detect cancer very early, you can prevent diabetes pretty easily. Just looking at the GLP-1 receptor drugs, and dementia is coming down rapidly. We are at a world, especially for those who have the financial resources to spend on all these tests, where you don’t have to die from these diseases anymore.

RAJ SHAMANI: (01:41:04 – 01:41:20) True, true. Now it’s getting better, and it’ll keep getting better thanks to people like you. There’ll be a time, probably next decade, where we won’t worry about half the diseases we talk about today.

DAVID SINCLAIR: (01:41:20 – 01:42:07) Right, right. Even in the past 12 months there have been huge breakthroughs — about 15 new drugs on the US market and some breakthroughs in cancer, pancreatic cancer is now treatable. It’s incredible, the progress happening now, and AI is going to speed that up.

It’s also really exciting to think about what’s happening in my lab. We discovered this eye age reversal about 9, 10 years ago. Since then we’ve continued to innovate — we now have the ability to give a mouse a pill and reverse its age and rejuvenate it. We’re working on getting it into humans, to see if we can do this without an injection, just by swallowing something.

RAJ SHAMANI: (01:42:07 – 01:42:08) How much is AI going to help you?

DAVID SINCLAIR: (01:42:09 – 01:43:04) A lot. We’ve been using AI for a few years now. One way is to use a camera to see whether an old cell has been rejuvenated — using a camera we can look at millions of cells and say, those cells were 90 years old and now they’re 20. That’s AI.

But the other thing that’s even more impressive is we can start with a trillion theoretical molecules, like resveratrol, but trillions of them, and instead of doing each experiment at the bench in the lab, which would take hundreds of years even with robots, we can do it virtually. AI can look at a target protein — we actually know what the targets are that we want to reverse aging — and say which of these trillion molecules will reverse aging. It’s given us a few hundred to test, which we’re testing right now.

RAJ SHAMANI: (01:43:07 – 01:43:20) In basic language, simple words — if you weren’t using AI, how many years would it have taken you to do exactly what you’re doing right now?

DAVID SINCLAIR: (01:43:20 – 01:43:24) Well, I asked an AI model to estimate this.

RAJ SHAMANI: (01:43:24 – 01:43:24) Yeah.

DAVID SINCLAIR: (01:43:25 – 01:44:18) It did all the calculations, and it said, in my lab, with let’s say 20 people working, it would have taken 160 years and over a billion dollars to do what we did — instead it cost us about $20,000 and a few months’ worth of work. And that was a few years ago — now it’s probably, you could do it on your phone. It’s going to get to the point where anybody can design a drug using their phone, we’re almost there.

The hard part, though, is taking the chemical that’s been designed by the AI and putting it into humans — that’s hundreds of millions of dollars, which is why, unfortunately, I think these claims that we’re going to cure diseases in the next few years are wrong, because finding the design of the molecule is the easy part. We’ve done this many times in my lab.

RAJ SHAMANI: (01:44:18 – 01:44:18) Yeah.

DAVID SINCLAIR: (01:44:19 – 01:44:27) It’s making them work and testing them — that’s the slow part, because it involves humans, the government, regulation, money.

RAJ SHAMANI: (01:44:28 – 01:44:29) Yeah, other mafias.

Competition, Pharma, and a Painful Chapter

DAVID SINCLAIR: (01:44:32 – 01:44:56) Well, we face a lot of competition. My company, Life Biosciences, is leading — some of the competitors are Jeff Bezos, Sam Altman, and others, who’ve put in billions trying to catch up with us. But the good news is there’s not just one winner — it’s a whole big industry that will come, and there are lots of diseases that can be tackled.

RAJ SHAMANI: (01:44:56 – 01:44:58) Do you think there’s a pharma mafia?

DAVID SINCLAIR: (01:45:01 – 01:45:03) Oh, tell me a bit more what you’re thinking.

RAJ SHAMANI: (01:45:04 – 01:45:06) No, I’m asking you — what do you think when I say this?

DAVID SINCLAIR: (01:45:07 – 01:45:51) I’ll tell you what I don’t believe. I don’t believe that pharma companies — well, I hear this sometimes, that pharma companies don’t want me to be successful because it will put them out of business. Everybody I know at pharma companies wants to help people, and if they see a new area of science like what we’re doing, they’ll do it too. A lot of large pharma companies are working on age reversal now — they’re jumping on it, not trying to stop it.

Are they banding together? I don’t think so — I think they’re competitive. But I have seen really bad tactics against my lab, against my companies, from certain pharmaceutical companies.

RAJ SHAMANI: (01:45:51 – 01:45:52) Like what tactics?

DAVID SINCLAIR: (01:45:55 – 01:47:22) Doing poor science that was wrong, to invalidate patents that we had filed, and these stories get into the newspapers and the journals. One of them is the resveratrol story — we published that resveratrol activates this enzyme SIRT1, which is true, it’s all been proven now, it’s not disputed. But one company — I’m not going to name them, because they’re one of the most powerful companies in the world — put out a paper that said Sinclair’s work is totally wrong, and they tried to invalidate our patent.

