Death is Inevitable but Aging is Not

Aging is something that we can tackle just as we have been tackling cancer and heart disease.

Welcome to the doctor's Pharmacy. This is Dr. Mark Hyman. That's Pharmacy with an f-f-a-r-m-e-c-y place for conversations to matter. In today's conversation, I think will matter to a lot of you because it's about aging. And we have one of the world's experts on Aging here, Dr. David Sinclair from Harvard, who I've known for well over a decade, and we're both getting younger together. Every time I see him, he's got basically no less wrinkles and he has no gray hair and he's over 50. I don't know what he's doing, but I wanna know. We're gonna find out. David is the professor in the Department of Genetics and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School. And he and his colleagues study longevity and aging and how to slow down that process, which sounds good to me as I'm approaching my 60th year. More specifically, they're focused on studying sirtuins, which are these protein modifying enzymes that respond to changing levels of something called NAD, which is a very important molecule we're gonna learn about today, and ducloric restriction, which is eating less. Now, I don't think that's fun, so we're gonna find a way around that, right? Is that true? And, he looks at other factors around aging like metabolism, neurodegeneration, cancer, how to reprogram your cells, which sounds good to me. He's the co-creator and co-chief editor of the journal Aging, and he's co-founded several biotech companies and is inventor of 35 patents, like Thomas Edison over here. He's among, one of the most revered scientists out there. He's been included in Time Magazine's list of 100 most influential people in the world and Time's Top 50 in Healthcare. He's also the author of a book called Lifespan: the Revolutionary Science of why We Age and why We Don't have to, which is out September 2019. So it's really great to have you here, David.

Thanks, Mark. It's good to see you, too.

Okay, so I first really got interested in the whole science of aging. When I went to this conference, I don't even know if you were there, was with the Dalai Lama. It was at Robert Thurman, Uma Thurman's dad's place up in Menla Retreat in upstate New York. And there was all these Tibetan doctors and the Dalai Lama, but all these extraordinary scientists, people like Elizabeth Blackburn, who studies telomeres, and Leonard Guarte, who was one of your mentors at MIT who studied aging. and I remember just sort of walking down the field with Leonard and saying, so what is the deal with aging? Why do we age? And essentially, and how do these sirtuins work and what's driving them and how do they get regulated? And what he said to me was, shouldn't have been surprising, but it was kind of surprising. It was like sugar. Like sugar is the thing that's screwing up our aging process and our mitochondria. And that's what actually causes these sirtuins not to function the way they should. And I thought, wow, that's fascinating. And it sort of got me thinking about the whole process of aging. And then I was watching one of your interviews online and you mentioned that you are obviously studying aging, but you're also looking at your own aging. And you did some tests that indicated that you were older than you actually were chronologically. And then you did some things and you actually found that you were younger than you were chronologically. So how did that work? Let's start with your own journey of how do you actually made yourself younger? Well, because you're the guy who knows about this stuff.

Well, I gotta say, you're turning 60, I wouldn't have thought so. So whatever you're doing, keep doing that.

Yeah, look at him, he's like awesome looking. Well, so this is the book, Lifespan.

It's an awesome book. Well, this is a download of my brain into that book of everything that I've thought about over the last 25, 30 years. In terms of my age, this is not a clinical trial, so I'm not gonna be publishing these data anytime soon. And of one is good. And of one. But when you're on the cutting edge of science, if you start with an end of one, all science begins that way. So what I did was I went to a company that does blood tests. Should I mention their name? Doesn't matter to me. InsideTracker, I'm a consultant to them if anyone wants to know. And they have a five-factor blood test that goes with proven correlates for longevity. So glucose, ferment, testosterone, liver function, CRP, there might be one thing I'm missing, but those things add up. Looking at blood sugar, inflammation, definitely blood sugar is a major thing for aging. Actually, one of the best predictors of your lifespan is your fasting blood sugar.

Yeah. So, yeah, it does. And by the way, not within the normal range, it should be optimal, right? So, if we consider normal up to 100, but if you're going to get.

Up to 100, it's not good, right? Oh, yeah. We could get into that. I find it crazy that a lot of times we don't treat high blood sugar until it's too late. Anyway, so what I did was I had my blood tested and I've been doing it since 2011. I've seen things creep up as I got older. And at the time I was 48 when I had this test, when I got a real shock that it said that I was 58.

Oh, wow.

Ostensibly.

The aging researcher to be 10 years older.

Not a good look.

It's not a good look.

Yeah, right. I'm worried I might die from a heart attack and everyone will go, okay.

I'm writing this book about lifespan, but I'm actually like way older than I look.

Right. That would be bad. So I did a couple of things. I started taking metformin actually. So this is the, many people will know this is the frontline therapy for type 2 diabetes. And I felt justified doing that for two reasons. One is I'm a scientist, I can see what happens. It's fairly safe drug. We can talk about its safety, but millions of people have tried it. and I also have high blood sugar in my family and it was edging up so my father's on it, my grandmother was on it so figured why not start before it gets out of control. So that was the science part of me. And then I also, well I saw my age come down a little bit a few months after that. It wasn't great, it was better.

Yeah.

I came, so I started out at 58 and I was a bit worried, well came down to about 50, 7-56 as I recall.

Not that great.

No, no, it's still not good. So I went on the molecule that we were studying in the lab, which we were giving to mice and we could see was improving their health and making them run further. And as far as we could tell, reversing some aspects of aging, particularly in muscle. And I started taking it again, just as an experiment, not as a clinical trial. And next time I measured it again a few months later, It went down to 31.4.

Amazing. So you're now older but younger.

Well, it was a good day. My wife would tell you, I was running around showing her the graph going, Look at this! Independent studies show I'm younger. And it stayed down. But one thing that happened was with combination of these two things, I wasn't as hungry. I lost a bit of weight, about seven pounds, which certainly wouldn't have hurt. But one thing about this inside tracker thing and other things such as I noticed you've, I think that's same ring as I've got. The Oura ring, when you've got data in front of you every day, you think more about it and you can react. And before I would never know what was going on if I did something to my body.

Yeah, now they have these continuous glucose monitors.

Yeah, and that biofeedback, the bio tracking as we call it, it's beneficial in nothing more if nothing more just gives you more clarity about how you're doing and more mindfulness. We know more about our cars than we know about our bodies actually, with all the sensors, over 100 sensors in our cars, how many do we have on our bodies? Eventually we'll have many more.

