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David Sinclair (00:00):

Welcome to the Lifespan Podcast, where we discuss the science of aging and how to be healthier at any stage of life. I’m David Sinclair. I’m a professor of genetics at Harvard Medical School and co-director of the Paul F. Glenn Center for Biology of Aging Research. I’m joined by my lovely co-author and co-host, Matthew Laplante. Welcome, Matt.

Matthew LaPlante (00:24):

I love that you call me lovely.

David Sinclair (00:26):

I think you are lovely. You’re nice. You’re nice. You can be nice sometimes.

Matthew LaPlante (00:30):

Hey, today in our episode, we’re going to be talking about exercise and other what you call adversity mimetics. But before we get to that today, right after we stopped taping in the last episode, you went, oh my God, iron. And then we had a really great conversation about iron. And so I wanted to bring us back there before we could move forward today. Is that all right?

David Sinclair (00:52):

That’d be great. So the last episode, if anybody missed it, was about the foods that we can eat or not eat. Or not eat, right. To live a long time. And it was remiss of me not to bring up a pernicious element called iron. Pernicious. Yeah. It’s one of the elements that is turning out to be quite a dangerous element to have too much of in your body. Increasingly, we see that people who have high levels of iron have accelerated aging.

Matthew LaPlante (01:23):

Okay, yeah, but iron is essential, right? We all need iron. In fact, people supplement with iron a lot of times.

David Sinclair (01:29):

Right, well, we need iron. It’s a major component of hemoglobin, which carries oxygen, which we need. But the levels don’t need to be as high as we once thought. In fact, people who live a long time and have these diets that are recommended, I typically see they have lower levels of iron and lower levels of hemoglobin. And this is not necessarily a bad thing. Conversely, people who have very high levels, either genetically, hemochromatosis, or take a supplement and end up with high levels of iron might be predisposing themselves to accelerated aging.

Matthew LaPlante (02:03):

Okay, so what about just, I mean, this plays into your idea about why people should limit their meat intake, though, because meat intake, meat is high in iron, especially red meats, especially are higher in iron.

David Sinclair (02:13):

That’s one aspect. But typically, if people are taking multivitamin with high levels of iron, this could be a really bad thing. It’ll accumulate in tissues. And we know now that particularly ferrous iron leads to the production of free radicals that damage tissues in the body. And even worse, it leads to the accumulation of these zombie cells, which we call senescent cells, and those drive the aging process, in part, large part, because they leach these inflammatory molecules that cause other cells in the vicinity to become inflamed, to age, to senesce, and even cause cancer.

Matthew LaPlante (02:47):

Let’s back up for a second here, because I think we’re gonna talk more about senescent cells in a coming episode, but we have mentioned free radicals before, and I think that’s a word that gets thrown around a lot. And maybe not everybody understands free radicals.

David Sinclair (03:02):

Right. And we’re not just talking about people in Portland, Oregon.

Matthew LaPlante (03:05):

Or Eugene or Berkeley.

David Sinclair (03:07):

Yeah, so these are free radicals. These have been around for millions of years, of course, and we’ve known about them for at least the last 70. These are, there are three main types of free radicals. There’s the superoxide molecule, which is quite damaging. It can lead to what are called advanced glycation end products, which are basically proteins that are damaged. It’s one of the reasons you want to fast, sometimes during the day, to get rid of these damaged proteins. There’s a superoxide anion, it’s called, which creates most of the oxidative stress in the body.


And then there’s a third one, hydrogen peroxide, which you can buy a bottle of and dye your hair blonde or orange, as my hair went during the pandemic. Those three things are really bad. And you dyed your hair during the pandemic? I did, I got bored, just dyed it. How did it look? Horrible, it really went orange. I’ve been dying it ever since just to cover it up, but it’s almost gone, thank goodness. But this is, this is where iron comes in. When you have a superoxide molecule, it’ll be turned into peroxide by an enzyme called superoxide dismutase, which is extremely important to get rid of that superoxide, which is gonna damage the cell. But then you get hydrogen peroxide, and we know how bad that is. Look at my hair, you don’t want that circulating. So then what happens is there’s a molecule called glutathione which will turn that into water. But if you have too much iron around, there won’t be enough chance to detoxify it. And it’ll be turned into this hydroxyl radical. And that’s a really damaging molecule that goes on to damage your DNA, your RNA, lipids, proteins, and drive aging and senescence. So you wanna have iron enough not to be lethargic, to have enough oxygen transported, but not super high levels that’ll cause accelerated aging.

Matthew LaPlante (04:54):

And this is gonna be different for different people. 10% of the population in the United States has the HFE gene, which makes them more susceptible to hemochromatosis, which means they have to be even more concerned. You can’t know this without knowing if you carry this gene though, right? I mean.

David Sinclair (05:11):

Right, you do need to measure things. And that’s why I, myself, and I recommend people measure their blood biochemistry and determine whether their iron, whether it’s free iron, which is the worst type, or even the bound iron, are out of whack. And you can correct for that. In the case of a normal person, I would say don’t take an iron supplement necessarily, although women may need it certain times of the month. But people who have hemochromatosis, they’re particularly susceptible to aging. And the recommendation typically of a doctor is donate blood if you can.

Matthew LaPlante (05:42):

Okay, so just to like go over what we talked about last time really quickly, you advocate for a plant-based diet. You advocate for low iron levels. What am I missing?

David Sinclair (05:57):

Well, we’re gonna talk about that today. What type of exercise works best?

Matthew LaPlante (06:01):

I was just talking about how we should eat, but yeah.

David Sinclair (06:04):

Well, we eat less often. Eat less often. Yeah, so I’ve gone from not eating breakfast now to not eating lunch as well and just focus on dinner and giving my body a rest from food overnight and through the middle of the day so that it turns on our defensive genes against aging. Those three buckets, the mTOR, which senses amino acids or lack thereof, the AMPK, which senses energy, which is glucose mainly, and the sirtuins, which I work on that sense all of those things, including exercise. And those three protective mechanisms we can turn on by eating the right things, eating less often, and exercising.

Matthew LaPlante (06:41):

And this leads in really well actually to what we’re talking about today, because what we’re talking about is bringing your body into a state of perceived adversity as a way to turn on these genes. Before we can do that, we’ve got some business to take care of.

David Sinclair (06:55):

We do, because this podcast comes to everybody for free. We should definitely mention the sponsors that make that possible. Our first sponsor is Athletic Greens. Athletic Greens is a greens powder developed from a complex blend of 75 vitamins, minerals, and whole foods sourced ingredients. It’s filled with adaptogens for recovery, probiotics, and digestive enzymes for gut health. They also have vitamin C and zinc citrate for immune support. I’ve been drinking Athletic Greens for a number of years now. I do that not just because it tastes good, but because I travel and I often don’t eat perfectly. And by having it every morning, I rest assured that I’m getting all of the vitamins and minerals that I need for optimal health. If you’d like to try Athletic Greens, you can go to slash Sinclair to claim a special offer. They’re giving five free travel packs plus a year’s supply of vitamin D3 for immune support and K2, which will keep the calcium out of your arteries and put it into your bones. Again, go to slash Sinclair to claim this special offer.


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Matthew LaPlante (09:33):

All right, so let’s get into this. In this episode, we’re talking about some of the things that people can do to create and mimic in their lives the biological adversity that’s more conducive to better lifespans and health spans. We call these.


We call these that. I mean, like when you say we call these that, is it like you and I call them that? Because I know we call them that, but is it like, is that a term that scientists use that people actually use right now? We just made it up. You’re just making it up, but it’s a good word, right? We’ll use it. Okay, so, and the reason why adversity is important ties back to this idea that you’ve proposed of a survival circuit. So before we move forward in this, let’s talk about the survival circuit. We don’t have to go way, way back in history but we don’t have to go way, way back in history.

David Sinclair (10:21):

Not 4 billion years. We’ll come forward in time a little bit.

Matthew LaPlante (10:23):

Yeah, you can go back 4 billion years and that’s in the book, but we’re gonna start in the 1990s with Cynthia Kenyon and her work on C. ellians.

David Sinclair (10:34):

That’s a good starting point. So in the 1980s, it was all about just free radicals. We didn’t know that aging could actually be controlled by any genes or certainly not single genes. And Cynthia came along as a young graduate student and looked for worms that would live longer. And she mutated them and found a strain of worm, a mutant worm that was living twice as long. So instead of living for 15 days, 30 days. And that was a remarkable finding because when she dissected the worms, bred them out, found that it was due to a single gene mutation.


