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RHR: How to Slow Aging and Increase Healthspan, with Dr. David Sinclair


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Is aging inevitable, or can it be reduced—or even treated? In this episode of Revolution Health Radio, I talk with Dr. David Sinclair about what causes aging and strategies to reduce its effect on our lifespans and healthspans.

Revolution Health Radio podcast, Chris Kresser

In this episode, we discuss:

  • How much genes contribute to our lifespan and healthspan
  • What aging is
  • The mechanisms of aging
  • Strategies to combat aging
  • Resveratrol, NMN [nicotinamide mononucleotide], metformin, and other longevity defenses

Show notes:

Hey, everybody. Welcome to another episode of Revolution Health Radio. This week, I’m really excited to welcome Dr. David Sinclair as my guest. Dr. Sinclair is a professor in the Department of Genetics and co director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School, where he and his colleagues study the molecular causes of aging and how to improve healthspan and lifespan by slowing its effects.

David’s the author of the new book Lifespan: Why We Age—and Why We Don’t Have To, which came out on September 10 of [2019] and has spent multiple weeks on The New York Times bestseller list. David has been named one of Time magazine’’s 100 most influential people in the world. And while he now lives in Boston, he has even been knighted in his home country of Australia. So I’m really looking forward to talking to Dr. Sinclair about aging and healthspan, and the various things that we can do to improve our healthspan and reduce or mitigate the impact of aging. Let’s dive in.

Chris Kresser:  Dr. David Sinclair, welcome to the podcast. I’ve really been looking forward to this.

David Sinclair:  Hey, Chris. Yeah, I’m looking forward to it, as well.

How Much Genes Contribute to Our Lifespan and Healthspan

Chris Kresser:  So, I thought we’d start with kind of a 30,000-foot view question. You work in the Department of Genetics and [have] spent a lot of time thinking about genes and the contribution of genes to our healthspan and just [the] lifespan in general. So where, what do you think, at this point, in terms of the contribution that genes make to healthspan versus the exposome? Environmental factors, sleep, stress management, nutrition, physical activity, air pollution, all the environmental factors that we are exposed to on a daily basis?

David Sinclair:  Well, here’s where the good news is. Through twin studies, people have calculated the influence of genetics on longevity and healthspan. And it’s surprisingly low. It’s very disappointing for geneticists like me. But it’s estimated to only be 20 percent. But then, if you look at the glass half full, what that means is that something like 80 percent is now in our own control. And we can greatly affect how we will be in terms of health in our old age.

And for me, that’s actually been one of the most important messages that I’ve been spreading. And I wrote about [it] in my book, which is, often we feel powerless. We think, well, I’m going to die at 75. My dad did; my mother did. This is my lot in life. It’ not true. You can have a massive difference. If you do just some very simple things in life, it’s estimated you can live another 14 years over someone who doesn’t bother.

Chris Kresser:  Yeah, I actually wrote an email recently about that study that it was something around 12 or 14 years of life for just following the top five health behaviors. Nothing fancy, not talking about intermittent fasting or biohacking or anything like that. Just:

  • Maintaining a healthy weight
  • Getting enough exercise
  • Not smoking
  • Not drinking excessively
  • Getting enough sleep and eating well

So that’s a really empowering message. And I wanted to start there because I agree with you. I think a lot of people can be fatalistic and unnecessarily so based on what the data are telling us.

David Sinclair:  Yeah, absolutely. And what does that mean for people like you and me and the listeners, if we already, most of us don’t smoke. We already eat well. So how far can we push it? Can we get another 20, 25 years? And that’s what I think is really the cutting edge. And what we’re going to talk about today is how you go beyond just those simple five things.

Aging doesn’t have to be inevitable. Check out this episode of RHR to find out what drives aging and what you can do to slow the process. #optimalhealth #chriskresser

What Is Aging?

Chris Kresser:  Right. So I also want, another kind of 30,000-foot view question, which I think can be helpful in framing the discussion, is why do we, what is aging? Why do we age in the first place? It seems, it’s like a deceptively simple question, but one that hasn’t been easy to answer until maybe recently.

David Sinclair:  That’s true. And what I’ve come to the conclusion [of] and put forward [in] a new hypothesis is that if you boil down everything that happens during aging, the diseases that occur, the cellular changes that we know occur, the loss of stem cells, the senescent cells, nutrient deregulation, the telomere shortening, the ends of chromosomes getting shorter. I’ve been pondering this for many, many years, and I distilled it down into what I thought was truly going on to drive all of those things.

It came down to an equation, a mathematical equation. And this year, earlier this year, I went to the premier conference on aging run by the journal, Nature. Now it was in Amsterdam. And my first slide was, but you know, I like to push people’s buttons. Wake them up there. I said, in my view, aging is this, and I showed an equation. And it got a few chuckles; it got, I think some people thought that I was insane. But what that equation was, was information lost due to entropy. And what that simply means is the information that we get from our parents and we perfect in the womb, when we’re born, were working optimally usually, that information is lost over time. And that is what I believe leads us into a world of pain and suffering in our seventh, eighth, and ninth decades.

Chris Kresser:  So would it be correct then to say that the primary driver of that information loss is environmental? All the factors that we were just discussing?

David Sinclair:  For most of us, yes. I mean, most of us don’t have the beautiful combination of centenarian genes that some families are blessed with. So, for most of us, we have extra work to do. And some of the genes that we work on, they’re called sirtuins. The “SIR” in the name stands for “silent information regulator.” The information part of that name was one of the clues to this hypothesis. And the SIR proteins (there are seven of them in different flavors in the body) protect the body, [and] they preserve information.