So it's fascinating, you know, one of the things that we think about in terms of aging is that it's this inevitable and extra process that goes in one direction. And you're challenging that idea. You're saying maybe what we see as aging isn't actually healthy aging, it's abnormal aging. And then it's really based on a series of biological dysfunctions that we can understand and we can modify through either diet or lifestyle or maybe nutrients that we take or supplements.

Right. Well, why not? First of all, just philosophically, let's talk about that. Is aging a condition? Well, I believe it is. I think you could argue, I make the argument in the book, that Disease is something that happens over time that's deleterious, reduces function if it happens to less than 50% of the population. If it happens to 51%, we call that aging and it's arbitrary. And the mere fact that it happens to most of us, if we live long enough and if we're lucky enough, doesn't mean it's any less important. In fact, I would argue it's more important. And so one of the things that I'm very keen on explaining to everybody is that aging is something that we can tackle just as we have been tackling cancer and heart disease. And this inevitability, cancer is inevitable if you live long enough. So is heart disease. So is dementia. The longer you live, the more chance you'll get it. Okay.

But not inevitable.

Well, I would say every disease of aging is inevitable as long as you live long enough.

So you have to die of something? For sure. You can't die of old age.

Well, something has to go wrong. But what is the driver of all of those diseases? Science says it's aging. If you're a teenager, you don't get Alzheimer's, you don't get cancer, and we don't often think why that is. But the most important factor, by a factor of 100 or more, is the aging process. So if you can keep the body younger and functioning like it did when we're in our 20s, you're literally not going to get heart disease, you're not going to get Alzheimer's. And as we learn more and more about how to reverse not just the effects of aging but actually the age of cells themselves, I believe we will be able to prevent in large part these diseases because we've removed the largest cause of these diseases.

Yeah, I mean, I think what you said is sort of implying that there's common root causes of all these diseases we see with aging. Then if we focus on those root causes, that we can modify the trajectory of all those diseases and we don't have to treat all of them independently.

Right. Well, I call it whacK-A-Mole medicine the way we do it now, which is fine. You know, I think anybody who focuses on medicine and research is doing a great service to the world. I do think we can have a big impact if we can find out what's driving all those diseases. And it's not intuitive unless you're in the field that what's driving those diseases that we all see in our families, there's something common. And actually, in the book, I have a theory that explains why or what is the underlying cause of all the diseases that we get as we get older. Not just all the diseases, wrinkles and gray hair and all of that stuff. It's all the same. I believe it's all the same process that can not just be slowed down, but even reversed.

Well, this is such a radical shift in thinking in medicine, right? In traditional medicine, you've got your diseases and they're all separate and dementia is different from heart disease, different from diabetes, different from cancer, different from all these hypertension, right? They're all separate illnesses. In functional medicine, we think about the body as a system and it's having a few common root causes and a few key systems that when they function well, disease doesn't have a chance, right? So whether it's the mitochondria, which you've been studying when you're talking about the powerhouse of the cell, whether it's inflammation in your immune system or whether it's your microbiome or whether it's your hormonal regulation, these are all connected. And the key to solving the puzzle of disease and aging is really understanding these common links, right?

Well, that's why I think we hit it off over a decade ago, is that I'd rarely met a doctor who talks like you do. More and more are, but it really, it's been missing. And I teach medicine at Harvard Medical School for what that's worth. And the way we teach it is treat the symptom, not treat the cause.

Yeah. Yeah, and so in aging, it seems like there's things that happen and I want to get into why, but we see increase in inflammation and aging. We see a decrease in mitochondrial function, which are these energy cells. So we lose energy. Basically, our engine gets the carburetor gets full of whatever and it doesn't work. We see hormonal changes, lower testosterone, higher cortisol, lower growth hormone, increased insulin, increased blood sugar. We see changes in the microbiome that degrade over time. We see changes in in our ability to sort of metabolize things and toxins. These are all things that we can understand now with the science we have, which we couldn't even a few decades ago. It's what we've been doing in functional medicine without really understanding that much of the science because it's all emerging. But your work has really started out with looking at the mitochondria as a key to aging. And that has sort of led you to some of these other linkages, right?

Well, mitochondria, I didn't set out to study mitochondria. It's how our research pointed in that direction that they were part of the puzzle. We started out when I was with Linda Guarini. You mentioned my former mentor and still friend. We started out with the question, why do organisms grow old in the first place? Simple question. Very few people had actually asked it. And so we studied yeast cells from, you know, bakers and brewers use it all the time. Why do yeast cells not live forever? And they typically live a week. We actually found out that these genes that you mentioned, sirtuins, are regulators of yeast aging. And we have seven of these genes in our bodies, and they do phenomenal things. They repair DNA, help telomeres, and one of the things we found they do very well is keep the mitochondria healthy. And actually, we found what was surprising was how reversible the aging of mitochondria are in animals, at least, and we're now doing human studies in clinical trials that within just a week of treatment with a molecule that a few molecules that we've tested that enhance the function of sirtuins, whereas veratrol was a famous one we worked on. Now, NAD boosters all seem to be able to reverse mitochondrial dysfunction within days. And we never knew that aging was that malleable until then.

Yeah, we see it all the time. I see it in treating patients where their literally biology can reverse at any time. You see people who are in their 60s who have all these end-stage diseases like heart failure and diabetes and severe obesity and hypertension and kidney failure. And you see these things go away when you start to modify these factors that drive inflammation and blood sugar and mitochondria.

It's pretty amazing. Yeah. Well, there have been a few paradigm shifts in the field. So when I started out, and this is we're talking about the early 1990s, the idea was our bodies are like cars. We eventually wear out. There's not much you can do about it. You can slow down the rusting. freen radicals, and that's about it. But what we discovered in the '90s, thanks to works by Cynthia Kenyon and Lenny Guarenti and others, is that these genes sirtuins, and there are some others we can talk about later, I think. But these protective pathways exist. We didn't know that we had protective pathways. It's as though we've discovered not just that our bodies are better than cars, that we actually have inbuilt repair systems.

Yeah, it's like a body shop.

Like a self-cleaning oven, right?

Yeah.