It caused a lot of problems. I couldn’t get any money in my lab for years, my lab dwindled down to just a few people hanging on. I almost was put out of business as a scientist, because a large company, and the newspapers, and even the world’s leading scientific journal, believed that I was wrong. Even my university — I’m at Harvard, right — had a group of people come into my office and quiz me, like, what’s going on here? It was really bad. I stayed in bed for a week, I was so depressed, I thought of quitting. It was rough.

To this day, some people still think I was wrong, but we’ve been proven right since. That was really bad tactics they used, and to this day they’ve never publicly apologized or said they were wrong.

RAJ SHAMANI: (01:47:24 – 01:47:25) And what kept you going then?

DAVID SINCLAIR: (01:47:28 – 01:48:34) Because what I’m doing is bigger than me — what I’m trying to do is give everybody a healthier life, and if I have to suffer as a consequence, I’m prepared to do that. I’m prepared to die for this cause, it’s really that important to me. So having a little bit of trouble in my life, that’s okay. I was a little bit depressed because I felt like the world was ungrateful, but I got out of bed, went back to the lab, and we worked harder at testing the theory and seeing if we were right. We turned out to be right.

What I learned from that episode, which was 2010, is: believe in yourself, do great science, and don’t get discouraged, just keep going. That’s a lesson everybody in life should have, because if you do something important, there will be critics, there will be people in the media telling you that you’re not good, and you will face problems. It’s not going to be easy, but you have to expect it and have a very thick skin and not take it personally.

RAJ SHAMANI: (01:48:35 – 01:48:35) True.

DAVID SINCLAIR: (01:48:35 – 01:48:43) I think it was Benjamin Franklin, or one of the founding fathers, who said that if you don’t have enemies, you’re probably not doing anything important.

RAJ SHAMANI: (01:48:43 – 01:48:44) Yeah.

DAVID SINCLAIR: (01:48:44 – 01:48:46) How about you? Do you have critics?

RAJ SHAMANI: (01:48:46 – 01:48:47) Of course.

DAVID SINCLAIR: (01:48:47 – 01:48:47) Really?

RAJ SHAMANI: (01:48:48 – 01:48:50) Of course. Very, very few, though.

DAVID SINCLAIR: (01:48:50 – 01:48:50) Yeah, good.

RAJ SHAMANI: (01:48:50 – 01:48:53) Because I’m probably in a good green zone.

DAVID SINCLAIR: (01:48:54 – 01:49:02) Well, you’re also a very kind and honest person. But anyone who has fame will attract critics.

RAJ SHAMANI: (01:49:02 – 01:49:47) Absolutely. There will be thousands of people who won’t like even this part — there will be people who say, hey, why did you question that thing, he was wrong and you just listened to him, and they’ll bash me and say I was soft on you. And there’ll be people who say, oh, you were clueless in front of him. And if I do come very well prepared, understand your scientific theories, and then ask you on that, then people say, if it was only about science, you would have done it in some journal, why are you making podcasts about it? No matter what you do, there’ll be critics — you make it advanced, you make it curious, you make it simple, in all three you’ll face critics. So it’s okay.

DAVID SINCLAIR: (01:49:47 – 01:49:55) Yeah, and the lesson here is just keep doing your best — be honest, be authentic, and you’ll be okay.

RAJ SHAMANI: (01:49:55 – 01:50:14) Yeah. But the work that you’re doing — I keep reading, almost every year, some quote that says anyone who is inventing anything new gets ridiculed by people of that generation.

DAVID SINCLAIR: (01:50:15 – 01:50:15) Oh yeah.

RAJ SHAMANI: (01:50:16 – 01:50:36) And only the next generation actually starts reaping the rewards and becomes grateful. People who were peers and colleagues of Edison ridiculed him, right, and now because of him we’re doing all of these things. So Edison was getting ridiculed then — who are we?

DAVID SINCLAIR: (01:50:36 – 01:50:40) You have to expect it, and people don’t like change. They certainly don’t like—

RAJ SHAMANI: (01:50:40 – 01:50:41) Are you experiencing this?

DAVID SINCLAIR: (01:50:42 – 01:51:08) Oh yeah, it’s been rough. The most vicious attacks are from my scientific colleagues — the public is generally very supportive. It’s the scientists — but it’s a scientist’s job to criticize other scientists, that’s how science progresses. There’s nothing wrong with cordial, professional, gentlemanly arguments.

RAJ SHAMANI: (01:51:09 – 01:51:14) Fair. Do you get stressed because of all of these things?