And when she cloned the gene and found out where it was, it was in a gene that sensed insulin. It’s the insulin receptor gene called DAF2. That was remarkable because it had nothing to do with free radicals, it had nothing to do with DNA damage. It was a signaling molecule. And that was the start of a revolution in understanding how to control aging by using genes and supplements and drugs that turn on the body’s defenses.

Matthew LaPlante (11:33):

And this was the first so-called longevity gene.

David Sinclair (11:36):

Yeah, I would say that was the first. It came very close to the work that we were doing at MIT. We were maybe a year later than her. But we—

Matthew LaPlante (11:46):

You seem a little annoyed by that.

David Sinclair (11:48):

Not so much me. I’m careful because my supervisor, Lenny Gerenty, used to get really annoyed when he was told that he was slightly behind. He thought his work was being done at the same time. So those two used to be the, I guess, maybe still are at the forefront of this field. They’re certainly the grandparents, if nothing else. And they both showed, so Cynthia in worms, and then Lenny in yeast, where I was at MIT, made the finding that a single gene alteration can have a huge impact on an organism’s lifespan.

Matthew LaPlante (12:22):

And these genes, there’s a few of them now that we’ve identified. And all of them seem to work on a very similar circuit that all starts with adversity.

David Sinclair (12:31):

That’s right. These signaling proteins, like the DAF21 that Cynthia discovered and the sirtuins that we work on, we didn’t know what they were doing at first. It was like, this is crazy. It’s got nothing to do with DNA repair and free radicals. But then when we tracked what they were actually doing, it turns out they’re speaking to the rest of the cell to keep the cell healthy and alive. So in the case of that worm, those worms weren’t just longer lived. The program to survive was activated. Those worms are stress resistant. You can hit them with heat. You can hit them with cold. You can starve them or just put them in happy conditions. They live longer. The paradigm is that normally a worm responds to its environment. If it’s starved, it’ll hunker down. It’ll survive. But here we had a worm that was mimicking starvation and was able to have the benefits without having to starve itself.

Matthew LaPlante (13:25):

How do these genes, for lack of a better word, know? How do they know that the conditions are adverse and they need to turn on?

David Sinclair (13:35):

Well, there are various sensors. And so the three main pathways that control this, we’ve talked about mTOR, which is sensing the levels of amino acids in the cell, lower levels of certain amino acids, branched chain amino acids are good for the cell because they downregulate mTOR activity. That’s one way. The AMPK senses energy, glucose, and then the sirtuin sense NAD, which is a molecule that goes up with exercise and hunger. Together, those are the sensors. Now, how does a cell communicate with other cells? Well, there’s insulin. We know when we eat a meal, insulin goes from our pancreas into our bloodstream and tells the rest of the body, hey, you got sugar already, suck it in, use it.


That’s a signaling protein. And what Cynthia’s worms ended up when they were mutated is that that signal to bring in the glucose was mutated. And this insulin signal was absent. And when you don’t have the insulin signaling and you’re a worm, it means you’re hungry and you get the benefits of being hungry without having to starve.

Matthew LaPlante (14:38):

So our body is this always active monitoring system. We’re perceiving the world around us and the world around us is constantly throwing different stressors at us. Or at least it was in human history, right? We’ve always been a little cold or a little hungry or a little scared or having to run from this animal or that animal that wanted to eat us. This is the environment that our species evolved in, that all species evolved in, right? Is this constant state of adversity.

David Sinclair (15:11):

Right, and that adversity we’ve evolved to fight back. And so in the past, our bodies were constantly fighting disease and deterioration throughout life. Even before birth, we’re fighting against entropy. Things are falling apart. The aging clock that we can now measure begins at conception. But if you fast forward to now, our society is built on comfort. We’ve got most countries have enough food and shelter. We can sit down. We don’t have to run away from predators very often. And this is a real problem because these longevity defenses that normally would be activated by being cold and hungry and running are lethargic.


The body doesn’t expend energy to defend itself unless there’s a need for it. And modern society is the worst thing. We’ve taken away those needs. Yeah, we love comfort. It feels good, but that’s the worst thing for long-term health. We need to trick the body into getting out of its comfort zone by doing these things. We’ve talked about eating the right foods, including foods that are stressed, eating less often.

Matthew LaPlante (16:14):

Which puts stress on us, which causes our body to feel like it needs to protect itself because if we’re not filling it with all of the nutrients and calories we want, it perceives a need, it perceives adversity, and it turns on these genes.

David Sinclair (16:28):

Right, and as long as we have adequate nutrition, that’s why we call it intermittent fasting with adequate nutrition or IFAN. This is another term we just coined in this podcast. That allows the body to turn on these defenses without suffering long-term negative consequences. What’s interesting, I find, is that even though we know the fridge is probably full with food, our bodies are not that smart. Our bodies don’t get that message. And we can trick it, trick the body into thinking, oh my goodness, the fridge is running out of food or the field or the forest is lacking in food. We better get to hunger down and survive. What are those things? You burn fat, you increase your metabolism, so you’ve got more energy to run around and find food, you become more alert because you’ve got to go find more food, and you defend your body against insults, whether it’s incoming infections or diseases from within. And that’s cool that we can trick our bodies. And it’s not that hard. We just need to do the things we’re talking about on this podcast.

Matthew LaPlante (17:25):

And when we’re talking, we’ve already talked about the real key effects that come from eating less often to basically turn on this adversity mimetic effect. There’s another really easy way to do this though.

David Sinclair (17:39):

Right, and that’s get off your butt. Just get off your butt. Yeah, it’s not that hard, as we say, sitting here doing this podcast. But one way I do it is I have a standing desk. So my butt actually atrophied. When we were writing this book, Lifespan, I ended up with a cramp in my piriformis muscle, which is the one that- Wait, your what? Yeah, yeah, it’s a small muscle. Where is it? Size doesn’t matter. It’s right in your hip. It goes through that hole in your pelvis. And it’s essential for standing. And it was cramped up-

Matthew LaPlante (18:09):

I always wondered what that hole was for. Yeah, it’s- There’s a muscle that goes through it?

David Sinclair (18:14):

Yes. Okay. All right, and then so, but it was cramped up on my left-hand side. So I was limping for about nine months after we wrote the book. And I thought, great. You know, I’m writing about health and longevity, and I’ve now crippled myself. I eventually got it to go away with a combination of exercise, physio, and an injection of NAD in my butt, which we’ll get to in probably the next episode. But the point here is that sitting down is bad for us. You atrophied, you have less muscle, which means your hormone levels, particularly testosterone, will go down, and you become, you know, in pain.


That’s not a good thing. But ultimately, if you have not a lot of muscle in your hips, particularly, you can break your bones when you fall over, when you’re older. And all of that means you need to get off your butt, stand up, even better, go for a walk, even better, go for a run or cycle to get what we call a hypoxic state going. Your body needs to suck in more oxygen, and that has remarkable health benefits.

Matthew LaPlante (19:13):

And we really have to work hard at this, because I mean, you’re saying this, as we’re sitting in these chairs, right, a couple of days after I sat down in a chair for a long time in an airplane to get here, right, we’ve got a nice comfy couch over there that we’ve been working on. Like, we actually have to actively, like, pursue opportunities to do this, to get exercise to promote this adversity mimetic effect, because our lives are built around comfort and sedentariness.

David Sinclair (19:40):

Yes, that’s true. And what I think most people don’t appreciate is that exercise isn’t just beneficial for your fitness and for your vitality. It actually can stop diseases in their tracks.


Exercise can slow down cancer. In fact, it can prevent up to 23% of all cancers from occurring. That’s true for cardiovascular disease. In fact, it has an even bigger effect on that, 30% reduction just by doing moderate exercise every week. 50 minutes is sufficient, or three times a week with 10 minutes. All-cause mortality, right? So all-cause mortality is basically slowing down aging. That’s a 27% reduction in the rate of aging just by exercising.

Matthew LaPlante (20:22):

The thing that you just said, I love this idea of connecting the idea of all-cause mortality with aging, because as we’ve presented here, as you’ve been arguing for quite some time, most diseases which bring us toward the end of our lives are really just an accumulation of the symptoms of aging. And so if you bring down the disease rate across various diseases, which is bringing down all-cause mortality, you’re really just, it’s just another way of saying we’re bringing down aging.