And they get lazy if if you're lazy, they get lazy if you become obese and don't eat well and if you eat too much. There are other things you can do to kick them into action with how you eat, what you eat. But also what we found is that you can, they're basically inbuilt survival mechanisms that are very ancient. They're found in yeast cells and plants in our bodies, probably our microbiome plays a role. And that's so we can basically make a call to the to the Pentagon of the body and they can send out the troops without actually damaging the body. You don't have to have a war to get ready for war. And these protect us against diseases and many cases reverse aspects of aging. Another paradigm shift was that we could delete the bad cells in the body, the senescent cells that accumulate. And there are some molecules in clinical trials as well that might be paradigm shifting. How do you delete those? Well, they're called senolytics. Lytics, lytic meaning lice, the cells kill them. And there are molecules that can do that. There are some natural molecules, quercetin, quercetin from onions and apples, Dasatinib's a drug on the market. We, well actually work at the Mayo Clinic primarily and Judy Campisi out at the Buck Institute found that you can treat animals and delete their senescent cells.

And they get younger. So you basically like go in and.

Like clean up all the bad cells. Yeah, we call these the zombie cells, senescent cells and zombie cells. They're half dead. They sit there, they should be dead, but they're actually causing havoc. They're secreting inflammation factors, cytokines that cause other cells to senescent to become potentially cancerous. And when you delete them, mice live longer. And what's exciting about that technology, that's exciting. Science is you can, instead of taking a pill every day, which is the kind of stuff that I work on, if their stuff works, you can have a treatment once every decade maybe, and that's it.

And the treatment is a drug? Is it a supplement? It will.

It's like quercetin, you say? Well, you can supplement. There's nothing fully proven in humans yet. There are some early studies from the Mayo Clinic, just this year, a study in humans came out that was promising from Jim Kirkland. But in mice, a lot of studies now point to this being a phenomenal way to address aging.

So you have kind of different pathways you can work on at the same time, right? You can work on the killing all the bad aging cells and you can work on optimizing and revving up your engines or like tuning up your engine.

Well, we're in a remarkable time for aging because we've moved from just understanding what's causing it and how we might intervene to truly understanding what can be done. And now we're in a phase where the question is, what are the right combinations of diet, exercise, food, supplements, and eventually drugs that are on their way. And so I mentioned two paradigm shifts. There's a third one that maybe we can touch on later. And that's reprogramming cells with an understanding of actually what's controlling the clock of aging and how to wind it back.

Because you said, you know, this limit of 100 years or 120 is not necessarily a hard stop that there may be ways of understanding the aging process that we can interrupt that?

Well, there are plenty of animals and certainly species across the planet that live longer than we do. It's not a biological impossibility to live hundreds, actually thousands of years. There's even some corals that live for 10,000 years. So it's not a fact of life that we have to die at 120. If you remove predators and war and disease, species evolve longer lifespans. It's happening right now on a Japanese island where a lizard was released and it's got no predators. predators, it's breeding slower and living longer. That's what happens and give us a few more months.

It doesn't actually, it just sits there in the sun all day, right?

Well, you know, we don't have to necessarily live at the bottom of the ocean like a greenland shark or on a rock, but what these organisms show us is that life, lifespan is malleable. It changes over millions of years, sometimes in the course of a few generations as we're seeing with this lizard. what is happening? That's what I want to figure out. What is it about those organisms that we can learn from? And instead of letting us evolve, having to wait for us to evolve over millions of years, why don't we just accelerate?

Is it going to involve gene editing or is this going to involve more of these other kinds of technologies?

I touch on gene editing in the book. In my lab, we're using gene therapy to kind of leapfrog and really see how powerful our genome can be. We're having some remarkable results in mice and truly reversing the clock of aging and seeing what can happen. Maybe I'll reveal that later.

Okay, it's fascinating. I have an APOE2 gene and a three, which is two is like the ones who can live forever, drink, smoke, and not exercise and live to 120. And then the four is the bad one where you get Alzheimer's. So how do I change my three out for a two? Can I do that? I'm gonna get a double two.

It'll be possible. Where we're at with gene therapy is, so there are a couple of drugs on the market. that are used for rare diseases, because that's usually where new technologies are first used. You know, there are scientists who could probably do this to themselves if they were crazy right now. The technology is there. Where we're not at, the science doesn't allow us to change every cell in the body right now. Even in a mouse where we've been studying this longer, and my lab does this every few weeks in the lab. The problem is, we can infect about 30% of the cells and it infects and changes the genes in some organs more than others. So it's very easy to change most of the cells in the liver but not so much in the muscle and the brain. And you only get one or two shots at it because an adenovirus, which is what carries the gene therapy, causes an inflammatory response.

Right, that's not good.

So I'm not planning on doing that anytime soon. But if I had a rare disease and it was going to kill me or I was 95 and I had nothing else to lose. Maybe I'd consider it.

Unbelievable. So, the whole goal here isn't just to extend lifespan, right? It's to extend health span, which is how long vibrant years you have. And there's a lot of thinking that if we extend lifespan, there's going to be a lot of old people who are going to be sick and cost the system money and drain our society and that's not a great thing. and yet there are others that sort of pointed to research that maybe that's not the case, that if we figured out how to create health, that we can do what we call rectangularize a survival curve. James Fries wrote about this decades ago where he talked about how people who didn't smoke, who exercised and kept the normal body weight, live longer and were healthier and just didn't get sick. They just basically fell off the cliff and died as opposed to long, slow, painful deaths.

They died quickly, painlessly and cheaply. Yeah, well that's what the science is pointing to and in my lab we see that. a lot when we intervene with a molecule. We see those mice, they are healthier for longer. And actually, when I talk to people about living longer and I ask, how long do people want to live? A typical answer is, oh, I wouldn't want to live over 100 because people have seen what 100-year-old looks like. God forbid that we get there. But what changes their minds is, what if you could be 100 and still play tennis and hang out with your great-grandkids and still be productive? you don't have to be earning a living, you can be helping the community, nonprofit work. And then everyone raises their hand pretty much. So it's all about health. And that's the key point. I want everybody to know that I don't know how to extend lifespan without keeping people healthy. In fact, the reason- that's how you do it.

That's how we do it.

That's the only way we can extend lifespan is to keep animals and eventually people free of disease for longer. And then eventually something gives out fairly quickly, typically. and that's the idea. Someone like my father who's 80 now and still traveling the world and going out every night and hanging out with-.

Your girlfriend 20 years younger.