Learning Not to Get Stressed

DAVID SINCLAIR: (01:51:15 – 01:52:08) I used to, definitely, when I was your age, because I hadn’t made it yet — I hadn’t reached my goal, hadn’t done everything I wanted to do. I’m now at a point in life where I’ve already achieved more than I thought I would in my lifetime, so everything else is a bonus. I have 3 wonderful kids, a wonderful partner, a great job, I get to have fun talking about my work, and I have really smart students who do the hard work — they’re back at the lab today, working hard on a Sunday.

I don’t get stressed, and my heart rate is in the 40s usually at night, maybe 50 during the day. My heart rate variability, which you’d want to be high, is in the 90s, which is like a marathon runner’s.

RAJ SHAMANI: (01:52:08 – 01:52:09) Yeah, that’s cool.

DAVID SINCLAIR: (01:52:09 – 01:52:14) And I think that’s because of my practice, which is to never get stressed.

RAJ SHAMANI: (01:52:15 – 01:52:27) Nice. See, this is what we need to promote as well — we need to get a lot of people to go to India and promote the Indian ancient wisdom, they figured it out.

DAVID SINCLAIR: (01:52:28 – 01:52:33) Oh, they did — the food, the relaxation, the meditation, the routines.

RAJ SHAMANI: (01:52:33 – 01:52:37) There are so many things which are yet to be discovered by the world.

DAVID SINCLAIR: (01:52:37 – 01:52:41) It’s the world’s oldest religion as well — one of the oldest cultures.

RAJ SHAMANI: (01:52:41 – 01:52:43) It’s the oldest civilization.

DAVID SINCLAIR: (01:52:43 – 01:52:45) Yeah, so of course they figured it out early.

RAJ SHAMANI: (01:52:46 – 01:52:46) Yeah.

DAVID SINCLAIR: (01:52:46 – 01:53:00) We’re still catching up. Some of the medicines — Ayurvedic medicines — there’s a lot of truth to that, and we’re just finding the molecules that are working in those ancient medicines, from the plant world mostly.

RAJ SHAMANI: (01:53:00 – 01:53:09) True. And you’re a big proponent — you promote plants a lot, so of course you’d like that. I’m sure you like a lot of Indian wisdom as well.

DAVID SINCLAIR: (01:53:10 – 01:53:10) Yeah.

RAJ SHAMANI: (01:53:10 – 01:53:17) I’m sure. Okay, tell me — we were talking about stress. Is aging partly accumulated stress?

Psychological Stress vs. Biological Stress

DAVID SINCLAIR: (01:53:20 – 01:53:40) It is, in the sense that when cells, the body, get overloaded with stress — a little bit is good, but if you go too far, then these processes that drive aging happen faster. But we have to be careful not to confuse psychological stress with biological stress.

RAJ SHAMANI: (01:53:40 – 01:53:41) Explain both.

DAVID SINCLAIR: (01:53:42 – 01:55:37) Alright. Psychological stress, we all know — we’re worried, we have cortisol levels in our body, we’re in fight-or-flight mode. That will age you faster — we know that mostly because the hormones that come out of your system cause accelerated aging. That’s psychological, and you can change it within minutes. Right now, if we do breathing exercises, we can bring that down. That’s easy to fix — that’s step one.

The other is biological stress. A little bit of biological stress is good — fasting, exercise, sauna, cold plunge, these activate your body’s defenses against adversity. But if you do too much — if you don’t eat for so long that you start to chew up your muscles, that’s too much stress. If you go to a rock concert, or go out in the sun and get very sunburnt, that’s too much for your cells — that’s not mild stress, that’s not adversity, that’s serious damage. That’s going to help this process of unraveling.

Anyone who has spent their life in the sun will have experienced broken DNA from the light, and this process will accelerate. There’s a photo on the internet of a person who got sunburnt on one side of the face because the sun was coming through the window of the truck, and one half is much older than the other side. So we know the sun can accelerate skin aging, and it’s the same for the rest of the body — too much damage will accelerate aging.

RAJ SHAMANI: (01:55:38 – 01:55:40) But shouldn’t we be in the sun? That’s what everybody—

DAVID SINCLAIR: (01:55:40 – 01:56:06) A little bit, for sure, a little bit. There’s debate — some doctors say no sun is good. In my life I like to get a little bit of sun, but not enough to feel burnt, that’s definitely too much. I usually wear sunscreen and a hat. But yes, I like natural sun, just be aware that any sun is going to accelerate aging.

RAJ SHAMANI: (01:56:07 – 01:56:14) And at what point do these small damages become permanent stress damage in my body?

DAVID SINCLAIR: (01:56:15 – 01:56:34) That’s a very good point. Let’s go back to these balls here that I’ve got. What we want is for this to always stay stable, in this structure. A little bit of damage, a little bit of adversity, a little bit of hunger or sauna is not going to change this.

RAJ SHAMANI: (01:56:34 – 01:56:34) Okay.

DAVID SINCLAIR: (01:56:35 – 01:56:43) It’s when it gets to a point where these proteins have to react and go away and fix — that’s too much.