David Sinclair (20:56):

We must be, exactly. And we can also now measure that with the biological clock, the so-called Horvath clock, named after my good friend, Steve Horvath. That is now a measure of the process that leads to all of these diseases that kill us. And one way that we know for a fact to slow down the ticking of that biological clock is exercise.

Matthew LaPlante (21:17):

And any kind of exercise is good. This is why the 10,000 steps a day goal is popular. Generally speaking, it’s good. It’s not a magic number. I think there’s, somebody came up with 10,000 and actually some studies have shown health benefits that are, you know, exist at four to 6,000 kind of peter out from there. But the basic idea here is that when we move, we burn calories, we’re putting our bodies into at least a low state of adversity.

David Sinclair (21:51):

Right, so try to get 4,000 in. 10,000 seems to be even better.

Matthew LaPlante (21:56):

It’s a great goal. It’s a round number. It’s fine.

David Sinclair (21:59):

Get off your ass. That’s what we’re saying. That’s all it takes. It’s not that hard. Walk around the block a few times. And particularly after a meal, as we spoke about last time, walking after a meal gets your glucose levels to be more level, which is what you want.

Matthew LaPlante (22:12):

Which relates to this. We were talking about this old Chinese proverb, like 99 steps after a meal. No, 1,000 steps after a meal, you’ll live to 99, but walk after you eat. Right. Because…

David Sinclair (22:23):

Well, it’ll stimulate the uptake of glucose, but also it’ll get your muscles moving and stimulate the production of new blood vessels. Make sure that you don’t run out of oxygen later in life. But mostly what happens when you move, the first thing that happens is a really important reaction that involves one of these longevity pathways, the middle one that I referred to called AMPK.

Matthew LaPlante (22:43):

And we can turn on AMPK just with a low level of exercise. Just start that adversity.

David Sinclair (22:50):

Yeah, so AMPK registers energy in the cell, which is chemical energy called ATP. And when you have low levels of ATP, AMPK gets activated. And it stands for AMP-activated kinase. And AMP is what you get a lot of when you don’t have enough of this fuel ATP. Long story short, when you have high levels of AMPK activity, you will make more mitochondria, which gives you long-lasting benefits. So after you’ve exercised, your body will be making more power, more of these organelles, we call them, that will actually give you long-term health benefits that’s beyond the period of exercise.

Matthew LaPlante (23:29):

We know that low level exercise alone is good. It’s a good start. We also know that it’s really not enough. You need to also be getting a pretty consistent dose of vigorous exercise too. It doesn’t have to be a lot. A lot of these studies show 10 minutes a day, 15 minutes a day, even 15 minutes a week if you’re getting started, is gonna have health benefits. But vigorous exercise, the easiest way to think about it is your breathing rate goes up and your heart rate goes up, right?

David Sinclair (24:03):

Right. And there’s a reason why vigorous exercise is so important beyond just walking and standing. It’s that you have hypoxia. Low levels of oxygen are undoubtedly good for you, even though they may not feel good. And you know you’re hypoxic when you’re panting so much you cannot carry out a conversation. That’s what you’re aiming for, for at least 10 minutes a few times a week. So why is being out of breath important? Very rarely people ask that. Well, the main-

Matthew LaPlante (24:33):

Because it doesn’t seem to make sense, honestly. You need oxygen.

David Sinclair (24:36):

Right. So again, it’s this hormesis idea, a little bit of what doesn’t kill you makes you stronger. So what’s happening is when you’re hypoxic is you’re turning on what’s called HIF-1 alpha, hypoxia inducible factor. And that pathway turns on a bunch of really helpful genes that control new blood vessel growth and mitochondria. My good friend and colleague over at Harvard won the Nobel Prize in 2019 for discovering HIF-1 alpha and its role in biology. Now, the other thing that happens in that, there’s two things. So one is the HIF-1 alpha that turns on a genetic program, that’s good. But what also happens is you get free radicals generated. Because when you don’t have enough oxygen, those electrons that should normally be used by what’s called the electron transport chain in mitochondria, which generates ATP, they fly out and they become a superoxide radical.

Matthew LaPlante (25:28):

Can we talk about that electron? Because it’s really fascinating how this thing works. I mean, it is a little circuit around-

David Sinclair (25:35):

Yeah. It’s a little battery made of proteins. And there’s a string of proteins that come together in the membrane. And they pass along an electron, like a hot potato. They don’t want to hold onto it. They shove it along, get rid of it, get rid of it. And in doing so, they’re pumping protons, which are hydrogen atoms, into the inner membrane space. Because there’s two membranes that surround the mitochondria. And in that little space, they’re pumping protons, which are hydrogen atoms, into the inner membrane space. The goal is to make it really acidic by putting in these protons into there. And this electron transport chain does that.


You need oxygen because at the end, when you get to the end, you’ve got to get rid of this electron and they give it to oxygen, okay? And then that’s called respiration. It’s the reason we need to breathe so hard when we run.


Why we need oxygen in the first place. Now, if you don’t have enough oxygen, then that’ll lead to these free radicals being produced and it’ll damage the cell. So you might say, well, that makes no sense. If you’re running and you’re damaging the cell, it’s going to be bad, right? But remember, a little bit of damage can be good. So what happens is it stimulates what’s called mitochormesis, mitochondrial hormesis. And that has a whole variety of benefits as well, including the manufacturer of more mitochondria that gives you energy. But I want to mention something that’s really interesting. I think about this electron transport chain. Remember how I said those protons, those hydrogens get pumped into that little space to make it acidic.


So now you’ve got what’s called a gradient. You’ve got more of them in that space than inside the mitochondria in a bubble. They want to get out. If they got too much somewhere, they should equilibrate. And what the cell does is it puts little holes that the protons can escape through. It’s called the ATPase. And what happens is as those protons shoot through, it’s like a hydroelectric damn turbine. And as they shoot through, it literally spins like a turbine. There’s a little wheel at the bottom of this tube that spins super fast, many times per second. And that spinning allows it to make ATP or chemical energy, which then you use then to burn, to make the muscle work. And so what’s really interesting is that the more mitochondria you have, if you’ve been exercising for a few weeks, allows you to make more chemical energy and you don’t feel puffed as much as you did before. And the other thing that’s happened besides having more mitochondria is that you’ve built more blood vessels in your body. And so your oxygen gets transported to the tissues. Now, both of those things go awry as we get older. And we’ll talk later and tomorrow about how you can circumvent that and reverse your age to be able to regain that ability. With drugs and molecules and supplements. Besides what we’re talking about today, exercise itself. Yeah.

Matthew LaPlante (28:19):

We keep going back to this idea of a little bit of adversity is good for you. Like a lot of anything’s gonna kill you, but a little bit of a lot of these things that might in big doses kill you is really good for us because it puts our bodies into the state of adversity. Let’s talk about this in terms of another effect of exercise, increased glucose sensitivity.

David Sinclair (28:43):

Right, so as you get older, our muscles in our brain become less sensitive to the insulin. The pancreas is putting out increasingly more and more, trying to cope with this insensitivity that happens. Now, that’s largely, we think now, because of this aging biological clock, that the genes that are required for a muscle cell to function or a brain cell to function are getting switched on and off in the wrong way. We call this X differentiation. And if you didn’t see episode one, you might wanna go back and hear more about that.


Basically, cells are losing their identity as they get older and not putting out a particular protein called GLUT4, which is a glucose transporter on the outside of the cell. So the muscles are not bringing in the glucose. There’s two problems, right? First of all, you don’t have your energy to burn in the mitochondria to make energy. The other problem is that that sugar, that glucose that circulates in your bloodstream and doesn’t get taken up into your muscle and your brain starts to damage the lining of the blood vessels. And we know that is type 2 diabetes and cardiovascular disease.

Matthew LaPlante (29:39):

And that’s where VEGF comes in?

David Sinclair (29:42):

So VEGF is a little protein that signals the formation of new blood vessels.

Matthew LaPlante (29:49):

When you exercise- How do you spell this, VEGF, by the way?

David Sinclair (29:50):

Capital V-E-G-F.

Matthew LaPlante (29:53):

Okay, so if people wanna look this up, then yeah. Yeah. Okay. All right, so VEGF.

