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David Sinclair (00:00):

Welcome to the Lifespan Podcast, where we discuss the science of aging and how to be healthier at any stage of life. Hi, I’m David Sinclair. I’m a professor at Harvard Medical School in the Department of Genetics, and I’m co-director of the Paul F. Glenn Center for Biology of Aging Research. This podcast is about why we age and efforts and things you can do in your daily life to slow, stop, and even reverse the aging process.


In the last episode, we talked about the skin, the largest organ in the body. We talked about how to stay looking young and feeling good about yourself. But today, we’re talking about perhaps the most important organ in the body, and that’s the brain. I’m joined today, and on all episodes, so far at least.

Matthew LaPlante (00:47):

Wait, so far at least? Yeah, we’ll see how you do today. Do you know something that I don’t?

David Sinclair (00:51):

No, just, I’m enjoying this, it’s going really well. Matt and I have been together for years. We wrote the book, Lifespan, and he’s also my lovely co-host of this podcast series. Hey. Welcome, Matthew.

Matthew LaPlante (01:01):

I’m really terrified now. Like, we’re coming up on episode eight, and I’m not gonna be here for season two.

David Sinclair (01:07):

Well, we’re gonna do a season two, no doubt, and I would not do this without you by my side.

Matthew LaPlante (01:13):

Rob, can we make sure that that part of, like, that I will not do this without you by my side? We really wanna make sure that that gets broadcast.

David Sinclair (01:24):

Though I’ve been known to change my mind.

Matthew LaPlante (01:28):

So, so far in this series, we’ve spoken about how aging impacts our bodies. And even though, like, very clearly, there’s really actually no separation between our bodies and our minds. These are integrated systems. But we’ve sort of, up until this point, not talked a lot, or much at all, about the brain. And the reason for this is because nobody at all wants to stay healthy in their body if they’re not also healthy in their mind.

David Sinclair (01:57):

Absolutely. And we live in a world where modern medicine, as we call it, has been very good at keeping most parts of the body healthy. The heart, so cardiovascular disease, cholesterol drugs, heart drugs.

Matthew LaPlante (02:09):

Increasingly over the years, we’ve gotten better and better and better at that.

David Sinclair (02:11):

Right, we’re living longer. We’re not living better because the brain is still aging and getting these diseases, Alzheimer’s and other types of dementia, are becoming more prevalent because we’re living longer, but not whole body, not holistically slowing down the aging process.

Matthew LaPlante (02:24):

In fact, so currently about 6.2 million Americans who are over the age of 65 are living with Alzheimer’s. That’s just one of several forms of dementia. But because we’re living longer, that number could grow more than twofold, to 13.8 by 2060 if we don’t come up with some medical interventions that can prevent or reverse Alzheimer’s disease. And there’s very little.

David Sinclair (02:49):

There’s a recent drug that was approved, but it barely works. It makes a minor difference. So we have to make a breakthrough. And what we’re gonna talk about today is a totally new approach to treating dementia. And that is boosting the body’s defenses against not just Alzheimer’s, but against aging itself. And it’s my belief in my labs, evidence that if you reverse the age of the human brain, Alzheimer’s and other diseases of the brain will go away and you’ll even get your lost memories back again. So I think that’s a really good point. But also, it’s not just about Alzheimer’s today.


We’re talking about other things that happen in the brain. We’re talking about molecular changes that make cells forget what type of cell they are. So nerve cells become more like skin cells. And there’s another process that’s important during aging that we’ll touch upon, and particularly about its reversibility, and that’s loss of blood flow. And this is really important because a lot of people,

Matthew LaPlante (03:34):

if you just say Alzheimer’s, dementia, people think that’s far away. They’re going to fix that before I get to that point. But all of us, virtually all of us, go through some amount of cognitive decline in our middle years. And so this isn’t just about preventing these things that are way downstream. This is about making our mental, our intellectual lives better right now.

David Sinclair (04:01):

Well, the biological clock is ticking all the time. We’re not talking about a female’s biological clock. If you’ve listened to previous episodes, you know you were talking about what’s called the epigenetic or HOVATH clock. And this is ticking from conception. So even when you’re 20, 30, 40, and onward, that clock is ticking away. And what you do in your 20s and 30s will impact how healthy you are in your 70s, 80s, and 90s. So it’s never too early to listen to this podcast and do the kind of things that we’re talking about to slow down that clock.

Matthew LaPlante (04:30):

Before we can get to that, we’ve got to thank our sponsors.

David Sinclair (04:33):

Absolutely, because this podcast goes out for free, thanks to them. So first up, Athletic Greens. Athletic Greens is an all-in-one daily greens drink that supports better health and peak performance. It’s developed from a complex blend of 75 vitamins, minerals, and whole food-sourced ingredients. It’s filled with adaptogens for recovery, probiotics, prebiotics, and digestive enzymes for gut health. There’s also vitamin C and zinc citrate for immune support. I’ve been drinking Athletic Greens for a number of years now as a way to cover all my nutritional bases.