RAJ SHAMANI: (01:56:43 – 01:56:44) Yeah.

DAVID SINCLAIR: (01:56:44 – 01:57:33) A rock concert or X-rays will cause this — a little bit is okay, but too much means these proteins don’t always come back to where they started. That’s what we’ve seen. If you give a little bit of DNA damage, a tiny bit, it doesn’t cause this problem, the cells can deal with it. But if there’s a broken chromosome, not just a little nick but a broken one, that’s a very serious problem for the cell — if it doesn’t fix that chromosome, either the cell will die or the animal will get cancer. So it has to fix it, that’s panic for the cell, and this comes apart if you break a chromosome. Usually what happens with DNA damage is just a little bit gets broken.

RAJ SHAMANI: (01:57:34 – 01:57:34) Okay.

DAVID SINCLAIR: (01:57:34 – 01:57:43) And you can easily fix that, that’s not a big problem. But if your 6 feet comes apart into 3 feet and 3 feet, that’s a big problem — that’s called a double-stranded DNA break.

RAJ SHAMANI: (01:57:44 – 01:57:55) But how do I know what I’m doing on an everyday basis? Because this sounds very scientific — how do I know that what I’m doing is actually making me better or damaging me?

DAVID SINCLAIR: (01:57:55 – 01:58:43) Well, I would go with the evidence — we know the healthy fasting practices from human studies, we know the healthy sauna practices. With sauna, you can definitely overdo it — there are temperatures you don’t want to reach, you can dehydrate. But if you go to pubmed.org, you can read papers about saunas, and they’ll tell you that 20 minutes, 3 times a week, is associated with less heart disease. My point is, you don’t need to know molecular biology, you don’t need to understand this fully — I don’t even understand it fully. I go based on human studies, what works and what seems to work.

A Quick Digression on Sauna Habits

RAJ SHAMANI: (01:58:44 – 01:58:52) Since we’re talking about sauna — did you see the new thing about freezing your balls before you go to the sauna?

DAVID SINCLAIR: (01:58:52 – 01:58:55) Keep them cold if you want to procreate.

RAJ SHAMANI: (01:58:55 – 01:58:55) Yeah.

DAVID SINCLAIR: (01:58:55 – 01:59:03) I would wrap them in a towel. We know that sperm requires cool, that’s why it’s outside the body.

RAJ SHAMANI: (01:59:04 – 01:59:13) And now I’ve seen some videos where people are keeping a cold ice pack on the head as well — on the head, on the balls, and then they say—

DAVID SINCLAIR: (01:59:13 – 01:59:28) Why the head? That part I don’t know about. I actually think a bit of stress to the hair follicles could be good for hair — I use red light to stimulate my hair growth. But yeah, a little bit of stress on the head is good for you.

RAJ SHAMANI: (01:59:30 – 01:59:38) But freezing the balls — if someone’s going to the sauna and not putting an ice-cold pack down there, is it a problem over a long time?

DAVID SINCLAIR: (01:59:39 – 02:00:10) Not long-term, but in the short run you’ll make less sperm if you — even if you wear tight pants and get hot down there — it’s known that you need to be less than body temperature to make sperm productively. At my age it doesn’t matter, but for men who want to have children, I would think it makes sense to have, well, not freeze them, that would be worse, but just a cold towel down there, probably. I think that makes a lot of sense.

Can 10 Years of Bad Habits Be Reversed?

RAJ SHAMANI: (02:00:10 – 02:00:52) When you look at young people, typically from 20 to 30, it’s 10 years of hardcore hustle, bad work timings, toxic food, financial insecurity, struggle. These 10 years, you don’t know what you’re doing — even if you’re ambitious and things are going right for you, you don’t know when you’re eating, when you’re sleeping, what you’re doing, and you’re perpetually lacking something. So this 10 years of a bad environment, according to aging — can we reverse this damage?

DAVID SINCLAIR: (02:00:54 – 02:01:01) We’re working on it. We can, in animals, and I think one day we will be able to reverse it.

RAJ SHAMANI: (02:01:01 – 02:01:13) But today, if that’s today, we don’t have it — so anyone who has gone through these 10 years, or is going through them, putting themselves through this, will this become permanent damage that they will never be able to reverse?

DAVID SINCLAIR: (02:01:16 – 02:01:33) No, we think that all aging is reversible, theoretically — we’re doing it in the eye, we think it’ll work everywhere. But right now there’s nothing that really reverses aging by more than a year or two — it’s still early days.

RAJ SHAMANI: (02:01:34 – 02:01:36) So all these habits over 10 years are actually damaging us?

DAVID SINCLAIR: (02:01:37 – 02:01:50) Yeah, that’s why I tell young people, even teenagers, don’t go out and party, don’t drink so much alcohol, don’t just eat pizza — because what you’re doing now will affect the rest of your life.