David Sinclair (29:56):

So VEGF is made by muscles after you exercise. You go on for your run or even your walk, but running is even better. And there’s a gene called PGC1 alpha that is what’s called a transcription factor. It’ll be made, it’ll bind to the upstream side of the VEGF gene and make more of this VEGF protein. Now VEGF will be secreted out of the muscle and diffuse or just leak out into the lining of the blood vessels. Now the lining of the blood vessels is made of cells called endothelial cells, which pick up the signal. They have little receptors that sense VEGF. And when they get that signal, that says, oh, wow, we’re being chased by a saber-toothed tiger for the last week. We better build more blood vessels. And they do that. Normally, if you have a tube, which is a capillary, almost microscopic blood vessels, what happens is the endothelial cells will start to branch out to the side and make a new blood vessel. And that’s what you get with exercise. Conversely, if you sit around all day, you won’t build new blood vessels. You’ll actually have fewer and fewer and your muscle and your brain start to get starved of oxygen. Now, one of the big problems we discovered is during aging, that signaling pathway, that signaling mechanism is defective.


And even though you’re exercising as you get older, you’re not getting the benefits of it. You don’t get the new blood vessels.

Matthew LaPlante (31:17):

And you can see this in a mouse. I mean, when you take, when you pull the mouse apart, not to be too graphic, but you can actually see these thinning.

David Sinclair (31:26):

We don’t even need to hurt the mouse to see this. We can use imaging to see the blood flow in a mouse without hurting it. And we can see the bright red areas where the blood’s flowing nicely. And in an old mouse, you don’t get that, even with exercise. But we found a way to restore the youth of the muscle and restore the ability of that VEGF to trigger new blood vessel formation. And the trick was to turn on the production of NAD, which is the fuel for the sirtuin. N-A-D, which is the fuel for the sirtuin survival circuit.

Matthew LaPlante (31:55):

Which can be turned on by exercise because exercise upregulates N-A-M-P-T.

David Sinclair (32:02):

Yeah, also known as NAMPT. NAMPT. Some people call it that, but yeah, this is the relative of that ancient yeast gene that we talked about in the first episode that extends lifespan of yeast cells.

Matthew LaPlante (32:13):

So let’s add one more piece to this. And that is how exercise impacts the epigenome.

David Sinclair (32:21):

Yeah, the epigenome. If you missed episode one, I encourage you to go listen to that and watch that because we covered what the epigenome is and how it affects the aging process. But the summary is that the epigenome is the regulator of the DNA. It tells the genes whether to be on and off. And that goes wrong during aging. It may actually be the reason we age. And one of the reasons we believe that is that you can measure biological age now in people. I could take one of your cells, Matt, back to my lab. Well, actually I have to take a chunk of your cells or a cheek swab. And we can measure the rate of your aging.


It’s called the Horvath clock or DNA methylation clock. And when you look at people that have lived a healthy lifestyle, say they’ve been exercising for the last 30 years, they are much younger epigenetics, they are much younger epigenetically, according to this clock, than someone who hasn’t. So that tells us that very likely that exercise is not just protecting you against cardiovascular disease. It’s slowing down your overall rate of aging.

Matthew LaPlante (33:16):

There are other clocks as well. One of our- There are many, actually. Yeah, so one of our researchers, Adeev Johnson, was involved in a study that used the proteomic clock, which works similarly. Let’s talk about that really quick because it’s another way to measure biological aging.

David Sinclair (33:31):

Right, so you can measure proteins in the blood which change predictably over time. There’s a protein called GDF15, which is circulating. It’s now a really great biomarker for aging. In fact, GDF15 is one of those genes that was used in that study we referred to last episode where the Mediterranean diet slowed the aging process. They found that GDF15, the methylation on that clock marker was also slowed down. The point here being that these proteomic clocks and the epigenetic clocks and some others like an immuno clock can be used now to understand what slows down aging, but importantly, how do you reverse it with various treatments? And we’ve gone from a field where we had no idea what was going on in aging. Really, we had to look at tens of thousands of people on metformin to see if it helped health to a point where we can take 100 people, treat them with something, two months later, see if they’ve gotten younger or not. And those experiments are being done right now.

Matthew LaPlante (34:29):

And one of the things we can treat them with is exercise. Exercise in the study we were just talking about, they looked at aerobic active people versus sedentary people and the aerobic active people were five and a half years younger on average according to this proteomic biological clock. Presumably, we’d see the same thing if we used a Horvath clock or an immuno clock.

David Sinclair (34:51):

Yeah, and that’s true, actually. It’s been done on exercised people and they are also epigenetically young. And what’s important about this clock to realize is that it doesn’t just tell you your biological age. You can actually predict when you’re gonna die or when someone’s gonna die. And when I say that, look, some people, probably about half of people, that I don’t wanna know this, well, consider this, that 80% of your future health is in your own hands. It’s modifiable.


20% is genetic, which you can’t do much about yet. That’s powerful. If you have the tools to change your rate of aging, first of all, you have to measure it to know if it’s working, so I recommend that. And we’ll talk about ways to do that practically. But once you have that number, then work with me. We can tell you here in the podcast how to actually slow and reverse that process.

Matthew LaPlante (35:41):

Well, and we use car analogies a lot, you and I. I think a lot of people do these, but it bears mentioning, like, you know that your car is not gonna last forever. There’s a shelf life for any car. You get to choose based on how you treat the car over time, whether or not the car is going to last 100,000 miles or 200,000 miles or three or four hundred thousand miles.

David Sinclair (36:01):

Take it to the body shop repair and the mechanics more often. That’s what we’re talking about for our bodies. And that’s why knowing is important. Well, you need to measure it. You need to know when the car needs a service. You need to know if you’re tweaking that knob, whether you’re doing harm or good.

Matthew LaPlante (36:18):

And to that end, one of the really cool and exciting developments that’s happening right now is there’s this sort of race for these clocks to become available widely for people to use, so much so that the price point is predicted to be, what, like a buck?

David Sinclair (36:40):

Well, it’s coming down all the time. For a Horvath test? Right. So right now, if you wanna check your biological age, you can go to InsideTracker, one of our kind sponsors. That’s a blood test. Or you can also have a DNA test, which is available for a few hundred dollars from various vendors. A student in my lab, Patrick Griffin, we’ve posted recently a paper, which can be accessed on, that describes a way to pool, put together thousands of people’s samples and run them all together, bringing the cost of that test down to less than a dollar, which means that very shortly in the future, when we bring out this product and we are bringing it out soon, you should be able to do this test routinely and see whether you try a new diet or a supplement or just meditation, whether you’re actually benefiting from that.

Matthew LaPlante (37:32):

A lot of people hear all of this and they go, okay, I get it, I have to exercise, but, and I hear this a lot, but I hate to run. Like everybody thinks of like, that’s the only thing they’re allowed to do. And I think doctors may contribute, physicians may contribute to this a little bit by saying like, okay, well, I need to get you running and jogging and whatever, it’s not just running, right? Like what’s the best kind of exercise?

David Sinclair (37:54):

Well, there isn’t.

Matthew LaPlante (37:56):

It’s the exercise you’re gonna do. It’s what you love doing.

David Sinclair (37:58):

And it can be a sport, it could be windsurfing, it could be sailing, but just move, that’s the main thing. There’s even sex, which is, we actually looked this up. It’s not as good as we thought.

Matthew LaPlante (38:12):

It’s not as good as we thought. We did look this up, we were really hopeful when we looked this up, but it burns like four calories a minute or something. It’s not as good as.

David Sinclair (38:19):

Well, I’m sure it depends on the individual, right?

Matthew LaPlante (38:21):

I mean, you can make sex more aerobic. You can make it part of your exercise regimen, but you have to have a partner, a consenting, willing partner who also wants to make it part of their exercise regimen.

David Sinclair (38:32):

It’s only 4.2 calories per minute, and we also looked up the average length of sex, and it’s about five minutes.

Matthew LaPlante (38:41):

Right, so you’re gonna burn 20 calories if you’re an average person, I’ll burn 10.

David Sinclair (38:47):

So instead of that, you probably need to go for a longer walk afterwards to really burn off those calories and get your blood flowing.

Matthew LaPlante (38:54):

And however you get your exercise, be it running or sailing, apparently, or sex, both the World Health Organization and the Mayo Clinic recommend at least 75 minutes of vigorous exercise a week. So that’s 15 minutes a day.

David Sinclair (39:10):

10 minutes. And it’s better if you spread it out over the week.

Matthew LaPlante (39:13):

Right, yeah, don’t do it all at once. But that’s the starting point, and most people can do that. You can be the busiest person in the world. You can be the most unhealthy person in the world. You can get your heart rate and your breathing up for 10 minutes a day.