I’m often traveling, and sometimes my diet isn’t the best. So by drinking Athletic Greens, I know I’m getting the vitamins and minerals that I need to stay healthy. So if you’d like to try Athletic Greens, you should go to slash Sinclair, and you can claim a special offer. They’re giving five free travel packs, plus a year’s supply of vitamin D3 for immune support and vitamin K2, which keeps the calcium out of your arteries and puts it in your bones. Again, go to slash Sinclair to claim this special offer.


Today’s podcast is also brought to us by Inside Tracker. Inside Tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and reach your health goals. I’ve been using Inside Tracker for over a decade, and I’m the chair of their advisory board. The reason I’ve long used Inside Tracker is because they provide the best blood and DNA analysis that I’m aware of. They make it easy to get your blood drawn. You can either go to a clinic or have someone come to your house and have it done there like I do. Inside Tracker then presents your blood analysis in an easy way to understand. There are graphs, and then they give guide and lifestyle recommendations that’ll improve your blood biomarkers.


Another feature that Inside Tracker has is their inner age test, which I helped develop. The test shows you what your biological age is, how it compares to your chronological age, and what you can do to improve it. So if you’d like to try Inside Tracker, you can visit them at slash Sinclair to get 25% off any of their Inside Tracker plans. Use the code Sinclair, my last name, at the checkout. Today’s podcast is also brought to us by Levels. Levels is an app that syncs with a continuous glucose monitor that they provide, and it interprets your glucose data for you. I’ve been so impressed using Levels that I recently joined the company as an advisor. By monitoring your blood glucose levels, the app allows you to see what different foods do to impact you. I’ve had lots of fun running tests of my own seeing how different foods impact my blood sugar levels. For example, I’ve learned that white rice really spikes my blood sugar, whereas potatoes don’t. As we’ll discuss on today’s podcast, having stable blood glucose is very important, not only for daily mental and physical energy, but also for long-term health. If you would like to try Levels, you can skip the 150,000 people on a wait list, and you can join today by going to slash Sinclair. That’s slash Sinclair.

Matthew LaPlante (07:36):

Anyone who’s been following along knows that we have presented a case over the last few episodes. The aging is largely a result of X differentiation of cells. Let’s touch on that really quickly because that’s going to be an important point drawing through this episode.

David Sinclair (07:53):

Right. Well, you won’t read a lot of this in textbooks. This is new science.

Matthew LaPlante (07:56):

You won’t even read the word X differentiation.

David Sinclair (07:58):

That comes out of our work, yeah. And this podcast, you heard it here first. The idea, the new idea of aging is that it’s not just random stuff going wrong. It’s that there’s actually a program that begins at birth. What happens during birth and prior to that is that cells gain an identity. We start as a stem cell that’s fertilized, and these cells get different identities. Brain cells, skin cells, liver cells, everything that makes our body up, the many thousands of different types, tens of thousands actually, are given their cell type specificity by turning on different genes out of the same genome.


Through epigenetic signalers. It’s called epigenetic. The epigenome is the regulator of the genome. And the epigenome is not as easy to describe as the genome. The genome is just a chemical with four letters, four chemicals that is the instructions. But then there’s a computer that reads that software called the epigenome. Or we also use the analogy, the reader of the compact disc, that old device we used to fit like 20 songs on. It was really exciting. But what we can now do instead of 20 songs, there’s 20,000 genes, but the reader is the epigenome. And over time, by that analogy, aging is due to scratches on the CD. And you cannot read the right songs at the right time. And a brain cell over time starts to play the music of a liver cell or a skin cell and doesn’t function as well. And we get diseases of aging, including Alzheimer’s as a result.

Matthew LaPlante (09:19):

In the last episode, we said that skin, it appears that skin ages faster than most other systems in our body. And we can use these clocks also and have used these clocks to measure aging in the brain. And when we measure aging in the brain, we find something really interesting.

David Sinclair (09:34):

That the brain ages slower than the rest of the body.

Matthew LaPlante (09:36):

Like significantly slower. Your brain is biologic, very good chance that your brain is biologically younger than you are.

David Sinclair (09:44):

Well, thank goodness, because it’s the most important organ. Without a functioning brain, we’re really quite useless.

Matthew LaPlante (09:50):

So one of these studies was led, actually a couple of these studies, was led by your friend and sometimes collaborator, Steve Horvath.