RAJ SHAMANI: (02:01:51 – 02:02:00) But how do people stop partying? How do people stop working really hard and sleeping for 4 hours? Because that’s where—

DAVID SINCLAIR: (02:02:01 – 02:02:26) Well, working hard and sleeping for 4 hours is pretty common — I still do that myself. It’s hard, but it’s the really bad habits — the overdrinking. I used to drink some red wine every day, I don’t do that anymore. I think there are a lot of young people who have stopped drinking alcohol. Did you ever drink alcohol?

RAJ SHAMANI: (02:02:26 – 02:02:27) No.

DAVID SINCLAIR: (02:02:28 – 02:02:37) Great. I did, and I regret it. Smoking is the big one — smoking has chemicals that break DNA, so you’re going to be like that mouse that got older faster if you smoke.

RAJ SHAMANI: (02:02:37 – 02:02:37) Agree.

DAVID SINCLAIR: (02:02:38 – 02:03:06) So there are some pretty easy things to avoid doing. There was a study from Harvard that showed the men who lived the longest had 14 years of extra healthy life if they just did 5 things — from what I remember, it was: don’t overdrink, don’t smoke, don’t be overweight, don’t stress, and eat healthy. Those are what your grandmother would tell you, probably.

RAJ SHAMANI: (02:03:06 – 02:03:06) Yeah.

DAVID SINCLAIR: (02:03:06 – 02:03:10) If you just do the basics, that’s already 14 extra healthy years.

RAJ SHAMANI: (02:03:11 – 02:03:15) But how do you get rid of the part which is — no alcohol is easy, no smoking is easy.

DAVID SINCLAIR: (02:03:15 – 02:03:16) Yeah.

RAJ SHAMANI: (02:03:16 – 02:03:51) No stress is such a part of your life today — if you’re young and living in a large city, you’re stressed about financial insecurity, stressed about AI taking your job, stressed about what’s going to happen, stressed about your health, stressed about reversing the damage from all the sugar and alcohol you’ve consumed, stressed about finding a partner, starting a family — or maybe you have a toxic boss and you’re stressed about that too. How do you get rid of that?

DAVID SINCLAIR: (02:03:52 – 02:05:15) It’s difficult, and I was not good at it until I was 50 — that’s when I met Serena. What I’ve learned to do is have faith in myself. That’s the key. I was hard on myself, and you probably are too, because you’re very successful — I could do this better, I should do this better, why am I not doing this better, why didn’t I sleep more. You’ve got to stop that, it’s destructive.

What I do now is — yeah, I’m concerned my lab could run out of money, I’m concerned the trial might not work, I’m concerned some newspaper will make up a story — but I don’t dwell on it. It comes to my mind and I push it away, and I tell myself, I believe in myself, I can’t control what they’re doing, but I can control what I am doing, and this is what I’m going to focus on. I’m older, so I have a little more experience, and I know I can do it. I wish earlier in life I’d had this attitude — I believe in myself, I’m not going to worry, I will figure it out, I will face trouble, but I know I’m strong enough to get through it, and I will defeat whatever comes my way. That’s how I live now, so I don’t get upset with these things.

RAJ SHAMANI: (02:05:16 – 02:05:20) It’s good to hear. It’s very difficult to practice.

DAVID SINCLAIR: (02:05:20 – 02:05:20) It is.

RAJ SHAMANI: (02:05:21 – 02:05:21) I’m trying.

DAVID SINCLAIR: (02:05:22 – 02:05:29) It took me 50 years, but yes, try — it’s so important, your life will be completely different if you can master that.

The Top 3 Habits Damaging Young People

RAJ SHAMANI: (02:05:30 – 02:05:36) What do you think are the top 3 things young people are doing that damage them the most?

DAVID SINCLAIR: (02:05:37 – 02:05:44) Oh well, overeating, number one — being obese is the number one globally.

RAJ SHAMANI: (02:05:45 – 02:05:45) Okay.

DAVID SINCLAIR: (02:05:46 – 02:07:38) We know that accelerates aging. The second would be not moving enough — we sit down too much, we play computer games, we’re at a desk job. The third would be the quality of the food is terrible — it’s easy and cheap to buy fast food, and the food is engineered to be addictive, and it’s not as fun eating hummus or lentil curry. I thought of plants as the side dish to meat my whole life until recently.

Those are the 3 things. If you can maintain a healthy weight — for me, as soon as I start to build up more than that on my chest, I know I need to fast and get rid of it. Then there’s move, move, move — get a standing desk, go for a walk, go for a run, get to the gym, do something, just don’t sit all day. In my office I have a standing desk, I’m rarely sitting the whole day — my feet get a little tired, but it’s great, it’s very good for my muscles, my legs are strong.

And the third one is quality of food — fresh food, fresh colored food, you’ll feel so great. Don’t overcook things — I know most cultures, including India, overcook their vegetables. Keep it crunchy, it’s not bad, it actually tastes better, because you’re destroying a lot of these polyphenols if you overcook it or over-microwave it. Slightly steam, slightly boil, or eat fresh vegetables. Salad is great.