Well, yeah, multiple friends, multiple girls. I don't know if they're girl friends, but that's a life that I think is well lived. And if he can keep going and helping my family and his community, which he's doing for another 10 or 20 years, the economics show, and we've modeled this for Australia, we've done some- Others have done this for the UK. GDP goes up. It's not that there's a drain at all. In fact, the amount of healthcare, it's 17% of GDP right now in the US. It's only going to keep going up. The reason is we're getting older and sicker. The last 10 years of life can be spent in wheelchairs and not going outside and being spoon-fed. I've seen that with my grandmother. So my father's mother at 80 could barely walk. She was in a wheelchair, spent the last 10, 13 years of her life in a state that you wouldn't wish on your enemies. And the expense to keep her alive was ridiculous. My father, on the other hand, he's contributing. That's what I talk about in the book, is that the future is bright if we can tackle this problem, keep people healthy for longer. The problem is if we don't succeed, we have an issue too. The world's economy is going to be dragged down by all the sick, elderly people that are coming along.

It's true. I just read a study the other day that was a macroeconomic analysis of chronic disease, just the United States, the direct and indirect costs over 35 years, it's $95 trillion with a T, that's over 3 trillion a year. And if we figured out how to fix that, we literally have money for everything we need in this country, infrastructure, free education, forgiveness of student loans, free health care for everybody, raising everybody out of poverty. I mean, it just would be a game changer, right?

Yeah, I couldn't have said it better. One of the things that that people challenge me on. They say, why work on aging? Don't we have more important problems? Global warming, species extinction. I'm all for that. I'm the biggest greenie and I was going to be an animal rights activist if it wasn't working on aging. But I think the best way to tackle the problems we have is actually first solve the biggest drain on the planet, which is taking care of the sick and the elderly. And then, like you said, there's trillions of dollars. If we could just reduce one disease of aging by 10%, it's about $3 trillion over the next decade. We're talking about a lot more than that. And that's money you can use to fix the world.

And your thinking is actually the thinking that I think can solve the problem because in medicine, most of the thinking is focused on disease. You're focused on the mechanisms of health.

Well, sure. I mean, it's important to know why people die. And we have a list of 14,000 diseases in there.

Well, it's 155,000.

Yeah, but knowing why people- yeah. fall off a cliff, I would argue it's also just as important, if not more important, to know what drove them to the cliff in the first place.

Yeah, so let's get down and deep a little bit. So the thing you're working on now is similar to what you're working on around resveratrol, which is the active ingredient in red wine, except the equivalent amount of dose you'll use, I think, was like 1,500 bottles of red wine. So it's not something people should try at home. because that worked on sirtuins, it worked on mitochondria. But now you're working on a different mechanism which has to do with increasing the function and health of mitochondria using a compound that helps increase NAD. Now, can you explain what NAD is? A little bit about why mitochondria is important. And before you do, I just want to sort of back up a little and say that all the studies on aging that have shown any benefit to increased lifespan in animals have all been often through calorie restriction, which means you eat less, like two-thirds, a third less, you live a third longer. And also new things like fasting, mimicking diets are being studied and other things related to calorie restriction. Now that apparently affects the mitochondria. That's how it works. And that's really what you're trying to figure out.

How do you get around having to starve yourself all the time? Yeah. Well, a large part of it is mitochondria. They do other things which we can touch on. They probably do a hundred things that will we're still working on. Let's go back to yeast, because I think that's a good framework. When we started in yeast, we didn't know why they were dying. We figured that out. It's mainly genome instability that affects their cell identity and then they die. Discovering the sirtuins was a game changer because what we figured out was there are three levels to aging. There's the base level, which is the things that kill you, DNA damage, telomere shortening, mitochondrial dysfunction. Okay, that was pretty much worked out in the 90s. Then there was a level above that, that there were these regulators of aging. The sirtuins are major regulators. And, but then in the 2000s, my lab and others found there was this top layer, which is the environment. And when the environment is a little bit harsh, adversity, or even perceived adversity, it kicks these protectors into action. And then they slow down or reverse these causes of aging. So think of it as a hierarchy pyramid. Yeah. So what you want to do is start at the top. So how do you trick the body into thinking that it's going to run out of food or that there's some other adversity? And we found in yeast cells, if you reduce the amount of sugar, getting back to sugar, they kicked into action, the sirtuins. We'll talk about how they did that in a minute. And then the yeast cells lived longer.

They protected the DNA, they boosted mitochondria, and they lived longer. Wait, I just wanna pause here. So sugar, you're saying accelerates aging and restricting sugar actually helps increase longevity in these experiments?

Well, certainly for yeast and a lot of data on humans that lower sugar is better and fasting blood sugar is lower is better too, for longevity. But there are other ways to kick the sirtuins into action. So there's in humans, intermittent fasting is easier, I find, than calorie restriction. I tried calorie restriction for a week, it was pretty hard.

I met a guy once I said he's doing calorie restriction and he was a member of the calorie restriction society. I said, what do you have for breakfast? I have five pounds of celery and three pounds of tomatoes. And I'm like, no, thank you. Right.

Well, eating is one of life's pleasures, but I find for me, if I skip breakfast, it's no big deal.

Yeah. So intermittent fasting is basically time restricted eating where you eat within a certain time window of eight hours or or 10 hours, right?

Yeah, there are plenty of varieties. I talk about them in the book. There are some other books that talk about that. You mentioned this many times on your show. There are some skip a meal protocols that skip two days a week. There are some people, Peter Attia's doing skip a week of food. He says after three days, magical things happen. He thinks, I haven't tried that yet, but I'm going to. But yeah, no one knows actually what the optimal amount of fasting is. But what I can tell you is some time of being hungry is good. We can see that in our animals. There's no question if we give our animals, our mice, food every other day, they live longer. And in fact, if we gave them resveratrol and the combination of eating every other day, we got some very long-lived mice and the combination was great. So that's one of the things I do to myself is have resveratrol and try to be hungry once in a while.

That's what the Okinawans do. They call it Hara Hachi Bu, which is 80% full. So you push yourself away from the table when you're 80% full.