But what we discovered in the early 2000s, in my lab, is that they are responsive to the environment. When the organism, in this case, we were studying yeast cells, but we have a lot of evidence now from thousands of papers around the world, that it’s true in our bodies, as well, these sirtuins, they sense when there’s adversity; they perceive adversity. So how do you trick your body into thinking that you might die? Well, it’s go hungry, you might run out of food. Run, you’re being chased by a saber-tooth tiger. Be hot, be cold, the environment’s changing. And these and other things are what wake the body up out of its state of complacency.

The problem is actually that because most of the 20th century was companies trying to give us perfect luxury, enough food, we don’t need to run, we don’t need to walk anywhere, we’ve done a great job at shutting down those longevity protective factors. And over time, our cells lose their information and cease functioning, and that is actually what I think is now limiting our lifespan.

Chris Kresser:  Reminds me of the movie WALL-E. Have you ever seen that?

David Sinclair:  Yeah. Exactly.

Chris Kresser:  So, if you look at it this way, information, aging is information loss due to entropy, would you classify aging as a disease?

David Sinclair:  I definitely would for many reasons, not just molecular. If you look at the definition of aging, and it sits on my shelf in a book called The Merck Manual of Geriatrics. If you go to “disease,” the definition is “a process that happens over time that causes disability, dysfunction, and often death.” So, if you now turn to aging, a process that over time causes dysfunction, suffering, and death, you say, well, that sounds a lot like a disease. Why don’t we put aging in the same category as at least a medical condition?

[It] turns out that if something that happens as a disease that happens to more than 50 percent of us, we put it in that bucket of aging, because it’s natural. And I’m quite militant about this just because something happens to 49 percent, and we tackle it with billions of dollars versus something happens to 51, and we say, “well, that’s natural. Too bad, we’ve got to deal with it.” That’s insanity. If an alien civilization came down to look at humans and judged us, they would say, “of all the stupid things you’re doing besides climate change, ignoring what’s causing most of you to be sick and die is the second dumbest thing we’ve ever seen a species do.”

Chris Kresser:  I couldn’t agree more. I often say there’s a big difference between what’s common and what’s normal. It’s now common for humans to be obese in the [United States]. But we know from anthropological studies of extant hunter–gatherer populations, and even just looking back in our own history 50 to 60 years ago, that that’s not a normal condition for humanity. But I think we’ve become so accustomed to what is common, we start to believe that that’s normal. I’ve had so many patients come to me and say, “Oh, I started having this problem and that problem. I went to my doctor, and she just shrugged and said, ‘You’re aging.’” And what’s the problem with that hypothesis?

David Sinclair:  It drives me insane. One of the things I write about is, we should all be treated the same no matter what age we are, right? How many doctors have said, well, you’re not 40 anymore. Big deal. You’re supposed to, you’re supposed to get diabetes. No. It’d be like saying, “Oh, you know, most people get cancer if they live long enough. We won’t do anything about that. That’s just part of natural living.” We don’t do that. We rail against these diseases; we hit them on the head one by one in what I call whack-a-mole medicine.

But the problem with that approach is you’re really only tackling the very last symptoms of aging, and you’re going to have very little effect overall. Even if you cured cancer in the world today, you only get about two to three years on average extra life, which is not a big deal. We need to address what’s causing all these diseases. And there is a single cause, I believe. So, if we can go upstream and dam the upstream part of the river, we would have a much better outcome than trying to dam these way down with 15 different medicines that all have side effects and interact with each other, sometimes in bad ways.

But yeah, the medical profession, I’m not sure if they’re upset with me. I haven’t heard any major pushback. But behind the scenes, they might be saying, “This Sinclair guy’s a real menace because he’s saying the way we practice medicine right now is the wrong way to be going about it.”

Can Aging Be Cured?

Chris Kresser:  That’s right. It’s disease management rather than health, true healthcare. But I think we’re on the same page there. The obvious question then that comes up, if we follow this thread that we’ve been pursuing, is [if] aging is a loss of information due to entropy. That very clearly then puts aging into the category of a chronic disease. Then, the obvious question is can aging be cured?

David Sinclair:  Well, I would rather say can we treat it? A cure is a long way away. Maybe not within our lifetimes. I mean, eventually, I think we’ve got some glimpses into the future that it might be reversible multiple times. But within our lifetime, I think being able to delay aging and push the period of our lives that we’re sick into a shorter, shorter period, that’s really the goal here. And that’s doable. Already, we can do that.

We know enough about how to activate longevity genes to give us the best chance at a long, healthy life and to die fairly quickly. So the future is here. The question is, how will people adopt it? There are things you can do in your daily life that are easy, and there are some molecules that, some of them are natural, that I take and my father takes to augment the lifestyles that are never perfect.

The Mechanisms of Aging

Chris Kresser:  Right. So let’s do a little bit of a deeper dive into some of the mechanisms starting with the role of epigenetics and cellular reprogramming. This is a bit of a mouthful, but you talk about the re-localization of chromatin modifiers, RCM hypothesis in your book. Tell us a little bit about that and its significance in aging and slowing aging.