David Sinclair (39:29):

Sure you can, and the benefits will be huge. You’ll feel better, you’ll look better, and you’ll also have a better resting heart rate. That’s one of the best measures of your fitness. If you’re less than 50 for a resting heart rate, that’s really good for someone my age, in my 50s. Mine’s usually around mid-40s. That’s a good indication of how well you’re doing. And if you’ve got a high heart rate, it’s you’re either too stressed or you’re unfit, try to bring that down again. You can measure your heart rate pretty easily. Just put your hand on your arm, but you could also either wear a ring or a new fitness, these fitness abs that are on your wrist.

Matthew LaPlante (40:01):

Oh, there’s all kinds of wearables now that are gonna help you do this.

David Sinclair (40:04):

Yeah, and I’m a big proponent of measuring things, right? Because otherwise you’re flying blind. So I wear a ring, I wear a wrist, a watch. I sometimes wear- You’re wearing a ring right now. I am. This also measures sleep, which we’ll get to in another episode. But I also, there are some advanced bio monitors we’re also gonna cover. There’s one that I stick on my chest for two weeks that measures my body a thousand times a second for various parameters, including my heart function. And in the future, these will be used by people to predict heart attacks, as well as the flu and all sorts of issues like depression. In the future, we’re not gonna be flying blind. We’re gonna be monitored a thousand times a second, as opposed to now where you go to the doctor once a year and they spend 15 minutes asking you how do you feel, which is a joke.

Matthew LaPlante (40:46):

Right, right. Because in addition to the fact that it’s a single, it’s a single assessment at a single time, it’s highly subjective, it’s self-reported, it’s just crap data.

David Sinclair (40:56):

Yeah, this is a bit of an aside, but it’s worth noting here that I’ve been measuring myself for over 10 years using InsideTracker. And that data is wonderful. It’s graphed and you can see when things go wrong, I’ve corrected it. They do an inner age study. There’s a measure called inner age 2.0, which tells you how you’re doing compared to others your age and you try to keep that low. And based on that calculation, I’ve been getting younger for the last 10 years, which is great to talk about, but it also means that I’m optimizing my body every time when I do something. And if something doesn’t work, then I won’t do it.

Matthew LaPlante (41:32):

And we are gonna get into this, but I’ve got a friend, Nate Price, who helps people do this at the Institute for System Biology. And they help people create these charts that they can then bring in to show their doctors. And he was telling me about this woman who brought her chart into the doctor and the doctor was at first dismissive. And she said, well, won’t you at least look at it? And the doctor looked at it and went, oh, wow, this is really helpful.

David Sinclair (41:55):

And that’s exactly the response of my doctor too. My doctor said, well, how do you feel? And I said, I’m good, I’m sleeping well. And he said, okay, see you next time. I said, no, hang on, let’s do some more. I’ve got some data, can I show you? And I showed him the inside tracker data on Zoom. And he said, this is wonderful. I wish all my patients had this data. Of course, he cannot order 43 biomarkers every time. The health insurance won’t pay for it, but individuals, if they want to spend their money instead of coffee, they can put it into a blood test. Doctors actually do respect those data because they’re actually produced by the same companies that the doctors would use anyway.

Matthew LaPlante (42:31):

And to bring this all back, to tie this all back to exercise and these other adversity mimetics, which we’re going to get to, having this data, I’m a big soccer fan. The first time I saw a soccer player try to cough his shirt and he was wearing a bra and I thought, what the heck is going on? But it’s actually holding these trackers that are measuring things in the middle of games, in the middle of practices. The world’s best athletes are doing this right now, and it’s becoming more and more available for other people to track as well. And once you have this data, you can start to act on this data. You can start to arrange your exercise routine so that you’re getting the most out of it.

David Sinclair (43:07):

Exactly, and they can be fun too. You can use GPS to see where you’re going. You can compare it with your colleagues, your friends, I’m running more than you.

Matthew LaPlante (43:15):

Let’s move along here because we’ve got a lot more to talk about, but before we get away from exercise and start talking about these other adversity mimetics, there’s another form of exercise that I know you enjoy, that I enjoy, that a lot of people enjoy, but maybe doesn’t get as much attention as aerobic exercises, weight training.

David Sinclair (43:34):

I’m glad you said that. All right, so weight training. Yeah, I do that fairly often, I would say at least, every other day, if not every day. The way I do that is I have a gym in my bedroom and I also have weights next to my desk.

Matthew LaPlante (43:47):

You also have them in the trunk of your car right now,

David Sinclair (43:50):

I saw. I do, it’s because I travel a lot, and so I’m taking weights with me. But the reason that I do weightlifting is that it’s gonna maintain my hormone levels. It’s gonna maintain my ability to walk well and stay upright and have good posture. It makes me look better. Although you may say that’s debatable, but also as I get older. It’s not debatable, you’re a really good looking guy, David. Thanks, you’re lovely, Matthew. Thank you. The other thing is that is often not appreciated is it’s harder to build muscle as you get older and you wanna maintain that muscle mass. I’m losing about 1% of my muscle mass every year unless I maintain it or build it up. As you get older, you’re gonna fall over, right? Everyone falls over, especially as they get older. And if you break your hip, that’s close to a death sentence. A lot of people, well, 19 people every minute fall over and break their hip in the United States, which is a major cause of mortality.

Matthew LaPlante (44:46):

In the mortality rates after a hip break, just like skyrocket.

David Sinclair (44:49):

Well, it’s equivalent to having metastatic cancer. That’s how bad it is. But if you’ve got muscles and you’re flexible, you do say Pilates in your older age and stretch, build up the muscles, particularly around your waist, then you’re much less likely to break a bone when you fall.

Matthew LaPlante (45:05):

Yeah, building muscle mass also helps maintain youthful hormone levels.

David Sinclair (45:09):

Right, so I had trouble maintaining testosterone levels like most men my age. Now there are two ways to go about it generally. The main one is that your doctor will give you an injection of testosterone to apply at home or a cream that you can rub on your forearm. Those are the two ways you can do it. There are others, but the other way, which I prefer, is to naturally boost it by maintaining large muscles, exercising my thighs, my butt, my back.


And I’ve compared the two. I have tried cream on my arm for testosterone. It worked okay. My levels went up maybe by 20%, wasn’t great. I really maxed out my testosterone levels by doing leg exercises and back exercises. I’m talking about things like leg extensions, leg curls, as well as hip hinge, which is bending at the hip and lifting weights. And I also do deadlifts, which is standing up with lifting a really heavy weight with a straight back.

Matthew LaPlante (46:08):

There’s another way that we know that exercise is impacting aging. And we talked about senescent cells in terms of what iron may be doing to cause cells to go senescent. But let’s talk about that as one of the key aging, what are called the aging hallmarks. Exercise prevents senescence. It turns back senescence. What’s exercise doing in the brain? It turns back senescence, what’s exercise doing in terms of these zombie cells?

David Sinclair (46:38):

Well, let’s start with what a senescent cell is. So when the epigenome becomes too dysregulated and this X differentiation process happens, cells can either die, they can become a cancer. But what the body tries to do is to prevent that by shutting these cells down and make them more like zombies. They’re alive, but they’re not dividing and they’re causing havoc. And-

Matthew LaPlante (46:58):

They’re causing all these chemicals into the bloodstream.

David Sinclair (47:01):

They are, it’s called the SASP, the senescence associated secretory phenotype. And these proteins cause inflammation. They also cause cancer. So the fewer senescent cells you have in your body, the better. And we’re starting to find that lifestyle and supplementation and some drugs slow their formation.


Remember, keep the iron levels low, but also we can kill them off. And there’s this study, the one you’re referring to, which took 34 individuals for a 12-week exercise program and looked at the amount of senescent cells circulating in their immune, in the blood immune system. And it was dramatically lower in the exercise people arguing that you can actually kill off or reverse that process. 12 weeks? Just 12-

Matthew LaPlante (47:46):

Is 12 weeks to like destroy some senescent cells seems like a pretty good deal.

David Sinclair (47:51):

Yeah, it’s one of the best ways to kill off senescent cells.

Matthew LaPlante (47:53):

That’s the study that was just out this year in aging cell England et al. We will link to that in the show notes. Let’s put a wrap on exercise, but let’s have a few takeaways here. And there’s really, there’s three big ones. The first is a low level of exercise and this is just steps, right? Get off your butt. Get off your butt and dig.