Healthy Vegetarian vs. Unhealthy Vegetarian

RAJ SHAMANI: (02:07:40 – 02:08:11) All-day salad. I was exactly like you until last year — I used to see vegetables as a side thing, not the main dish, even though I’m vegetarian, because I would eat overly cooked lentil soup, which we call dal in India, or vegetables filled with oil and curries, mixed together. I always used to think that was healthy, I’m eating vegetables, but it’s—

DAVID SINCLAIR: (02:08:11 – 02:08:33) That’s so true. There are studies that show vegetarianism is pretty good for longevity, but what’s really interesting is if you break it down into healthy vegetarian and unhealthy vegetarian, there’s a big difference — healthy vegetarians are way ahead of unhealthy vegetarians. So just being vegetarian is not sufficient.

RAJ SHAMANI: (02:08:34 – 02:08:40) Give me the differences between healthy vegetarianism and unhealthy vegetarianism.

DAVID SINCLAIR: (02:08:41 – 02:09:38) An unhealthy vegetarian would eat french fries, chips, bread, overcooked soups, and other things — winter food is not healthy vegetarian food. Healthy vegetarian is, yes, salads obviously, but also legumes — baba ganoush, hummus, these are also full of protein and vitamins. A typical meal for me and for Serena would be some fresh fruit, fresh vegetables, maybe a bit of olive oil, balsamic vinegar. If we steam the vegetables, it’s very quick, very light — the asparagus would still be crunchy, the broccoli would be crunchy. If your vegetables start to lose their color, you’ve gone to the unhealthy side.

RAJ SHAMANI: (02:09:39 – 02:09:46) Yeah, that’s a good metric — if the original color is no longer there, you’ve made it unhealthy.

DAVID SINCLAIR: (02:09:46 – 02:09:54) You know why? Because these chemicals, these polyphenols, are the colors, and they’re the health. So when the color disappears, the health disappears.

Sleep, Supplements, and a Daily Protocol

RAJ SHAMANI: (02:09:54 – 02:10:05) Interesting. Okay, tell me the ideal protocol for a young person — how many hours of sleep? This is the most basic thing, but I still want to know.

DAVID SINCLAIR: (02:10:06 – 02:11:53) Alright, I’ll say a few things, but the detail is in Lifespan, my podcast — everyone tune into that for the detail. The cheat sheet would be: try to eat less than 3 meals a day, see if you can join a gym so you can lift weights, if not get some weights at home, that’s pretty easy. If your gym has a sauna, great — if you can afford one, get one at home. And move, move, move, move — walk upstairs, don’t take the elevator, get a standing desk, walk to the shop. These small things add up, and monitor yourself — you have a ring on, I have a couple of rings on, I’m always looking to do better, more steps, lower heart rate, more heart rate variability, better sleep.

Speaking of sleep — we haven’t touched on that. What I’ve learned, and Serena also taught me, is it’s not the number of hours you sleep, it’s the quality. You can measure deep sleep, and the amount of deep sleep you get is really what determines the brain fog in the day and how energetic you are. She and I can go for a week with only a few hours’ sleep, and that’s not a problem for us, because we’re very efficient at sleeping — we get into sleep quickly, we dream, we get deep sleep, and we wake up fresh even after just a few hours. We don’t do a few hours forever, we catch up on weekends usually. But I do want everybody to know you can still have healthy sleep as long as it’s efficient — some of these devices will tell you your efficiency, and over 90% is typical for us.

RAJ SHAMANI: (02:11:55 – 02:11:56) I need the Sweet Dreams.

DAVID SINCLAIR: (02:11:57 – 02:12:06) Sweet Dreams is Serena’s — we were talking about this earlier. Sweet Dreams is Serena’s product, I take it pretty much every night to get into deep sleep.

RAJ SHAMANI: (02:12:06 – 02:12:16) And the protocol you talked about — is it true for a 25-year-old, a 45-year-old, a 65-year-old, all the same? Or do they do it differently?

DAVID SINCLAIR: (02:12:17 – 02:13:07) Well, exercise, sleep, and diet are universal. But when we get into the next level of detail — which supplements, which medicines, then stem cells, peptides, blood transfusions — there’s another level of complexity we talk about on my podcast. I’d say in your 20s, what we’ve talked about today is a very good start, and I know your listener demographic is 20 to 30 — start with the basics, get those right, and then consider some supplements. The ones I take, for example — resveratrol in the morning, NMN in the morning for the NAD boost.

RAJ SHAMANI: (02:13:07 – 02:13:08) Should young people take that?