Epigenetics and Aging

David Sinclair:  Yeah, I’m glad you brought it up. I haven’t talked about RCM specifically before publicly, so this will be fun. So the fundamental knowledge that you need to have to understand what I’m going to say is that there are two types of information in the cells in our bodies. The one that we all know about is the genetic information we get from our parents in equal amounts. And that digital information stored is not ones and zeros, but As and Ts and Cs and Gs. And that’s very robust.

You can boil DNA, you can extract it from mummies, and there’s very little evidence that mutations are so abundant in old people that they’re driving the aging process now. There are some nuances, I think, mutations in mitochondrial DNA; they have their own genome at little mitochondrial power packs. They contribute to aging later in life. But what we’ve found in others is that these mutations are not common in midlife. And you can actually reverse mitochondrial aging very quickly. We’ve got molecules that we can turn mitochondrial age and function back within a matter of days.

So what we’ve been left with is a question of, well, if it is information, what type of information could it possibly be? And having discovered these or linked these sirtuin genes, these silent information regulators to aging way back when I was in my 20s working at MIT, the lab of Lenny Guarente deserves some credit here, for sure. What I realized was that, more importantly, it was the loss of epigenetic information. So what’s epigenetic information? That’s just the structures that control how the DNA is read. And we don’t turn on every gene in every cell. Otherwise, we’d be the world’s biggest tumor. What we have is essentially a piano not with 80 keys, but with 20,000 or so keys, each one being [a] different gene. And the music is different for a nerve cell, for a skin cell, [and] for a liver cell, and it’s played beautifully when we’re young.

But what I’m saying is that over time, the structures that play the right genes at the right time become messed up. And skin cells start playing genes or notes that should be only on in liver, and a brain cell becomes more like a skin cell. And it’s a real cacophony. So what we’ve been trying to figure out is what causes those notes to get messed up? And can we reset the pianist so that [they play] the beautiful symphony of our youth? Now, one other thing to know is, what is the epigenome? It sounds complicated, but really, it’s just, at its essence, the structures that control whether a gene is on or off. And if you go to the very fundamental level, boil it down, what’s happening is that DNA that you want switched off for your life, silenced, in other words, get bundled up very tightly, like a hose would be spooled on your driveway in loops. And genes that you want on for most of the time, you put them in big open loops that are looped out so the cell can access them and read those genes.

So it’s a code, but instead of ATCG, it’s actually loop, bundle, bundle, loop, loop, bundle, bundle. And what controls those loops, in part, are chemicals called methyls. That’s just a carbon with three hydrogens on it. Those glom on to DNA over time, and we can read the, what seems to be like plaque on your teeth or crust, think of it as crust on our DNA. And that messes up these loops and bundles so that cells start reading the wrong genes at the wrong time and lose their identity and function. And I think what’s happening as an outcome is that we’ve become susceptible to cancer, heart disease, [and] Alzheimer’s [disease].

So, with all of that, what I can tell you is, if I took your blood, Chris, I can tell you quite accurately how old you are biologically, not based on your candles, but on your actual biological age. I suspect that you’d be younger than your actual age. But those people who smoke and are obese who don’t do any exercise, they are typically older than their actual age, and we can measure that crust on the DNA. And that means their cells have lost their epigenetic information over time.

Chris Kresser:  Right. So it’s this, the epigenetic modification of the cells is, of course, one of the mechanisms that is determining our actual age, as you put it, and methylation is one of the mechanisms that affects epigenetics. And, of course, we have lots of research that suggests that things like nutrition, exercise, and sleep affect methylation. So it’s another way that the choices that we make on a daily basis are driving our health on a molecular level.

David Sinclair:  It’s really true. So, when you eat a high-fat, well, a terrible meal. Let’s say you’ve had a giant soda and processed food, you might say, “well, you know, it doesn’t hurt me. I’ll, it’ll be out of my system in 24 hours. I can forget about it. My body’s just a trash can anyway.” But what we’ve realized is that this clock, it’s always moving forward as far as we know. It’s pretty hard to reverse it, but we’re getting there.

But yet, what I, I now view my body differently than I did just a few years ago. If you recognize that there’s a clock ticking, everything you do that’s bad will accumulate, and everything you do that’s good will slow that process. And so, you don’t get away with anything. Right? Your body is registering what you do to it every day. And so, I’ve been much more careful about what I eat, thinking that I used to think I could get away with it, but I really don’t think we can. And you need to be vigilant over decades for this to work.

Chris Kresser:  Yeah, it really needs to become a habit and a pattern that’s just built in rather than something you occasionally do. New Year’s resolutions or something like that.

David Sinclair:  And you don’t want to start when you’re 60 or 70, if you can help it, because the clock is ticking, and trying to rewind, it’s pretty hard. So I wish I’d started even earlier in my life. I started in my 20s on exercise and diet, but really only rigorously fasting over the last few years.

The Mitochondria’s Role

Chris Kresser:  So let’s talk a little bit about the mitochondria and the role that they play in aging. Because I think after that, some of the specific interventions and things that we’re going to talk about affect the mitochondria. And that’s one of the main ways that those interventions can help us. So tell us a little, just generally, about the role of the mitochondria in aging.

David Sinclair:  Well, every time my lab studies aging, we end up bumping into the mitochondria. So there’s, it’s definitely telling us something. It’s definitely one of what we call the eight hallmarks of aging. And probably, everybody who’s listening is educated enough to know mitochondria generate a lot of energy for the body, in the form of chemicals, one called ATP [adenosine triphosphate]. Which, if we do without, we’re dead in about 10 seconds.