David Sinclair (48:18):

Yeah. Standing desk or a desk with a treadmill, walk around the block after dinner or lunch. Those are the simple things.

Matthew LaPlante (48:25):

And you don’t have to hit 10,000 steps, but shoot for four. Four, four is great. Okay, all right. And then that’s the low intensity exercise that everybody should be getting throughout the week, every single day. And you can also get a high intensity exercise.

David Sinclair (48:39):

For sure. A few times a week, 10 or 15 minutes, lose your breath. It can be the form of HIIT, high intensity interval training or running on a treadmill. That will get your blood vessels flowing and your mitochondria amplifying.

Matthew LaPlante (48:51):

10 to 15 minutes a day.

David Sinclair (48:53):

Yeah. That’s 75 minutes a week. Yeah, that’s what all the experts recommend.

Matthew LaPlante (48:58):

Okay, all right. And then muscle building.

David Sinclair (49:01):

Weights, that’s just as important. So maintain that muscle mass for your hormones, testosterone, particularly for men and women. Exercise the big muscles, particularly. Don’t forget about those. Don’t just work on your upper arms so you look good. But it’s pretty simple. You don’t need a gym in your bedroom like I do. You can do pushups, sit-ups, or just have some weights lying around. That’s sufficient.

Matthew LaPlante (49:22):

Okay. Okay, and all of this is, the goal is, it’s not just we want to look good. We want it right. All of this is aimed toward the goal of longevity through putting your longevity genes into or alerting your genes, your cells to a state of adversity.

David Sinclair (49:40):

The adversity mimetics.

Matthew LaPlante (49:41):

The adversity mimetics. I really do like this word. I think this is going to catch on.

David Sinclair (49:44):

Yeah, we trademarked that one, Rob. Okay.

Matthew LaPlante (49:47):

So let’s, but this is not the only, exercise is not the only adversity mimetic. There are others. We’re going to talk now about a few other categories. We’re going to talk about cold temperatures. We’re going to talk about heat. But there’s a really exciting one right now, and it is related in some ways to exercise or the effects, the genetic effects, the cellular effects that we get from exercise. And it’s really fast moving. The latest studies are only out in the last couple of years, and this is hyperbaric oxygen treatment. Right, or HBOT.

David Sinclair (50:17):

Yeah, this is really fascinating because for a while, we knew that wounds repair or heal faster when you give them more oxygen. Because why? Well, it’s not clear. It could be hormesis, free radical generation, could be that more oxygen in the tissues allows them to grow better. Those are all theories, but we know that it works. But then people started putting themselves in hyperbaric chambers. The military, certainly the Navy, have been doing this for a long time to prevent the bends. But it’s found to be quite therapeutic, particularly for neurological disorders, but increasingly for aging itself. And we should say what a hyperbaric chamber is, right?

Matthew LaPlante (50:55):

The hyperbaric chamber is a very, very, very, the hyperbaric chamber is a room or sometimes just a little tube where the pressure is increased. And when the pressure is increased, the amount of oxygen that you get when you breathe is increased.

David Sinclair (51:09):

Right, you can go up a couple of atmospheres or more and you supplement that with oxygen. You can breathe in a bit more oxygen or pure oxygen. And so I recently tried this, actually. I went out to LA. Fortunately, unlike you, I’m not claustrophobic.

Matthew LaPlante (51:25):

I’m so, I can’t do this. I cannot do this.

David Sinclair (51:27):

You probably can’t, but it’s a glass cylinder, so you don’t feel it. And I just watched Schitt’s Creek for a while. It was pretty cool, especially when I was high on oxygen. You said it was funnier when you… Certainly it was funnier, but it might just be because every time I watch it, it gets funnier. But it’s really relaxing. I believe I was in there for about an hour and it was, you know, you can meditate in there or you can fall asleep or watch TV. It’s really a great experience.


But that aside, what the science says is that it actually can reverse an aspect of aging, which is telomere shortening. The ends of the chromosomes, many of us of you will have heard of this, like the ends of the shoelaces, the agalates, they’re called. If they wear out, it actually leads to cellulose and essence, these zombie cells. And this happens over time as we get older. And what we’ve been looking for, we scientists, for many years is a molecule or a treatment that makes them grow back again, because that should help slow down aging and give us longer life. And that’s what was reported last year from a group in Israel, who I know well. I’ve been over there and checked out their giant chamber.

Matthew LaPlante (52:30):

And you actually got wind of this before, while they were working on it, and you went to kind of like peek in on what they were doing.

David Sinclair (52:36):

Yeah, I mean, this is one of the fortunate things about my job is that I get to hear about things before they’re public and I get a sneak preview. And I went over there and sat in their giant chamber, which looks like the inside of a bus and with a mask you put on, and they showed me their data. Actually, it looks like a control room from Star Trek. It’s really high-tech. And, but the data that they showed me in mice and in humans was really compelling. It looked like, at least in the mice, that those plaques and tangles in the brain of mice that were given Alzheimer’s went away.

Matthew LaPlante (53:06):

Do you have little miniature hyperbaric chambers for the mice?

David Sinclair (53:08):

We’re building one, because I’m going to use one in my lab. But they’re not ready yet. But also what they were finding was that the humans that were put in there that had dementia or Parkinson’s were dramatically improved after a few sessions of this. And it’s become a real craze throughout the US. A lot of this is happening in LA where a lot of these trends start. People are reporting remarkable benefits. Now, what we need are more studies like the one in Israel to actually measure things and, if possible, do a placebo control as well.

Matthew LaPlante (53:40):

But at least what we have right now are some studies, most of them fairly small on scale, but human studies, memory improvements, telomeres, T helper cells.

David Sinclair (53:53):

Right, they go up as well. So that in cognitive performance, there was six elderly patients suffering from memory loss. And in 2020 on, this new study came out and they all improved.

Matthew LaPlante (54:03):

And the really cool thing about this treatment, even though look like not everybody has access to a hyperbaric chamber, obviously, but it is a pretty easy intervention and it’s easy to treat people this way. It’s easy to test people in this way.

David Sinclair (54:21):

So now we have the clocks. We have the clocks. We can test if aging actually goes backwards. That would be a good experiment is to take people who have done seven or eight, 10 bouts of this treatment before and after and see if their biological age went backwards.

Matthew LaPlante (54:35):

So it’s still early. It seems like these things are working across a variety of ways that we can measure aging and the problems of aging. If this is working, why is it working?

David Sinclair (54:46):

Yeah. Well, we don’t know for sure, but one of the theories is that it’s working similar to exercise. So hypoxia, the low oxygen, when you go for a run, what it’s doing is turning on this HIF-1 alpha protein that I talked about earlier, and that helps promote health in the body. The other thing that happens with exercise is the free radical generation that gives you a little bit of mitohormesis. It looks very much like hyperoxia.


Hyperbaric chamber treatment does the very similar thing. You get a production of these free radicals and that stimulates also a mitohormesis response that gives you very similar benefits to low oxygen. There’s one theory that I have, is that when you come down from the high levels of oxygen, it stimulates hypoxia. Like you’re running as you come down from high levels to low levels.

Matthew LaPlante (55:38):

So it’s not so much the oxygen, the like explosion of oxygen that you’re getting, but it’s like once you like temporarily get used to that, then you come off of it.

David Sinclair (55:47):

It’s the differential, and that fits with the new findings, which is going up once and coming down once is not as good as going up and down and up and down within a treatment.

Matthew LaPlante (55:57):

Before we move away from hyperbaric oxygen treatment, I know you’re most familiar with this Israeli study. Let’s talk about the protocol in that one.

David Sinclair (56:07):

Yeah, they took 30 people and put them in their large chamber, the one that I visited, and they did 60 daily sessions of 90 minutes, five of those per week, and had a look at the number of senescent cells in the bloodstream before and after and telomere length. And what they found remarkably was that those aspects of aging were reversed.

Matthew LaPlante (56:25):

They saw impacts on senescent cells too.

David Sinclair (56:27):

They did, they looked at in the immune system, looking at these immune cells, you can measure senescence, you can stain them blue, which is bright blue when you get older. And they found that there was a dramatic reduction in the number of those senescent cytotoxic T-cells, as they’re called.

Matthew LaPlante (56:43):

Okay, so 60 sessions, 90 minutes. This is not something anybody, most people can do every day right now. This is not gonna be a common part of people’s longevity regimens anytime soon.