David Sinclair (09:57):

All right, before I get into Steve Horvath’s work on the cerebellum, important stuff. Let’s talk about how that clock is actually measured. Cause that’ll be important later for when we talk about diet. Steve measures the methylation on the DNA. It’s a chemical called a methyl that the cells add to the DNA and it sticks there. It doesn’t wash away. And it makes sure cells have their identity and play the right genes for the rest of your life. The problem is with aging that changes and you can measure that. In my lab, we can do it for about a dollar. And then the readout tells you, okay, that brain, even though the person is 40 years old, actually is 50.

Matthew LaPlante (10:30):

But you could look at the liver and you could see that the liver is actually 55. And you could look at the skin and say, oh, the liver is actually 62 in equivalent numbers. Horvath and his associates looked at tissue samples from 112 year old woman.


And they measured the clock in all these different parts of her body. And the regions of the brain were all much, much less methylated than her other organs. So that was the first study. And then they’ve done other studies. Just a few years later, they did a study that showed across a lot of samples, predicted age is lower in the brain than really anywhere else in the body. Sometimes just like a quarter of the age of other parts of the body.

David Sinclair (11:14):

Well, there’s a practical and an evolutionary explanation for those. The practical one is that our brain is protected. There’s a blood brain barrier. It doesn’t get hit by UV light like our skin does. You have these big thick skulls where basically lollipops on a stick. But our brain needs to be protected from these toxins that are in the environment. And of course, anything that leads to brain aging. But of course our brains will still age. DNA breaks, we’ve talked about. Broken chromosomes accelerate that clock. And this happens naturally even to cells that don’t divide including neurons, the nerve cells in our brain.

Matthew LaPlante (11:44):

One thing to note is that a cellular turnover is relatively low in the brain. So even though these cells, even if they’re not dividing, they still do age. That process of slow cellular turnover could explain some of the reasons why the brain doesn’t X-differentiate as fast as other regions in the body.

David Sinclair (12:02):

Yeah, that’s probably right. Unlike the liver, you can cut a piece out, it grows back. The brain doesn’t easily do that. There’s a little neurogenesis in the brain. Neurogenesis, we call it. But mostly those nerve cells are gonna be there for your whole life. And so they have these super protective mechanisms, these adversity systems that keep the brain younger for longer. But they’re not perfect, of course. We do have an aging brain, but there are ways to turn on those defenses greater than they naturally would be activated.

Matthew LaPlante (12:29):

And so all of this is the good news. The good news is in general, our brains age more slowly than the rest of our bodies. The bad news, as we said at the beginning of the show, is that we are living longer. That’s actually good news too, but it’s got a bad news component because our bodies are now outliving, in some cases, our brain. The average onset of dementia is 80 years old. And in most advanced patients now, the average lifespan is more than 80 years old. And so what that really means is that more and more of us are living with dementia at the ends of our lives. And other cognitive impairments, that’s a terrible fate. That’s something that we should all be working to prevent.

David Sinclair (13:13):

Well, that’s why I work on aging and not Alzheimer’s disease or cancer specifically. As we’ve said in earlier episodes, by working on aging, we can keep the whole body young, including the brain, which is really what we wanna do if we wanna have maximal gains in longevity and health and mental capacity right up to the end.

Matthew LaPlante (13:32):

And again, because you work on the whole body, you’re not working on the whole body when people become old. We’re talking about the whole body across the span of a human life. And there are advantages to that too, because everybody suffers some cognitive decline. This is a little terrifying. The volume of the brain after the age of 40 reduces about 5% per decade. And that’s got cognitive implications for all of us as we enter what used to be called our middle years.

David Sinclair (14:04):

Well, yeah, I’m 52. I can already feel it happening, but I’m doing certain things in my lifestyle. We’re gonna tell people about some of those things you can do to slow that process down and even reverse it later in life.

Matthew LaPlante (14:15):

So a lot of people might think like, well, okay, it doesn’t make a lot of evolutionary sense that the brain starts to have struggles at 30, 40, 50. But for one thing, for a long period of our history, people didn’t actually last that long in general.

David Sinclair (14:31):

Right, most males would die from predation or war or starvation in their 40s and 50s. Some people did make it to their 80s. But for most of our history, we didn’t need our brains as an 80-year-old. Same for women.

Matthew LaPlante (14:43):

Well, and we didn’t need really super sophisticated executive functioning to survive even when we were in our 30s and 50s. 30s, 40s, and 50s, if you made it that far, your life was gonna be pretty much the same on Monday as it was on Sunday. And it was gonna be pretty much the same on Sunday as it was two Sundays before and two months before and two years before and even like 200 years before.

David Sinclair (15:05):

Right, as we talked about in the last episode, getting gray, losing your hair were signs of wisdom and you got respect and presumably didn’t need to be that quick-witted. You had a lot of wisdom and experience that would compensate. But we live in a world now where every year you have to be learning something new and jobs are turning over. And it all started in the 1700s. Now we find ourselves at the point where it’s really difficult even for young people to keep up with this change.