So we’ve got to have mitochondria. It’s the reason we breathe oxygen, because mitochondria essentially combust it and generate ATP out of the sugar. But what we find is mitochondrial number and activity goes down. In our muscle, we can have hundreds of these per cell, and we lose them, and they do become less active. So what can you do? Well, the sirtuin genes promote mitochondrial biogenesis, we call it. So we get more mitochondria, and they become more active. And we found that we can pretty quickly boost the activity of mitochondria, either using SIRT2 and activating molecules like resveratrol from red wine.

But also, more recently, we’ve been working on what are called NAD [nicotinamide adenine dinucleotide] booster molecules. And I’m actually in the office of a company that I co-founded, in full disclosure, [and] I just happened to be out here today, discussing the results from clinical trials. And we’re hoping that the NAD booster that we’re developing will help patients who suffer from mitochondrial diseases or a lack of energy. And after two years of research so far in humans, it looks like we’re on the right path. And we’ll probably know the answers to these questions by the end of next year.

​Nicotinamide Adenine Dinucleotide (NAD+)

Chris Kresser:  Wow, that’s exciting. You mentioned SIRT earlier. But I want to go into more specifics on SIRT1 and discoveries on how that relates to NAD+, because I know that’s one of the molecules you’re a fan of and we will be talking about. So I want folks to understand the basis of that.

David Sinclair:  Right. So the sirtuin genes, as I mentioned, there are seven of these, [and] they do different things that they’re in. Three of them are actually physically in the mitochondria with enzymes. So, just [as] a baseline of knowledge, these genes produce enzymes that then move to different parts of the cell to take care of different activities. So three of those enzymes are in mitochondria. Three of them are in the nucleus taking care of the genome and the epigenome, silencing genes, repairing genes. And there’s one lonely sirtuin number two in the cytoplasm in between the mitochondria and the nucleus.

And they do wonderful things. But they don’t work unless, don’t work efficiently unless they have an accelerator pedal pushed and the fuel. So they have an accelerator pedal, essentially, it’s a protein arm that sticks out, that when, say a molecule like resveratrol from red wine sticks to it, it will do a maneuver like a bear hug, and it’ll be more active. So it’s an accelerator. But the fuel, which is, you could argue, even more important for a car, in this case, the enzyme is actually a molecule we make when we’re alive; we’ve got probably 20 or so grams of NAD in our body. NAD is a small molecule that the sirtuins are sensing. And so, we need NAD anyway. So NAD is in old high school textbooks as a molecule that is used in mitochondria to make energy and to make new metabolites. So it’s very important, but it’s extremely boring. We typically learn it and forget it in high school.

But what has, NAD has experienced a renaissance because these enzymes are sensing NAD concentrations in the cell. And unfortunately, we think, as we get older, we make less NAD and we consume more of it. So that by the time we’re 50, if you take a skin sample, it will have half the levels of NAD that you had when you were 20. We definitely see this in mice, too. So we’ve taken the approach of either providing the accelerator pedal, or the NAD-boosting molecules, which we usually use, what we usually use are precursors, molecules that the cell can turn into NAD quickly. And those raise the NAD level back up to being young again or beyond. We can get the levels up about two- to threefold in mice and in people. And then, at least in mice, we see remarkable things happen to those mice. We see rejuvenation of mitochondria, we see lowering of inflammation, [and] we see a dampening of the hypoxic response, which drives inflammation. And we also see a growth of new blood vessels in muscle, as though the mice had been exercising.

And then, when we put those mice after three weeks on the molecule, they actually act as though they have the physical endurance of mice that have been exercising and are much younger; specifically, two-year-old mice could outpace the young mice after just two months. And they get less lactate, so they don’t get the lactate burn. And their blood flow is beautiful. So their muscles are perfused and the toxins get taken out by the muscle. And if you have an occlusion, if we block the femoral artery and give our precursor raise up NAD, they will reroute blood vessels much more quickly and recover. So that could be useful to someone who has a blockage, as well.

Chris Kresser:  That’s really exciting. And I’ve read a lot about NAD, and it seems like it’s, I mean, I don’t think there are that many panacea-type molecules, but NAD certainly seems like one of the most promising at this point. I want to come back to how to boost NAD when we talk about some of the other specific interventions that you are doing yourself and that you recommend. But before we do that, I want to kind of frame the bigger picture again. So if, let’s say somebody is currently living a relatively standard American lifestyle. They’re not eating that well, they’re not getting a lot of sleep, [and] they’re fairly sedentary.

What I see sometimes, what concerns me, is that there are some folks that will skip the healthy diet, healthy lifestyle and go right to taking resveratrol or NMN or some of the other things that certainly can have an impact on healthspan and lifespan. And I don’t think that taking them would be a bad idea in that situation. In fact, you could argue that it’s a really good idea. But there’s sometimes a mentality where, if I just do these things, I get a free pass, and I don’t have to worry about the diet and lifestyle pieces. I’m assuming you think that’s a bad idea?

David Sinclair:  Well, it’s certainly not giving you the best chance at a long, healthy life. And we also know that exercise and fasting will work from live studies of people and NMN and other NAD boosters, and, to a lesser extent, resveratrol. We don’t know if they work in the long run. And so, yeah, anyone who thinks they can just take an NAD booster, really, you’re just hoping that the mouse results will translate to humans. We don’t actually know that yet.