David Sinclair (56:56):

Well, there are a number of centers that are run by doctors in major cities. It’ll become more popular, it’s growing rapidly. But I think it’s a great way in the future for people to mimic exercise. I wouldn’t say don’t exercise, right? But it’s an interesting idea that you can lie down, watch TV, go to sleep and get your run in by mimicking hypoxia, but in this case with high levels of oxygen in your body for a short period of time. It’s really cool.

Matthew LaPlante (57:25):

So let’s shift now to talking about cold therapy, which is another thing that a lot of people are experimenting with now, another thing that there are centers for all over the place, but that the research is still sort of catching up to the excitement. So we’re sort of on the edge here of our understanding, but we do know some things about what cold does to the human body and actually what cold does to organisms across the spectrum.

David Sinclair (57:55):

Yeah, in fact, when we wrote Lifespan, there was almost no data on this, but now we know actually that one of the huge benefits you get from being cold is the production of brown fat. So what is brown fat? Brown fat, or it’s often called beige fat, is found in babies. It’s typically to allow them to stay warm because they don’t shiver and they’re about one year of age. And what was discovered about 10 years ago at Harvard by Bruce Spiegelman and Ron Kahn, a couple of my colleagues, is that adults also have some brown fat and they discovered this with pet scanning. And they found it mostly exists on your back, in your shoulder blades. And when you get cold, it revs up, you get more of this brown fat. And this is a good thing because brown fat is extremely healthy. It revs up metabolism. It burns white fat. And we think that there are these factors, little chemicals, little proteins that get secreted out of brown fat that make the rest of the body healthy as well.


One of the reasons we know that is because there’s a gene that makes brown fat, makes cells turn brown from white to beige to brown, and it’s called PRDM-16. And mice that lack this gene, they don’t have brown fat, but they also develop type 2 diabetes and cardiovascular disease as a result.

Matthew LaPlante (59:12):

– Cold impacts not just humans, it impacts all organisms. We’ve seen this in model organisms too, these effects, right? There’s the studies in worms, there’s been studies in mice. You’ve got a couple of favorites I know. Do you like talking about the mice that got to spoon together?

David Sinclair (59:27):

– Oh yeah. So that one is a bit of a disappointment in the field that we had these dwarf mice that Mike Bonkowski, who was working in my lab, he was the guy that generated the longest-lived mouse. He called it Yoda. And it was very long-lived because it had a mutation in a gene, the growth hormone receptor, which means there was small and dwarfs. And these little small dwarf mice would live up to three times longer than a normal mouse. It was quite an amazing thing. And the field was rejoicing. Wow, we figured out how to make mammals live that much longer. And then it was noticed that they were shivering, but little cold mice. And so the researchers thought, we’ll just give them friends.

Matthew LaPlante (01:00:06):

So they weren’t shivering because the lab was cold. They were shivering because?

David Sinclair (01:00:10):

They didn’t have a companion. You know, mice like to live, not solitary, but with other mice. And so they gave them a buddy. Each of these dwarfs had a buddy. And then the majority of the lifespan extension went away.

Matthew LaPlante (01:00:22):

When they got their buddy.

David Sinclair (01:00:23):

Yeah, which is super disappointing, right? But what it told us was that a large effect of longevity was due to them being cold.

Matthew LaPlante (01:00:31):

And why is that happening? When we go back to like thinking about the survival circuit, what’s happening?

David Sinclair (01:00:36):

Yeah, well, the trick is, let’s go back to the brown fat. What brown fat has a lot of is mitochondria. And within those mitochondria, they’re actually quite different. They have high levels of proteins called UCPs, or uncoupling proteins, which insert into the membrane of the mitochondria and allow those protons that were built up to leak through. Instead of going through that pump that makes the energy, they leak through. Why is that interesting? Well, first of all, that generates heat. So if you look at the amount of heat that’s in the membrane, the amount of heat that’s in the membrane is actually quite different than the amount of heat that’s in the membrane of the mitochondria. Interesting, well, first of all, that generates heat. That helps the animal and we survive cold. But also you get fewer free radicals produced when you uncouple mitochondria with these proteins.


And consistent with that, if you make an animal, let’s say it’s a worm or a fly or even a mouse that has high levels of these UCP genes, they actually live longer. So uncoupling and reducing that free radical load, and you can do this with cold therapy, we think, is beneficial to health.

Matthew LaPlante (01:01:31):

And cold therapy, people call it cryotherapy, is this like short-term, acute, super intense. You’ve done this before, right? You did this with Rogan, didn’t you?

David Sinclair (01:01:42):

Yeah, yeah, Joe said, let’s go do that after the show, which I did. It was pretty chilly. I had to strip down into my underwear and put gloves on and socks and whatever. But you get to play music, at least. I got to choose help by the Beatles, which was quite appropriate because by the end of those three minutes- You wanted out. Well, the first two minutes, I’m like, what’s the problem? This isn’t cold.


But that last minute, I really thought I was gonna get hypothermia and my ears might break off. You’re chattering and shaking. Yeah, you really start to shiver, which is your body’s way of generating heat by moving your muscles. But it was really enjoyable. I found afterwards, I felt stimulated. I felt lucky to be alive. And I felt good for a number of days afterwards, which is probably because my mitochondria were revved up and I was building more brown fat. The one thing I think it’s worth pausing here to talk about is why would you do this now? Why don’t you wait till you’re old to do cold therapy? And what’s been found, at least in mice, is that old mice don’t make brown fat as well as young mice. So what you wanna do is middle age, do these treatments and so that you’re ready for old age when it becomes harder.

Matthew LaPlante (01:02:47):

Just like right now, we need to be doing vigorous exercise. We can’t wait until we’re old to do vigorous exercise.

David Sinclair (01:02:52):

Yeah, though it’s never too late. We do find that things work in elderly mice and elderly people, but it doesn’t work as well if you start midlife or even earlier.

Matthew LaPlante (01:03:00):

Okay, and maybe that’s like the cryotherapy stuff is sort of akin to a vigorous exercise, but you still have to have that low level of perceived adversity, just like we have to get like lots and lots of steps in every day, but we live in these environments, these temperature controlled environments where it’s like 68 to 72. That’s not how our ancestors lived at all.

David Sinclair (01:03:21):

No, we were shivering probably most of the time during the ice age, for sure. And our bodies recognize that. We’ve got those genes that respond and they keep us healthy as we’ve talked about. So there are a number of ways you can, if you don’t have a cryotherapy center near you, what do you do? Well, you can take cold showers. Some people do that. I don’t, I find that unpleasant, but you can do that. It’s very cheap to do that. Or you can do something that I do actually do, which is sleep with very few covers on my bed and lower down my body temperature. And that’s also been shown to activate these uncoupling proteins and build brown fat.

Matthew LaPlante (01:03:51):

The opposite side of this is heat, which is also something that throughout our evolutionary history, we’ve had to deal with. We didn’t always live in temperature controlled buildings. And we’re, we’ve got some emerging research on that as well.

David Sinclair (01:04:05):

Right, taking your body out of its comfort zone. And so the-

Matthew LaPlante (01:04:08):

All of these things are about taking your body out of its-

David Sinclair (01:04:10):

They are, they are. And some of them are really enjoyable. I think sauna bathing, as it’s called in Europe, is super enjoyable and it also is good for your skin. You get to sweat and get those pores unclogged. This is one of the most ancient therapies for longevity. Even before Roman times, they were bathing in these saunas, though the Romans would use fires under the floor.


But this is something that Europeans still carry on as a tradition, particularly in Finland and other Scandinavian countries, where these studies are typically performed on men for some reason. But the data that I’ve looked at, which we’ll put in the show notes, is that there’s absolutely no doubt that men who partake in sauna bathing a few times a week, often at home, because they build this into their houses, have a dramatic reduction, up to 20% in the rate of cardiovascular disease and mortality caused by heart attacks.

Matthew LaPlante (01:05:02):

This isn’t happening for the same reason as cold therapy work. This has nothing to do with brown fat. There’s another thing that’s going on here.

David Sinclair (01:05:08):

It’s different in this case. What we think goes on in a sauna is you’re activating HSPs. And these heat shock proteins are helping to fold proteins correctly and also stimulate pathways that are beneficial, such as building new blood vessels, making more mitochondria. And one of the reasons that I believe it’s true is that in model organisms, if you take a worm, if you turn up heat shock proteins, either by giving them a lot of heat or genetically modifying them, they also live longer.