DAVID SINCLAIR: (02:13:10 – 02:13:55) Well, I never make recommendations because I don’t know everybody’s blood work. I’d say the science is strong that taking it can have benefits at any age, though we haven’t tested it on people in their teens and 20s yet, so there’s an unknown — but based on mouse research, which we’ve done for the last 15 years, it should be fine. I want to say, though, and it’s important that everybody listening knows — I measure everything, I know when something’s changing, I know if it’s doing good or bad, and it’s all done under a doctor’s supervision. That’s important.

RAJ SHAMANI: (02:13:55 – 02:13:56) Yeah, right.

DAVID SINCLAIR: (02:13:56 – 02:14:34) We don’t want to just take something and hope for the best, and we don’t want to do it without our doctors knowing about it. I’d encourage everybody to do what I do, what my father does, what Serena does — we measure things and talk to doctors. Serena and I talk to 3 different doctors every week — that’s a bit excessive, that’s our life — but I do encourage people not to just trust what they hear on the internet. Research it yourself, talk to your doctor, take one thing, see if it works for you, measure it. If you don’t see a change, why do it?

RAJ SHAMANI: (02:14:34 – 02:14:34) Fair.

DAVID SINCLAIR: (02:14:35 – 02:14:35) Yeah.

Which Supplements Should Young People Avoid?

RAJ SHAMANI: (02:14:35 – 02:14:56) This is a better question — one supplement that young people should never take, that’s specifically for people above the age of 40, that people under 40 or under 35 should not take at all.

DAVID SINCLAIR: (02:15:02 – 02:15:43) There are medicines that people my age sometimes take for longevity. There’s a diabetes drug, metformin, which lowers blood sugar — that one, I think, is extreme for someone in their 20s to take. Why? Unless you have a family history like you do, your body is still very sensitive to insulin, able to deal with a lot of metabolic changes, so it’s not necessary — why take the risk with a medicine?

There’s another drug that’s even more risky, called rapamycin. Have you heard of this drug?

RAJ SHAMANI: (02:15:43 – 02:15:43) No.

DAVID SINCLAIR: (02:15:44 – 02:16:53) Rapamycin is a favorite of the longevity field, because when you feed it to different types of animals, they live longer. But it also affects the immune system — if you take too much, it makes your immune system go down, and it has a lot of side effects at high doses. So that one, for me, if you were to force me to say what not to take, seems too extreme and unnecessary for young people to try, because the risk is too high versus the reward. That’s my opinion, some may differ, some people love rapamycin. Even I am cautious with rapamycin at my age, because it has toxicities, affects the immune system, and I’m concerned about the long-term side effects of this drug. The ones I take, like resveratrol and NMN, are natural molecules — they exist in our food, in our bodies. So the risk is really low and the potential gain is great.

RAJ SHAMANI: (02:16:54 – 02:17:00) But is there any specific supplement that’s easily available, that people are taking right now, that we should not take?

DAVID SINCLAIR: (02:17:00 – 02:17:42) I see what you mean, as a supplement that’s out there. There is some scientific debate about one particular supplement, an amino acid called taurine. There was one study that gave taurine to mice, and they lived, I think, 15% longer. So I started taking taurine and didn’t see much benefit to me based on my blood work. Then a study, I think last year, came out and found there was no decrease in this amino acid in older people, so I stopped taking it for that reason. I think if people are taking high-dose taurine, they should look at the science and make a decision for themselves.

Can You Get Too Obsessed With Longevity?

RAJ SHAMANI: (02:17:43 – 02:18:06) Is there a point where someone could get obsessed with all these longevity tools and protocols, and at what point is it actually detrimental for your body, actually damaging, not helping? You’re waking up, tracking this, tracking that, doing cold plunge, doing sauna, doing eating — you know how you have these ninjas about it?

DAVID SINCLAIR: (02:18:07 – 02:20:50) Yeah, there are definitely people who obsess about it — I don’t know if it’s overdoing it, but they’re obsessed for sure. I’m not in that category — I’m a scientist and I do it for a learning exercise, I want to learn, I want to teach, and it’s also enjoyable, it’s like a hobby. If you read up about it, you become knowledgeable, and if you follow me on social media it can become enjoyable, like something you do as a hobby.

But hobbies can become detrimental if you become obsessed with anything — you can collect a few cars, but if you want to spend all your money on cars, that’s detrimental. Same with longevity — if it’s taking too much of your salary, too much of your time, if you’re taking too many supplements at once without testing them on yourself, then you’ve gone too far.

I have a bag of supplements that I take with me when I travel — I’ve worked with and tested them on my body, some for over 15 years, it’s like a symphony of supplements. I know what I’m taking, I’m at a point where I’ve adjusted my life and I’m happy with it. Occasionally I try something new, occasionally I stop taking something. I think that’s a healthy way to exist — you do it for fun, and if I skip it or forget my supplement, I’m not going to worry. If I eat some meat, I’m not going to worry. If I have breakfast, I’m not going to worry. But it’s the consistency — I’ve been taking resveratrol almost every day for 15 years or more, missed a few days, but it’s consistent. Exercise, walking, all these things.