So the best bang for your buck is to do the right things with exercise and diet. And I’m actually, myself, taking some of these molecules, because there’s very little downside that I know of. But there’s also another fact; there’s a third thing that most people don’t know. We study resveratrol and NMN, the precursor we use in the lab, and the one that I take, we combine that with healthy diets and exercise. And what we find is that they’re additive. They’re not substitutes. Well, they are partial substitutes, but when you add them, you get the best bang for the buck. For example, a little-known fact, when we gave resveratrol to mice that were on a Western diet, okay, they were healthy like a lean mouse.

But if we gave resveratrol to mice that were periodically fasted, we got mice that lived longer than any other group. So it was an adjunct, an additive to fasting, and fasting was an additive to resveratrol. Right? So that means that you want to do both. In the case of the NMN, what we did was we combined exercise with NMN. And even though NMN mimicked exercise, when the young mice were exercised on top of NMN, they ran the farthest of any mice we’ve ever had in the lab. In fact, one of them broke the treadmill because it ran so fast. So really, it’s not an excuse; it doesn’t subtly substitute for having a healthy lifestyle.

But, honestly, for people like me who spend my time sitting in chairs and airplanes and typing, I really need some help. I do what I can, but some of us need more help than others.

Chris Kresser:  Absolutely. We’re all fighting against this mismatch of the modern lifestyle and what our genes are really programmed for. And it’s, I don’t know anybody who’s, like, living 100 percent the way that would be optimal at this point. So I agree, it’s, anything that can help to mitigate those effects is welcome.

David Sinclair:  And Chris, we may not be able to live optimally. There may be downsides to running and fasting that we don’t know, that the mouse is showing can be offset by adding in something a little extra.

Strategies to Combat Aging

Chris Kresser:  Absolutely. What about the contribution of things like saunas? You mentioned hot and cold. So sauna or doing cold plunges, or you’ve talked about fasting. Both, there’s extended fasting and intermittent fasting and other, let’s say more advanced strategies that might have an impact on epigenetics and mitochondrial function. Is there a way to sort of quantify or qualitatively assess the impact of those strategies collectively versus things like NAD boosters or resveratrol, or even metformin, which we’ll talk about?

David Sinclair:  Yeah. Yeah, well, so the hot and cold concept, even though we were the first people in my lab to show in yeast cells that temperature, increases in temperature, low amounts of protein, low amounts of sugar were extending their lifespan and health by the same mechanism. In fact, the sirtuin genes and NAD we showed way back in 2003. We’re all working through the same mechanism, which now we kind of take for granted. But in those days, it was a real shock to the scientific community, that exercise and diet and heat had anything to do with each other. We, I think still some people think differently.

Chris Kresser:  Right.

David Sinclair:  But I still was pretty skeptical that you could go in a sauna and that would be enough to activate your longevity pathways, or cold, for that matter. But for my book, I started researching it. In fact, to be honest, I was prodded by my editor who said people will want to know about this cryotherapy. And I said, I’m a world-class researcher, at least I’m trying to be. If I start talking about these things, no one will take me seriously. But I started to look into it. And actually, the data were surprisingly compelling. I wouldn’t say proof.

But if you look at thousands, in one study, [in] 10,000 Finnish men who go to the sauna, or go to their own home sauna three times a week or more, the rates of cardiovascular disease [that] were reduced by it was between 30 and 40 percent. I don’t remember the exact number. Those were really compelling. Now, there are always downsides. Right? I know you know the literature really well, that maybe if you’re in the hospital or you’re sick, you’re not going to go to the sauna, and that biases the study.

Chris Kresser:  Right.

David Sinclair:  But I’d read enough to make me convinced that saunas are likely to be healthy for many reasons, and also, nothing less might actually make you feel good, as well, which it does. So I’ve gone now to weekly sauna baths. And also the cold. Let me talk about cold. I dip in a cold tub for as long as I can. Usually, it’s only for a few minutes. My son Benjamin, who comes with me, likes to stand in there for 15 minutes. It’s crazy. Mind you, he’s got a little bit of extra padding on him, which is another story. But hopefully, you won’t be listening to the story. So the cold story also makes scientific sense.

There’s a sirtuin called number three, which resides in mitochondria. And it is involved in making brown fat when the skin is cold. And what we found in mice is that mice with brown fat are very healthy. And it’s for two reasons. Brown fat is highly metabolic. It’s full of mitochondria, so your metabolism will be revved up and you’ll burn off energy, which is good with our lifestyles these days. But it also, we think that brown fat, or even beige fat, which is something in between white and brown, gives off these molecules. Many of them, we don’t know what they are yet, but it does seem as though they are protective against things like inflammation in the body. I was recently at a university where I spoke to a scientist who was studying brown fat conversion.

They put the mice in a cold room and they get brown fat. What he told me was that if you put old mice in the cold room, they barely get any brown fat. Now, if that’s true in humans, that means you’d better start early to build up your brown fat stores because it may be too late by the time you’re, say, a 60- or 70-year-old.

Chris Kresser:  One thing, I’m a lifelong surfer. And one thing I’ve always noticed, it’s interesting, is [that] you don’t see many fat surfers. And I’ve always wondered about that. Because, in other sports, you’ll see people, even, who are exercising regularly who are significantly overweight, [and] my theory has always been that the cold exposure that comes, even in relatively warm water, is still colder than body temperature. And if you’re spending a significant amount of time in that water, my guess is that that has benefits, metabolic benefits that are persistent over time.