There's a lot to that for sure. Having a lot of food and glucose in your bloodstream, just not a good thing. So getting back to how to mimic this, mimic exercise and diet, you can do it in yeast, you can do it in mice by either taking resveratrol, We showed that was one of the ways to activate sirtuin enzyme that protects the body. But we have something that's, I think, more interesting now, which is the NAD molecule you mentioned. So NAD, let me tell you what that is. Anyone who's studied biology will have heard of NAD but probably forgotten about it because it's a boring- It's a long cycle. Yeah, it's the molecule that nobody really wants to care about. What we discovered is that it isn't just a housekeeping molecule. for biochemical reactions. Germans discovered 100 years ago you needed it for life. Without it, we're dead in 30 seconds. But what became interesting was in thanks to Lenny's work when I was in his lab and then later in my lab, we showed that the NAD levels of an organism are important for controlling the sirtuin protective enzymes. And as they get lower, they're not as active. And if you can get them higher, either artificially or by exercising or dieting, they get kicked into action, we get the benefits of calorie restriction and exercise without actually having to do those things.

And the, but they're added to- I.

Don'T think that's a good message to give to people. No, I was going to add to that, which is, but if you add them to- Is that it? Well, we just published last year actually in the journal Cell that if you have a mouse and you give it an NAD boosting molecule and you exercise.

Then they become super mice and they can run beyond- that's good. So, it's a lot of added value if you Eat well and exercise. Oh, definitely. Because I remember reading original studies way back when and I was like, wow, these mice were eating terrible diets and they were metabolically younger. They were fitter and they didn't do any exercise. I'm like, whoa. But then I was like, wait a minute, it's 1500 bottles of red wine.

It's not gonna work. Yeah, well, in the research study, we did show that you could make a mouse live just as long on a high fat diet. as a healthy mouse with Rosalind in the diet. But I don't want to send the message that that's all you have to do and you'll be fine. No, there's other things that go wrong and we're not mice after all. And you feel better if you're healthier anyway, right? So anyway, getting back to the NAD. We can raise NAD in everything from a yeast to a human by giving them what are called NAD boosters and these are either NAD itself or precursor molecules to allow the body to make NAD. The one that we use a lot in my lab is called NMN, nicotinamide mononucleotide is its real name. And the cells in the body take it up, there's a transporter, they get sucked up into cells, and they immediately convert it into NAD. And we can see that there's a spike of NAD produced after NMN after about two to three hours, and then it eventually goes back down. But what we are seeing, especially in mice where we can take out tissues, look at tissues and blood is that that has phenomenal effects on the body's protective mechanisms through lightly through the sirtuins and mitochondrial activity.

So on the market, there's a lot of these products out there that are being sold as NAD or some varieties of them, combining them with resveratrol. Is it ready for prime time? Should people be running out and getting this stuff? Or is the data not there? I mean, is there clinical studies?

There are a few clinical studies. Lenny Garrenti and I, he's my mentor, we took two different paths. And I can only guess why I think one was that Lenny's, I think, 15 years older than me and clinical trials take about a decade. So, he was in more of a rush than I was. So, he's gone the supplement route and decided to use that supplement to test in clinical trials. And he's just had a paper that came out, I think, yesterday in Parkinson's that looks really promising. Parkinson's patients do better on his combination of another NAD booster called NR, which you can buy, and a resveratrol analog called terutalbine. Now, that's actually one of the first studies, if not the first, that says that there's some positive benefits in people. Yeah, there've been quite a few safety studies, and so far everything looks safe.

I know I just might conjure the main organelles are the things that get injured in Parkinson's and that mitochondria is really the cause of Parkinson's. In the sense, when the mitochondria aren't working well, you can't have proper motor function because it runs your muscles and they're easily damaged by toxins and other things. So using something that helps upregulate. And I've had patients where I've given.

Them NAD and their Parkinson's tremors get better. It's fantastic. Fantastic. Yeah, I hope that this is the the first glimmer that this is a really big change in how we can approach many diseases, not just Parkinson's. So Lenny took the supplement route. I'm taking the pharmaceutical route. They're both going to be complementary. There's no right way. We have clinical studies that are just finishing up phase one at Harvard where things look good. We can raise NAD in humans and no sign of toxic effects. Our plan is to next year, early next year, go into diseases where mitochondrial are dysfunctional.

Yeah, for example, in diabetes, half of primary relatives of type 2 diabetics, like, you know, son or daughter, brother, sister, they have a 50% function of their mitochondria, even if they're quote healthy. So, there's genetic things that regulate mitochondrial function that can be inherited but then can be modified through some of these approaches.

Well, they can. Going back to the mouse studies, we showed, I think, 2013 now, that within a week we could make all dysfunctional mitochondria function and appear exactly like a young animal's mitochondria in their muscle. And to me, that was remarkable because we were told that mitochondrial dysfunction was largely due to mutations that were irreversible. And that we can find mutations, there's no question about that. Very late in life, in a mouse and in humans, they exist. But if you catch it early enough, and in the case of a mouse, it was about the age equivalent of a 60, year old, we could turn a 60-year-old equivalent mouse back to a 20-30 year old within a week. And to me, that defied everything that we expected.

Yeah, it's true. I first became interested in mitochondria because mine stopped working.

Really? Yeah.

About 25 years ago, I lived in China and I got exposed to a lot of mercury and came back and got very sick. from the mercury and it caused severe muscle damage. And my muscle enzymes, CBK was like 600, which is really high. And I had muscle fasciculations and twitching and aching and pain and I had severe chronic fatigue and my systems just shut down. I went from like riding my bike 100 miles a day to not being able to walk up the stairs. My cognitive function basically was like, I felt like I was severely impaired. I had ADD and depression and dementia all at once. It was really bad. And so I began to sort of learn about functional medicine and mitochondria and started treating myself by actually up regulating all my mitochondrial pathways and all the cofactors and nutrients and removing the mercury. And I've used this approach and it made me get better. My numbers are great and I feel good. And I see this a lot in my patients who have sort of these weird sort of mitochondrial problems. Well, my wife has this. So if she goes for a walk or aerobic exercise, she'll feel crappy afterwards. towards it. And there's a syndrome of patients who just, when they exercise, they don't get the runners high, they don't feel good, and they feel tired and wiped out, have to take a nap. And so I started saying, well, why don't we just try to give you a mitochondrial cocktail? So I gave her a whole bunch of things, including NAD, CoQ10, carnitine, ribose, some amino acids, B vitamins, I don't know, something else maybe. And should we do that before she goes for a walk? And no problem. And I've seen this over and over again. So I think, you know, it's, it's a lot of these things that we have to think about, not just sort of one pathway.