Matthew LaPlante (01:05:38):

We don’t quite know what dosing is right for sauna baths at this point, or like how much, how hot, there’s not a ton of research in this area.

David Sinclair (01:05:49):

No, but it doesn’t seem like you can overdo it. I haven’t seen any evidence that it’s negative. And I used to, before the pandemic, I used to go at least once a week and do multiple bouts of the heat shock in the sauna for about 15 minutes and then jump in an ice bath, which was nearby, for four minutes, and then cycle that.

Matthew LaPlante (01:06:08):

You should probably consult your doctor before you do that.

David Sinclair (01:06:10):

I would definitely, and I did. But yeah, it can put some stress on the body, certainly on the heart. But yeah, the idea though is to shock the body, heat cold, heat cold. And that way, I think you get the maximum benefit from these adversity mimetics. And again, you don’t necessarily need to have access

Matthew LaPlante (01:06:27):

to a sauna to do this. I mean, some people can build them into their homes. Some people have them in their gyms. That’s kind of a point of privilege. Most people have a bath. Or a shower.

David Sinclair (01:06:37):

Or a hot shower. I certainly do that. I like to turn the heat way up. There are a variety of different saunas. There’s the old fashioned type, which is the cedar planks sitting in there. And you just throw water on hot rocks. That’s traditional. There are new ones, such as infrared saunas. And they’re very, very old-fashioned. It’s infrared saunas. And the infrared light actually penetrates the skin and is thought, and there’s some evidence, real believable evidence, that also in the skin layer can reverse aspects of aging as well, and including improve hair growth.

Matthew LaPlante (01:07:05):

There is, for some obvious reasons, there’s a lot of questions I want to ask about hair growth. We’re going to be discussing hair growth, skincare, all these sort of cosmetic aspects of aging things in a future episode. One of the commonalities that I’m kind of sensing in all of these things, right? You do vigorous exercise, and you get what we term a runner’s high. And you talked about doing the cryotherapy, and you felt like, what did you say? Like blessed to be alive, or I’ve done sweats and sweat lodges, and you come out of those things, and it’s just like, it’s the best drug in the world.


What do you think, why are these things so similar? Because it happens in the hyperbaric chamber too.

David Sinclair (01:07:49):

Yeah, yeah, that’s one of the nice side effects. That’s when you know that you’re doing a good longevity protocol, because what’s happening at the cellular level is those three main defense pathways get turned on. But at the physiological level, the neurological level, you’re getting endorphins as well. And that’s when you know you’ve actually done the right thing.

Matthew LaPlante (01:08:07):

So let’s talk about a basic protocol with the caveat that we always make, which is everybody’s gonna be a little bit different. But if we’re trying to get sort of like exercise, cold, heat, and hyperbaric, what’s a good way to do that? We’ve already talked about the exercise protocol. Actually, I don’t think we need to reiterate that. You need to exercise, get off your butt. Cold, heat, and hyperbaric.

David Sinclair (01:08:38):

Yeah, well, as I mentioned, I used to do, and I will do again, the cycling of the heat and the cold about five times during one day of the week. This was on a Sunday with my son, Benjamin. But I would say more is better. There’s no evidence that you can overdo this. You could even do it every day. If you don’t have access to a gym, you can always use your house. You can turn down the temperature, or you can use your shower. And that will work almost as well. As junking yourself into a cold bathtub. Or you could do what Gabby Rees and Leid Hamilton do, which is shove us into an ice bath with literally, with ice in it. I think that, you know, you don’t need to do that every day. Didn’t you almost drown? I did, but that was different. That was hypoxia. What they do is they make you do exercise with weights at the bottom of a pool below your height. So you’re underwater, and you have to jump up with those weights and you have to jump up with those weights to get a breath.

Matthew LaPlante (01:09:33):

We’re not recommending that at this time.

David Sinclair (01:09:36):

I think everybody should go knock on their front door and do it with them. No, it’s, but you can get hypoxia from exercise. It’s very similar. So we’ve talked about hot and cold. The hyperbaric is more of an issue. That’s a challenge. There’s not a lot of these centers around and it’s expensive. It’s hundreds of dollars per treatment. But that’s in the future. I think that that, I wanted to mention that because it’s really interesting how it’s so similar to exercise and hypoxia at the molecular level. But for most people right now, that’s out of reach.

Matthew LaPlante (01:10:05):

But that’s not the only thing in the future. There’s a lot of really cool things coming down the path right now that are going to be a fundamental part of people’s lives pretty soon. We’re gonna be talking about a lot of those in an upcoming episode.

David Sinclair (01:10:17):

We are, and it actually, I think a lot of people will be excited that we can mimic this adversity with molecules, with pills, with injections. And we’re gonna talk about that in the next episode. In the next episode.

Matthew LaPlante (01:10:28):

Yeah. So next episode, molecules, supplements, longevity. That’s gonna be a lot.

David Sinclair (01:10:34):

Yeah, I’m excited about this one because I get questions every day about it. And I think it’s gonna be one of the most downloaded episodes.

Matthew LaPlante (01:10:41):

Yeah, I think a lot of people are gonna wanna tune in.

David Sinclair (01:10:43):

I’m excited to dig in. Yeah. Okay, cool. Thanks for joining us this episode on exercise and other forms of acute stress. If you’re learning from and enjoying this podcast, please subscribe to it on YouTube, Apple Podcasts, and Spotify. On Apple, you have the opportunity to leave up to a five-star review. If you’d like to support us, please check out the sponsors we mentioned at the start. We’ve partnered with companies we truly love and partnered with companies we truly believe in, and they make this show possible.


We also have a Patreon. That’s forward slash David Sinclair. There you can support the show at any level that you like. Thanks again, and we’ll be back next week to discuss supplements and molecules for men, NR, resveratrol, and how these impact longevity.

Episode Info

In Episode 3 of the Lifespan Podcast, Dr. David Sinclair and Matthew LaPlante dive deeply into the science of non-dietary interventions that mimic adversity and promote health. They begin by highlighting how different types of physical activity (i.e., low-intensity aerobic exercise, high-intensity aerobic exercise, and weight training) protect against age-related disease and enhance longevity. David and Matthew additionally highlight the latest evidence behind hyperbaric oxygen therapy, cold therapy, and heat therapy. As they discuss different adversity mimetics, they also explain how these interventions influence aging at the molecular and physiological levels.

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(00:00:00) Introducing Episode 3: Exercise Hot Cold

(00:01:01) A Pernicisous Element Called Iron

(00:02:46) A Quick Primer on Free Radicals

(00:05:42) Review of Dietary Takeaways

(00:07:01) Sponsors

(00:09:32 Biological Adversity & the Survival Circuit

(00:13:24) Survival Sensors (i.e., mTOR, AMPK, and Sirtuins) & Communicators (e.g., Insulin)

(00:17:25) Get Off Your Butt

(00:19:40) Exercise Protects against Disease & Mortality

(00:21:17) Daily Step Count and Walking After Eating

(00:22:33) Exercise Activates AMPK and Creates More Mitochondria

(00:24:03) Vigorous Exercise, Hypoxia, the Electron Transport Chain

(00:28:19) Exercise Increases Glucose Sensitivity and Stimulates Blood Vessel Formation

(00:32:13) The Epigenome and Biological Age are Impacted by Exercise

(00:36:43) How to Measure your Biological Age

(00:37:31) Exercise Recommendations

(00:39:28) Wearables and Individualized Health Tracking

(00:43:14) The Importance of Weight Training

(00:46:08) Physical Activity & Senescent Cells

(00:48:01) Wrap-up & Takeaways

(00:49:47) Hyperbaric Oxygen Therapy

(00:57:24) Cold Therapy

(01:03:50) Applying Heat

(01:07:04) Adversity Mimetics Produce Endorphins

(01:08:07) A Basic Protocol for Mimicking Adversity

(01:10:04) Next Week: Molecules & Supplements

(01:10:45) Subscription & Support

For the full show notes, including the peer-reviewed studies, visit the Lifespan podcast website.

Please note that Lifespan with Dr. David Sinclair is distinct from Dr. Sinclair's teaching and research roles at Harvard Medical School. The information provided in this show is not medical advice, nor should it be taken or applied as a replacement for medical advice. The Lifespan with Dr. David Sinclair podcast, its employees, guests and affiliates assume no liability for the application of the information discussed.

Title Card Photo Credit: Mike Blabac

Special thanks to our research assistants, Adiv Johnson & Sarah Ryan.