David Sinclair:  Right. Well, I’d be shocked if that wasn’t true. It really, I think that we can assume that it’s likely. And one of the things that’s interesting is if you’re not a surfer, what can you do? Well, you can jump in ice-cold baths, or you can go for a walk out in snow if you’re on the East Coast here or in the Midwest. But another thing you can do, which I increasingly practice, is I don’t bundle up during the day. If I’m in a building, I’m wearing a T-shirt, if I can. And at night, one of the big biohacks, life hacks, is don’t snuggle under a really hot blanket.

Chris Kresser:  Right.

David Sinclair:  I like to wear a sheet. And, first of all, I sleep better, I’ve found, but also, you’re actually radiating heat, and that is the easiest way to burn off energy.

Chris Kresser:  Yeah, it’s interesting to frame this in the context of comfort versus discomfort. Like, you started talking about that at the beginning of the podcast. We’ve gone out of our way to ensure comfort so that we’re never cold. We’re never hot. We’re always sitting in a comfortable chair. We never feel hunger because there’s always food available at all times. And we’re seeing now there are some real downsides to a life that is characterized only by comfort and never by experiencing discomfort, which would have been a normal part of our ancestral experience.

David Sinclair:  Right. And, in fact, we’ve done a very poor job at putting our bodies into that defensive state called hormesis. We’ve done the opposite. So we have left to avoid everything. Not, don’t have to. But the goal is to avoid everything that makes you feel perfectly comfortable. Get out of your comfort zone. Not to the point where you want to quit. But skipping breakfast and occasionally skipping lunch is what I do, and that’s not difficult at all, actually. I feel a lot better because of it. But these things are very doable.

You mentioned long-term fasting, rather than just intermittent fasting. I think that’s probably even better if you can go for a whole day or even three days. Or, like our friend Peter Attia does, for a whole week every quarter. I think that’s even better if you can do it. I haven’t been able to just with my busy schedule. I’d probably lose my mind or kill somebody that I work with.

Chris Kresser:  Yeah, yeah.

David Sinclair:  And there are downsides to that, right? You do get aggressive. Our mice, when we put them on calorie restriction, they attack each other in the cage. So this is a real thing. But for me, skipping breakfast is something I know works for me because I’ve also measured my blood sugar. I have one of the glucose monitors that you stick in your skin. And I can see that my body makes glucose just before I wake up. And I’m not hungry. And it’s insanity for me to be eating cereal in the morning if my body already has more than enough sugar.

Chris Kresser:  Right. And then [there are] kind of in-between approaches, like the fasting mimicking diet, Valter Longo’s approach. And so, lots of different ways for people to experiment with fasting. And I don’t think, it seems like we don’t have enough data yet to really compare the relative benefits from one of those approaches to another. But they’re all better than nothing at all, I think we could say.

David Sinclair:  I couldn’t have said it better myself. Now, Valter is an opinionated guy, [a] good friend of mine, and we will argue over a glass of wine or a cocktail at these conferences. And he’s pretty militant. Whatever he thinks, he usually, he says is the best way. But you’re right, actually, when you really get down to it. Nobody knows the optimum. We’re at a point in history where we know generally what works, and what it’s probably going to boil down to is [that] it’s different for everybody.

People have different microbiomes, they have different genetics, they have different lifestyles, [and] they have different determination. And one will work for somebody versus another. And that’s why I’m very much into measuring your body, because you just don’t know. You can follow a recipe in a book of a diet, but it may not work for you as well as something else. And so, that’s why I think that the real trick to longevity is to optimize yourself. So how do you do that? I wear a ring. The Oura ring, many people now know about. I talked about it on Joe Rogan’s show, and it sold out. But I think you can buy it now. I’ve got, of course, the watches on my arm, one watch on my arm that tells me that, but I also go further. I mentioned the glucose monitor,

Chris Kresser:  I see you’re wearing a CGM [continuous glucose monitor].

David Sinclair:  Yes, I am. Not the super-duper one, just the one that you scan with your iPhone and get a reading. That works great. And I’ve learned to rely on it, actually. It’s also part of the game. It’s like a video game that you play with your body. And then, I also do blood tests on occasion through a company that tells me how to optimize myself based on a lot of other people’s data and AI [artificial intelligence]. And that’s been very useful. I’ve got over 11 years’ worth of data now that I can plot to see how I’m doing and if there are long-term bad trends that I need to correct before I get sick.

Chris Kresser:  Yeah, I agree wholeheartedly with that. I think, sometimes, we can get too wrapped up in the minutiae and lose sight of just doing something. Like with fasting, arguing over which type of fasting is best can become a distraction from just doing some fasting, skipping some meals, or eating less for a period of time.

David Sinclair:  Yeah, the worst case, Chris, is that I’ve got colleagues who say, these are my scientific colleagues, “Oh, I’m not going to try that until it’s proven to work.” Well, good luck.

Chris Kresser:  You’ll be waiting a long time.

David Sinclair:  Yeah, I’ll see you in the afterlife then. I’ll miss you when you’re gone.

Resveratrol, NMN, Metformin, and Other Longevity Defenses

Chris Kresser:  Yeah. All right. Well, I know we’ve got a few minutes left. I want to talk about the molecule, some of those specific molecules that you like, including NAD boosters, and let’s start with that. The best way to boost NAD, and then maybe talk a little bit about resveratrol and even metformin, if we have time.