Right.

Yeah.

Well, what's been amazing to me is that we, yeah, we used to think aging and these diseases were one-way streets, and we were lucky if a medicine could help and slow down the disease. But what you're saying and what I've learned is our bodies are remarkably good at healing.

Yeah.

Better than we thought. As long as you just tweak them the right way. And we're at that point in medicine in history, where we have a fundamental understanding. It's not perfect. We have a lot more to do. Future generations will look at us and think of us as primitive, but we do have the tools right now to be able to change a lot of our disease processes and our aging processes as well. It doesn't surprise me that this is happening. With my father, he was going downhill. He was approaching 80. He was seeing his friends go downhill. He started taking the Anna Mann and saw, in his view, the same thing we saw in the mice. What we saw was it wasn't just mitochondria going up. We actually found that the muscle started growing new capillaries or capillaries as though they were being exercised.

And so his blood- American and Australian?

I try. That's right. You've got a global audience, so may as well.

Sometimes when I'm watching these English shows with my wife, she's from New Zealand, I literally have to pause the show and say, what did they say? And she's like, We're watching the Crown. And I'm like, what did she say? She translates and then I'm like, okay. Right. Or Game of Thrones, like, what did he say?

Yeah, well, stop me if I'm unintelligible.

No, you're good. You've been here a long time.

So one of the things that is remarkable is one of the things I've found is that aging is also caused by a lack of blood flow. So, a buildup of toxins, lack of oxygen, and by inducing mitochondria to get them healthy and give them more energy, more of the ability to take in the nutrients and get rid of the toxins. In mice, it's remarkable. In people, we think we'll be able to give them a lot more vitality. If my father's any indication of what we're going to see, it's going to be remarkable. We haven't tested it on vascular dementia, but I'm hopeful that this could be.

A way around that too. I've seen data somehow on Alzheimer's and NAD2, right?

In amyloid. Yeah, at least in mice, do you.

Know of any human results? Yeah, in mice, yeah. Pretty exciting. So, does NAD also affect inflammation? Does it affect glucose and blood sugar? And how does it work to those other mechanisms that are so central to aging?

Yeah, so the sirtuins do a lot. They control blood sugar, they control liver and the pancreas and the muscle. So they do a lot. And often people say this sounds too good to be true, but it's not just my lab. It's now hundreds of people working on this. On the blood sugar side of things, that was shown way back in 2012 by Shin M. I Washington University in St. Louis. So yeah, it does reduce blood sugar. It controls the pancreas insulin levels. It controls uptake of blood sugar. On inflammation, we know a little less about that, but my lab has done a fair bit. We haven't published a lot, but we find that as macrophages, one of the main inflammatory cells in the body, as they become hyperinflammatory, they move into that stage. that requires NAD. And if you control that and don't prevent them from chewing up their NAD, which they need to convert into the inflammatory state, we suppress inflammation. So what we're finding is that if we give them our NAD booster or we block them from chewing up their NAD as they convert into this inflammatory state, we can reduce inflammation. And one of the problems with aging, we think, is that NAD levels of these cells and across the body, they go down with time. And not so much in the bloodstream, but in tissues, we think that the levels of NAD such as the skin, we can measure that, go down about half by the time you're 50. I don't know about a 60 year old, but I'm sure you're looking after NAD.

Hopefully, I'm taking it.

Well, that certainly is a way to boost it.

I like to sort of experiment on myself, so I try different things, see how it works.

Me too. If we wait 30 years for this all to be proven, we will be gone by that point.

My view is, what's the risk? What's the benefit? What's the cost? What do we know? Is there a scientific premise that makes a reasonable explanation of why this should work? Is it safe? Does it cost a million dollars or 10 cents? Just some simple metrics allows you to try stuff with pretty much impunity.

For sure. Well, let's get into that because that's a good point. The NAD levels are 50%. You get them back up to a young level or even beyond. That's when we see this reversal of aging. So that I think it makes sense what you're doing. Of course, we don't have proof yet, but we will.

A lot of people are doing IV. Is that better?

I don't know. We've done IP, which is in the gut for mice. I've heard a lot about it. I think it makes sense that that should work just as well. But getting back to the risk reward thing, that's really important. So it's a fact that a lot of these molecules are relatively cheap. In the case of metformin, what is it? Less than a dollar a day. It might be a few cents a day for some countries. Okay, so that's not a lot of money. All right, that's the cost. What's the risk? Something like metformin has been in probably 100 million people used for the last 40 years. Risk is extremely low.

No, there's some side effects like gut issues and things like that.

Exactly, you're a real doctor, I'm just a PhD, but Metformin, you can have, you know, I think the biggest risk is you'll have an upset stomach, but there can be some severe side effects. You wanna do these, wanna do these things under medical supervision, do some blood tests. Okay, so now we know the cost, we know the risk. Okay, so just use Metformin as an example. the downside. What's the upside? Well, the upside is you might have a few extra years, maybe another five years of healthy, longer life. That's a pretty good trade-off. What I think what most people have trouble in the calculation that we just did, and you and I have done this calculation similarly, is what's the risk if I don't do anything?

Yeah.

All right. But most people are in denial When you're five years old, you realize that everything dies. Your parents, you'll die. It's horrifying. Every kid goes through this and we don't remember typically going through this.

I remember.

It's horrifying. That may be why you and I do what we do. We haven't forgotten the shock. But I think most of us, we don't like to think about this every day. It takes a lot of guts to think about your loved one's mortality and it's even worse if you seriously contemplate your own mortality every day. That's brutal. You don't want to do that. But if you do think about it at least once in a while, that calculation that we just did becomes pretty easy to do. Yeah. Yeah, it's pretty scary what is going to happen to everybody. It's not pretty. And we're all in denial that this is something that we might be able to do something about. And that's what I'm talking about in the book.

So this book, Lifespan, the Revolutionary Science of why We Age and why We Don't have To. is kind of a manifesto for how we can think differently about aging and the things we can actually do to slow or even reverse aging. So, why don't you give us the take homes from the book about what after doing this for 30 years, what you've learned and what are the priorities? Because my guess is it's probably not just taking your supplement and going to McDonald's every day and sitting in front of the TV watching TV and having cake, right? It's not that.