Longevity doesn’t come overnight, it can take decades to appear — you can’t decide at my age, oh, I’m going to suddenly live long, not yet, we’re working on it. But to get to my age and have my kind of heart rate and heart rate variability, you do need to start, I think, decades earlier, or at least 10 years earlier, and optimize preferably at your age. I wish I had started at your age — I didn’t really get into it until my 30s, and in my 30s, the 2000s, we didn’t know much, there wasn’t much you could do. Now there’s so much information, it’s a wonderful time to be alive, and we can have a big impact on our future health by what we do, what we eat, what we swallow. And it’s fun too.

One Thing to Change Tomorrow Morning

RAJ SHAMANI: (02:20:50 – 02:21:02) True. If people listening right now feel overwhelmed by all the information in the world, by this podcast, by all the things they do in the world—

DAVID SINCLAIR: (02:21:02 – 02:21:02) Yeah.

RAJ SHAMANI: (02:21:02 – 02:21:12) And they could just change one thing in their life tomorrow morning, which will have the biggest impact on their aging, on their life, on making them better—

DAVID SINCLAIR: (02:21:12 – 02:21:13) Yeah.

RAJ SHAMANI: (02:21:13 – 02:21:13) What would that be?

DAVID SINCLAIR: (02:21:15 – 02:21:50) Alright, the first thing I’m going to say is it’s not confusing if it’s presented clearly, and what I’m building is a community where people will learn how to live their longest life — it’s called Lifespan. That’s what I’m doing, I want everybody to experience this, but it can be overwhelming, so we need to explain it simply. I would start with eating less often, and within those meals, eating fresh. That’s the start.

RAJ SHAMANI: (02:21:51 – 02:21:51) Okay.

DAVID SINCLAIR: (02:21:52 – 02:21:57) And then learn from there. So much to learn — it’s really fun, and you’ll feel so great.

The Cost of Becoming David Sinclair

RAJ SHAMANI: (02:21:58 – 02:22:09) Perfect, done. I have the last question, which I ask all my guests — what is the cost of becoming David Sinclair?

DAVID SINCLAIR: (02:22:11 – 02:23:20) Oh, I rarely have time for myself. I was not the father to my children that I wanted to be — I’m trying to make up for that, but I was often away and I wasn’t focused on the present, and I did not appreciate my life. I wasn’t grateful for the joy I could have had in my 30s and 40s, because I was so focused on making the impact, testing the science, getting the molecules into people, that I didn’t stop and appreciate that I had 3 amazing kids, a house, and a career that I loved. It was just go, go, go, always problem solving. I’m different now, but I missed probably 20 years of joy that came with being David Sinclair, of working, being obsessed with perfection.

RAJ SHAMANI: (02:23:21 – 02:23:39) Thank you so much for sharing that, I really appreciate it. Thank you for spending time with me, explaining the science, which was my nightmare — today I understand much better. I love this balls analogy and this structure. Thank you so much for doing all of this, I really, really love our time here.

DAVID SINCLAIR: (02:23:39 – 02:23:57) Raj, I appreciate you having me on, and this was a really great chance to tell people about what’s typically very complicated science. I think your questions were perfect, to be able to explain something I rarely have a chance to explain at this simple, but also very interesting, level.

RAJ SHAMANI: (02:23:58 – 02:23:59) Thank you so much. Thank you.

DAVID SINCLAIR: (02:23:59 – 02:23:59) Yeah, thanks.

RAJ SHAMANI: (02:24:00 – 02:24:15) So, you know, how I got exposed to your work — there was one guest on my podcast who ended up talking about the stuff you’ve written in your book. Then there was another guest who also spoke, and then a third — I was like, what is going on?

DAVID SINCLAIR: (02:24:16 – 02:24:17) Oh, that’s interesting.

RAJ SHAMANI: (02:24:17 – 02:24:21) Yeah, and I was so fascinated. Thank you for doing this, it’s a pleasure to host you.

DAVID SINCLAIR: (02:24:22 – 02:24:33) Well, no, it’s a pleasure to be here. I love how you educate — this is not a podcast about advertising, it’s not about making ourselves look good, it’s for your listeners to learn.

RAJ SHAMANI: (02:24:34 – 02:24:35) Yes. Yes.

DAVID SINCLAIR: (02:24:35 – 02:24:37) That’s why you’ve been so successful.

RAJ SHAMANI: (02:24:37 – 02:24:43) Thank you, thank you, that’s the whole goal — today we’re going to learn, as you can see, we have the whole classroom set up here right now.

DAVID SINCLAIR: (02:24:43 – 02:24:44) Yes, exactly.

RAJ SHAMANI: (02:24:45 – 02:25:03) Thank you for watching this episode till the end. We would love to know what you liked or disliked about this episode, and which guests you would like to see on the show — let us know in the comments. Your feedback helps us improve and make every episode a little better. I’ll see you next time. Until then, keep figuring out.

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