David Sinclair:  Okay, so the bottom line is we want to turn on these longevity defenses. These enzymes. I’ve mentioned sirtuins; these are the seven that I work on. There are another two categories of longevity pathway, we call it. One is AMPK [AMP-activated protein kinase], which is the target of metformin. And there’s a third one, mTOR, which is the [mammalian] target of rapamycin, a drug that’s used to suppress the immune system. But it’s evolved to sense the amount of protein that’s coming in typically certain amino acids. But the sirtuins are talking to these other pathways. So, if you activate your sirtuins, you’re also going to turn down your mTOR, and activate your AMPK.

So you’ll be all good. So, how do you do that? Well, sirtuins, you can activate the primary sirtuin called SIRT1, which suppresses epigenetic noise; it protects telomeres, [and] it helps with broken DNA. And so, you want to take an accelerator. Well, what I do is I take an accelerator, which is the resveratrol. I take a gram of that, or literally a teaspoon into a little bit of yogurt that I make every morning. Well, I don’t make yogurt every morning, I make a big batch of it. And it lasts me for a couple of weeks, and I could talk a whole show about yogurt, actually. But I won’t. I’m probably in my newsletter going to release the recipe for everybody. So, if you want to see the recipe of this special yogurt for my microbiome, sign up for my newsletter.

But the point is that, so resveratrol dissolves in yogurt or something fatty, which is what you need. Otherwise, you’re basically eating brick dust, and it’ll go straight through you. And some clinical trials have failed with resveratrol because they didn’t know how to deliver it. You can’t just pop a dry pill, unfortunately.

Chris Kresser:  Is it tasteless?

David Sinclair:  Yeah, it’s tasteless, but you know, it tastes like chalk.

Chris Kresser:  Right. But it won’t overwhelm the taste of a smoothie or yogurt when you mix it in.

David Sinclair:  Not at all.

Chris Kresser:  Yeah.

David Sinclair:  Nope, nope. It may be a little crunchy if you don’t dissolve it. That’s all.

Chris Kresser:  Right.

David Sinclair:  But I’ve been taking that since 2004, and I’ve got a very clean cardiovascular system. Everything’s looking good for someone my age. I’m 50. So that’s the resveratrol. I do that in the morning. I don’t do it at night because activating SIRT1 at night will screw up your circadian rhythms and you won’t sleep very well, we found. And that’s true in mice. There were a couple of science papers on this back a decade ago. So that’s all scientifically valid.

The fuel for these sirtuins is NAD. If you eat NAD, or inject it, it may work. It’s controversial. The reason that we suspect it’s not as good is because NAD is a very large molecule that needs to be broken down first, before it’s reconstituted back in cells. And so, the molecule that seems to work really well in our hands is called NMN. Long form is called nicotinamide mononucleotide. And it’s the immediate precursor to making NAD. It’s got the sugar on it. There’s a sugar, a little ribose molecule, which is the ribose. It’s got adenine, which is a piece of DNA. And it’s got the nicotinamide.

No, nicotinamide is not nicotine; it’s very different. It’s not going to act like nicotine. It’s more like niacin, vitamin B3. Anyway, that molecule will immediately be turned into NAD by the body. And we find in myosin in humans, it works very effectively. There’s another molecule that’s sold on the internet, called NR, nicotinamide riboside, which is an even smaller molecule. It doesn’t have a phosphate on it, so the body needs to pull phosphate from somewhere else to be able to rebuild NAD.

Now, this is a whole show, as well, about the difference between these molecules. There have been a few studies within humans already. Some of them didn’t show any marked effect for reasons that we don’t know yet, but we’ve seen some positive effects in other studies. For instance, there was a study on ALS that looked good, and there’s also one that looked at inflammation. Inflammation went down quite dramatically, actually, in those subjects.

But the question is, is NR the optimum? Is it NMN? Or is it something else? And I’m doing trials on some more optimal molecules that we think will work even better than the molecules that you can currently buy on the internet. Long story short, we’re at the point where it’s do or die for these molecules. A lot of people are taking these molecules because they’re very safe. We don’t know of any downsides. And the science sounds good. There are a lot of people that, they claim they feel better and they have more energy, just like the mice do. But as a scientist, I can’t say that we have any proof that they work yet.

Chris Kresser:  What are you taking?

David Sinclair:  So, I take NMN with my resveratrol. I take 750 milligrams up to a gram depending on how I feel in the day. And that seems for me to give me a real boost. If I stopped taking NMN, I actually become tired and grumpy and can’t be bothered getting out of bed. So, for me, it’s currently a requirement. Especially when I travel, I find that getting … So I’m going to Australia today. When I get to Sydney, I’m going to take probably a gram of NMN, and I think, I’m not proving anything, but I think it overcomes my jet lag pretty well.

Chris Kresser:  Interesting. Any particular considerations regarding specific delivery mechanism or form? Is it powder versus capsule, brand?

David Sinclair:  Well, I don’t jump into brands, A) because I don’t test them and B) because I don’t like being in lawsuits, and it’s happened before. A fairly litigious bunch out there. But what I can say is that I always look for GMP grade material. I look for ultra-pure, greater than 98 percent pure. And NMN, by the way, will taste a bit like burnt popcorn. So, if you get that flavor, you’ll have some idea that it’s the real deal. But also, please store these molecules in the fridge. They go off on the shelf at room temperature over a matter of months.

Chris Kresser:  Okay.

David Sinclair:  And that information isn’t made freely available.

Chris Kresser:  So, are you not mixing that with yogurt? Are you mixing it with water because you don’t want your yogurt to taste like burnt popcorn?

David Sinclair:  Yeah.

Chris Kresser:  Yeah.