It's not. And what we've found in our studies and many others around the world, so I've probably read 10,000 studies on this. So if I can synthesize it, which I've done in the book and in my life, and I do list what I do daily in the book.

Yeah, I want to see that.

So, I won't remember everything. And so you'll have to read the book. But one of the main take-home messages is if there was one thing I could tell people to do, if there was nothing else, it was eat less. Not to an extreme. I think there's a lot of mental diseases where people are eating far too little. But if you're a regular person and know how to eat the right thing, yeah, yeah. You know, teenagers don't do this. But anyone who's through puberty knows how to eat the right foods, a lot of plants, not a lot of carbohydrates in my view. Get most of your protein from plants. Occasional meat is fine, but I try to restrict my meat. I know there are a lot of carnivores out there. Joe Rogan doesn't like it when I tell him that meat might be- But.

You also don't eat carbohydrates. So people get confused. Carbohydrates can be good, right? Well, the right ones. Broccoli is a carbohydrate, but so is a bagel. and they're very different.

Exactly. Right. And you know, and you've spoken a lot about this, so I don't need to hammer it too much, but the right carbohydrates for sure. But yeah, be hungry once in a while. So that's the first point. So keep your blood sugar low if you can, but not too low because you need your energy, your brain needs glucose. Another thing I do is I exercise. Now, I'm always at a keyboard or on my phone, so it's hard. So I spend about four hours at the gym on a Sunday with my son, which does two things. It's fantastic.

Four hours.

Yeah, we'll have to make up for it somehow.

I don't think it works like that.

You don't? Okay. I'm probably wearing out my body, but I do a combination of weights and then some aerobic, some high impact training, intensity training. And then I also do something else that I think is becoming more common, which is... So, those are two what I call hormetic, what you would call hormetic inducers.

Small stresses.

Small stress, yeah.

To be better.

Exactly. What doesn't kill you makes you live longer.

Yeah. That's why organic food has more nutrients because the phytochemicals are there to protect it. And then when you have the stress of being organic, which is harder to survive, you actually make more nutrients. Right.

So, that was one of the theories that I put out, xenohormesis, the idea you can get the messages from stress plants and get them for our body.

Yeah.

So the other stressors, which we know less about, but there's enough data which I have put in the book that says this is probably real, is sauna and cold stress.

Oh my God, I do that every day.

Really?

I have like a steam shower and I have a sauna and I have a big bathtub and I go hot and then go in the ice bath.

Fantastic.

Ice bath. It's like the best thing ever.

Well, it'll certainly wake you up and it makes you feel good if nothing else. But I've looked into the data. I did a lot of research for the book. And so the cold stress, it'll boost your brown fat. Brown fat has a lot of mitochondria, puts out a lot of good molecules. So that's what you can do. Is cryotherapy not nonsense?

I don't think so. But there's not, hasn't been long-term studies.

But it makes sense.

And it's a Harvard professor.

But there's not been long-term studies. Yeah, I always have to do that.

You'Re tenured now. You can say whatever you want.

I get slapped on the wrist. But what's interesting about it is that the brown fat, we didn't know it existed in humans until fairly recently, only a decade ago. But it seems more you have, the better. And the best way to induce brown fat is to be cold, especially across your back. There's a lot of it back there if you can induce it. The problem is I found that at least in animals, the older you get, the harder it is to build up. so you want to start early in life if you can and build it up then. The heat stress I looked into, and I was really skeptical that any of this was real. My wife told me about saunas. I went, Come on, that can't be good for you. But you look, and actually there's a lot of studies in Helsinki.

Of course.

Yeah, well, they're selling the saunas, so they've done a lot of research. So thousands of Finnish men mostly have been studied, and in In those studies, it's pretty clear that men who go to the sauna a few times a week have less cardiovascular disease risk and heart attacks. Now, there's one caveat which they actually admit in one of the papers is that people who are sick or in hospital don't go to the sauna as often. So there's that caveat. But I looked at the data. To me, it looks like it could be real.

So I do both. And it does increase the resiliency of your cardiovascular system and something called heart rate variability improves and heart failure patients do better when they actually go on saunas.

Yeah, that's right. So yeah, these are the stresses that I do on my body. I take a gram of resveratrol in the morning with a tiny bit of homemade yogurt, not a lot of food, but I found that there's a type of yogurt that's really great for me at least.

Like wine yogurt now with the resveratrol?

Well, I don't know if you want me to talk about actual products, but there is one out there that I use and make it. It's pretty tasty. The resveratrol dissolves in the yogurt. That's the important part. If you just take a dry pellet of resveratrol, most of it won't be absorbed and that's the problem. I take metformin, a couple of them, a gram. Sometimes in the morning, sometimes at night, depending on how I feel. I don't do well on metformin. It's actually pretty rough on my stomach.

So, I don't really need it. No, not if you do the other things.

Yeah, well, probably. Probably. I'm trying to see on my body what works, what doesn't. It's an experiment in progress. What else do I do? So at night, I take the usual things. I take CoQ10. I take a statin. You'll probably frown on that, but I had very high cholesterol when I was a kid. I started on a statin when I was 29. And my grandmother had a stroke when she was in her 30s. So, I have really bad estrogen genes. Yeah, the mitochondrial effects of statins. I am, but I'm also worried about really high cholesterol up in the high 200s. Oh, yeah. Yeah. So, I had to do something. I'd like to go off the statin. That would be probably the best thing I could try.

Well, there's experiments you can do where you can change your diet, change your lifestyle, do different things, stop it, see where you do, restart it, check your particle size number.

I mean, those are all relevant. Right, right. I also have another bad gene on particle size, so not destined to live long unless I do something. Plant sterols, I'm trying that to see if I can use those to replace the statins. But CoQ10 is good and I take actually alpha-lipoic acid.

Yeah.

For mitochondria. Yeah. And one of the actually the thing that turned me onto that was I spoke to Denham Harman's family. So Denham Harman, you may know him.

He's a father of the oxidative stress theory of aging. Yeah.

And so, I was fortunate to win an award with his name on it. And I went out there and his family were very generous to host me. And he was still alive at the time. He passed away a few years ago, but he was still healthy and going into work at 92. And so I said, what's his secret? Lipoic acid. I thought, well, at the very least it didn't hurt him. So again, I take it every day.