David Sinclair:  It dissolves in water. So I just have it with my coffee. So I’m not averse to having coffee or tea in the morning. I don’t regard that as breaking a fast. Nor do I for a couple of spoonfuls of yogurt.

Chris Kresser:  Yeah. Okay. Let’s talk a little bit about metformin. I’ve heard you discuss this on other podcasts like with our friend Peter, and a few others, as well. And I know there are still some question marks about it, and especially whether you can, whether it’s beneficial on days that you’re exercising. So maybe just a quick summary of why someone might even consider metformin as a life healthspan extension molecule and then what the considerations are in terms of taking it.

David Sinclair:  Yeah. Right, so metformin will activate the second leg of the stool and augment sirtuins. And we think it works by inhibiting the mitochondria in such a way that the cell responds by making more mitochondria and turning up the mitochondrial activity in the cell. The drug metformin comes from the 1960s and ‘70s. It’s a version of a plant molecule from the lilac plant, French lilac. And what was found, just really by luck, is that it makes the body more sensitive to insulin, and works very well as the frontline therapy in type 2 diabetes.

And so, yeah, you’ll lower your blood sugar, typically. But what was found was that by studying more than 10,000 patients who have taken metformin for many years, and looking at their rates of other diseases besides diabetes, they were, people taking metformin were more protected against cancer, heart disease, frailty, and Alzheimer’s than someone who never had diabetes, and didn’t take the drug. Which is remarkable, right? And what that points to is that it’s doing more than just treating diabetes, it’s actually slowing down aging itself.

And so, with that data, and that’s being reproduced in a few different studies, and knowing that the drug is fairly cheap, and knowing that the drug has very little side effects for 9,999 people, then it’s, I’ve made the calculation that it’s worth taking myself. Which I do, 500 milligrams in the morning, [and] 500 milligrams at night with food. It can be rough on the stomach. So be aware, if you do take it, you might feel a little queasy at first. But you can overcome that with food or just over time. Now, you can’t just go to your doctor easily and they’ll give you metformin. Unfortunately, most doctors haven’t heard about this research. And they also are not taught to prescribe medicines to people who don’t yet have a disease.

So you may have some convincing to do. And I’ve heard that people have success, either [with] taking my book to the doctor as a present, or giving them that, or a combination of papers that are referenced in my book.

Chris Kresser:  Yeah, that’s a, I think, really another show, as well, I think, to talk even more about the mechanisms of that, and then how to sequence that in versus with exercise, travel, all of that.

David Sinclair:  Well, I can quickly tell you.

Chris Kresser:  Yeah, I know, we have a couple of minutes. Give us a kind of CliffsNotes version of that.

David Sinclair:  Right. So, I know what I’m talking about, because I’ve spoken to the scientists who did these studies. And they thought that the pundits overinterpreted the data. What happened was, because metformin interferes with the mitochondria, you don’t get the hypertrophy, you don’t get as much muscle building if you’re always on metformin. But here’s what happened to the elderly people taking metformin. They all gained muscle, and they all became just as strong as each other.

Okay? There was a slight difference in the amount of muscle gained. But there were far more similarities than differences in those groups of no metformin, plus metformin. Now, if your only goal in life was to win a weightlifting competition and bulk up, yeah, you probably don’t want to take metformin the day that you go to the gym and perhaps the day you recover. But if your goal is to live longer, and to have strength and survive if you fall over in your old age, then it’s not such a big deal.

Now, I’m testing this. In my body, I’m trying to skip metformin on days I exercise to see if it makes any difference. But I think that it’s not a major concern for most people who are not professional bodybuilders.

Chris Kresser:  Dr. Sinclair, thank you so much for this. It’s your wealth of knowledge, and contributing directly to extending people’s healthspan must be very satisfying. Where can people find out more about your work? And if they want to, kind of, stay abreast of new developments, you mentioned you have a newsletter. How can they sign up for that?

David Sinclair:  Sure. Hopefully, people have pens. I guess you can rewind.

Chris Kresser:  Yeah, we’ll put it in the show notes, too.

David Sinclair:  Cool, thank you. So, yeah, on social media, I’m on Twitter @DavidASinclair. Instagram is DavidSinclairPhD, and my website is Lifespanbook.com. And there, you’ll find a history of blogs and newsletters that I put out. You have to sign up by email to the newsletter if you want. You can always opt out if you don’t like what I’m writing. What I try to do is to give updates on things like the metformin story, on NMN versus NR, which is better and why. Or at least what the science says. And even perhaps the next one will be a yogurt recipe, if people are interested.

Chris Kresser:  The life, the healthspan-extending morning yogurt recipe, love it. And of course, check out Dr. Sinclair’s book Lifespan: Why We Age—and Why We Don’t Have To. It’s a very well-researched, thought-provoking, and mind-opening book. I highly recommend it. It was hard for me to put down once I started reading it. And David, [I] would love to have you back in the future to talk about your more recent research and new developments.

David Sinclair:  Well, thanks, Chris. I love what you do. Keep doing what you do. You’re a voice of reason among all the radical views. Keep up what you’re doing.

Chris Kresser:  I appreciate that. Have a safe trip to Australia, and hopefully, your jet lag hack is successful. I’m going to try it myself because I do a fair amount of traveling, and I’m always looking for a little extra support there.

David Sinclair:  Will do. Thanks a lot.

Chris Kresser:  All right, take care. Bye-bye.

David Sinclair:  You too. Bye.

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