If you understand what it does, it's basically one of the most powerful antioxidants that helps boost glutathione, which is detox fire. It's anti-inflammatory, it helps your mitochondria, it helps detoxify from metals. It sort of helps with blood sugar and diabetics, it helps with diabetic neuropathy.

I mean, it's a really well-studied molecule and it's all about the mitochondria. Well, yeah, I would say that too. The other thing that I should point out is, so I monitor myself fairly regularly. I'm not crazy about it. I don't like having my blood drawn often, but you know, I'm looking at myself with rings. I've got the watch, I've got the blood drawers. If something goes out of whack and I change my diet or I do something, I'll know about it. I measure through inside tracker. Others can do that.

Yeah.

About 34 different things. And, you know, I'm adding things, I'm subtracting them like you. I know if something's going wrong. So I just had a blood test because I'm going to Africa and I sat down with a, with the nurse actually yesterday, and she took me through my blood tests. And she went, Perfect, perfect, better than perfect, better than perfect. And so she said, and you're turning 50 and you've got those blood markers. Yeah, she goes, I'm jealous. I said, what do you think? And she goes, Just keep doing what you're doing. Right. So I think that's the proof that we're not hurting ourselves and we will.

Know it if we were. Maybe long term, you don't know. So what does it look like 10, 20, 50 years from now in terms of aging? turning 60, I'm like, what's going to happen in the next 20, 30 years in this aging research and what's coming on the horizon that's going to help me live long and meet my great-grandchildren?

Yeah, well, so I've been blown away.

Because it's all about me after all, right? I just want to live longer.

Well, sure. I mean, if we're all honest, we don't want to get sick and we do want to see what the future looks like, most of us. Well, so The last 10 years have been remarkable. Just made my head spin. We can challenge and test hypotheses in a week, things that used to take a decade. So we now have these hallmarks of aging that we've all in the field agreed on, cause aging, mitochondrial dysfunction, telomeres, we've heard them all pretty much, senescence, all I mentioned. There's been a new change and we're undergoing a new paradigm shift. And it's a theory that I put in the book called the Information- the Information Theory. Theory of aging. And the idea is that all of these hallmarks actually are manifested by a loss of cellular information from when we were young. And essentially what that means is that our genomes, which have the digital information in our bodies, are largely intact. It's the reason we can reverse mitochondrial aging pretty quickly in an old mouse. It still has the information to do that in its genome. The problem is that we have this other type of information called the epigenome, which is the next layer of information that controls the digital. Yeah. So it's similar to a DVD player. The information's on the disc, but the ability to read the songs at the right time degrades over time. And so the epigenome gets less and less accurate and It's similar to scratching the DVD and you can't read the genes at the right time. You can't read the songs. And what I've been questioning, or at least curious about for the last 10 years, and what's funny, let me just tell you something, Mark, as a secret with millions of people, is that I've been so busy, I haven't written a lot of these ideas down in scientific publications. I've been working on the book.

Yeah.

So it could be that the world will be able to read about all this science before a scientist do, which is very unusual. We are about to submit these. So what is the idea? Is that if you scratch the CD, do you end up with premature aging? And we've done that now in a mouse. We can actually do that. We can mess up the epigenome and the mice get rapidly old and they actually we can measure their age now we've got what's called the epigenetic clock or the Horvath clock named after Steve Horvath. And we can do that. I could take your blood and measure your biological age very accurately.

Okay, I'm coming in.

We should both do that. I haven't done it yet for myself. But those mice, we can accelerate their actual age. They're not just looking old, they're old. And so that's the scratch DVD. The question is, is there a way to polish that and get back the ability to read our genomes correctly like we were young again? and I think we've figured out a way to do that. And that's what we're working on. We have this, I can't say too much because I'll scoop not only the book, but my publications, but we've got this combination of genes that tells the cell how to be young again and reverse that clock of aging, the epigenetic clock, and polish the CD. And one of the things that's been remarkable is that if we take an organ or or a part of the body that normally would never get young, never would regenerate. And we chose the hardest thing of all, which is the eye. We looked at old eyes or damaged optic nerves. We can actually damage them or glaucoma. These are things that right now you just can't reverse. You're lucky if you can slow them down. If we give our reprogramming treatment, and it is a gene therapy currently, we put it in the eye and old mice can see like they were young again within just a few weeks of treatment.

Jesus. Well, you can see, right?

Well, when we discovered this, and I have to give full credit to my collaborators at Harvard who actually do this, I don't know how to do it, but they're exposed. I went home and said to my family, We've cured blindness in old mice. Who cares? My kids went, yeah, that's fine. Can you set the table? And my wife goes, oh, no, first can you empty the dishwasher? Come on, Jesus got respect. What's going on? But it's early days, but I think that we've cracked a big one is that we don't just slightly reverse aging, we might actually truly reprogram the body. This is so exciting.

So all these ideas are in your book, Lifespan: the Revolutionary Science of why We Age and why We Don't have to. I encourage everybody to get a copy because it's not just about aging, it turns out. It's about how to create health, which will help you with all the diseases you have, regardless of whether you care about aging or not, which is kind of the sort of silver lining in the whole thing is as we're discovering the magic of how to solve aging, we're actually solving all the other things as well.

Exactly. And it's a glimpse into where we've been, where we are right now, what.

You can do, and what the future looks like. So exciting. I'm glad we're living today and I'm not living 1,000 years ago. And David, you're around doing the science and helping us understand how to live well and live longer and die young as late as possible. So thank you for being on the Doctors Pharmacy. If you love this show, please share with your friends and family on social media. we'd love to hear from you. Please leave a comment and you can subscribe anywhere you get your podcasts and we'll see you next time on the Doctor's Pharmacy. Hi everyone, it's Dr. Mark Hyman. So two quick things. Number one, thanks so much for listening to this week's podcast. It really means a lot to me. If you love the podcast, I'd really appreciate you sharing with your friends and family. Second, I want to tell you about a brand new newsletter I started called Mark's Picks. Every week, I'm going to send out a list of a few things that I've been using to take my own health to the next level. This could be books, podcasts, research that I found, supplement recommendations, recipes, or even gadgets. I use a few of those. And if you'd like to get access to this free weekly list, all you have to do is visit DrHyman.com/picks. That's DrHyman.com/picks. I'll only email you once a week, I promise, and I'll never send you anything else besides my own recommendations. So just go to drhyman.com/pixks. That's P-I-C-K-S to sign up free today.