Matthew LaPlante (15:31):

And this is what we call a plastic environment, an ever-changing environment. And that has implications in terms of how our brains develop and the plasticity that we need to respond to these changes over time.

David Sinclair (15:44):

Yeah, I watched my grandmother who passed away and we wrote about in Lifespan. She was a mentor to me. Actually the reason that I do this research, she told me to make the world a better place. So she has a very dear spot in my heart. What I saw happen to her as she got older was she just shut down. She didn’t care about life but she also didn’t care about change. And so she didn’t worry about computers. She didn’t bother learning how to use that. She didn’t bother learning how to play a compact disc. And the last 20 years of her life weren’t that great. Nowadays, you cannot be an older person and ignore technology or you’ll be isolated. You can’t talk to your grandkids. There’s COVID-19 and the pandemic.

Matthew LaPlante (16:23):

Yeah, imagine what, I mean, and this did happen to a lot of people but this is a really terrible thing, right? If you were not able or willing to adopt new changes to your environment, you were not going to be able to talk to people during the shutdowns, during the pandemic.

David Sinclair (16:38):

Yeah, I was just at the Apple store getting a new phone just a couple of days ago. And I was there and there’s a lot of young people, but then in came an older person. She was probably 85 the way she looked and the way she wasn’t walking that well. But she went up and I reckon 20 years ago, it would be rare to see someone in a computer shop of that age. Now she went up and said, hey, I know about the new operating system. I need to get a new iPhone. And by the way, my iPad needs an update as well. I was shocked. I remembered my-

Matthew LaPlante (17:06):

Can I link this to my smart walker?

David Sinclair (17:09):

Yeah, exactly. And I find also in our generation, so you’re in your 40s, I’m in my 50s, we cannot slow down either. We can’t say, all right, I’m just going to deal with my compact disc or record collection. We have to be Spotify to talk to our kids. We share files. We’re social media. If you need dates, you need to figure out that. Jobs, the job market’s changing totally. We used to have one or two jobs in our lives. Now we might have three jobs. We’re mobile. We work remotely and it’s turning over all the time. That requires a brain that is highly, highly adaptable.

Matthew LaPlante (17:41):

And so what we want to talk about now is this idea of keeping our brains and bodies aging at about the same rate so that we don’t suffer physical decline and we don’t suffer cognitive decline through as much of the entirety of our lifespan as possible. And that’s really, as we’ve had all of these advances in keeping our bodies younger and healthier, it’s really about keeping the brain younger and healthier too. That comes down to some of the same things that we’ve been talking about throughout this podcast, these three longevity pathways.

David Sinclair (18:17):

Yeah, so those who’ve been with us will know that there are three main buckets of longevity factors that respond to adversity. And these have evolved to sense the environment when times are tough. We call them adversity mimetics that turn on these three things. So the buckets are mTOR, which respond to low amounts of amino acids, particularly leucine, isoleucine, valine. There’s the AMPK pathway. AMPK senses low energy, low glucose levels, and makes more energy, more mitochondria, boost NAD, and that’s important for the third group, which are the sirtuins that require NAD and can be activated by certain chemicals.


Importantly, they all work together. We’ll talk about later that sirtuins can activate AMPK. AMPK can activate sirtuins and mTOR. What they do downstream is complicated. We’re not gonna get into that except relevant to the brain, but they protect the body. They turn up metabolism, they burn fat, they repair DNA, they clear out senescent cells, they lower inflammation, among many other things.

Matthew LaPlante (19:16):

Could we dive a little into mTOR? We’re gonna talk mostly about sirtuins, but there’s a real key role that mTOR plays in autophagy.

David Sinclair (19:26):

Well, it does. They all play a role in autophagy, but mTOR is the most potent one. mTOR responds to insulin signaling and fasting, and in response, it mobilizes proteins to be recycled. And made into new proteins when you’re hungry. And that’s called autophagy, the garbage collection and trash recycling system of the cell. And that’s particularly important for the brain because as you get older, there are these misfolded proteins in the eye. They’re called lipofuscins, and then Alzheimer’s, the plaques and tangles of proteins. And to get rid of those, you need really deep cleansing. It’s called chaperone-mediated autophagy. And mTOR is a really great way, not activating, but down-regulating mTOR turns on those recycling pathways really effectively.


We’re not gonna talk so much about that, though we are gonna talk a little bit about changing your diet to ensure that all three of these pathways are working in the way that will promote brain health.

Matthew LaPlante (20:15):

And even though we’re really mostly gonna be focusing today on the sirtuin pathways, you can be assured that the lifestyle advice that comes along with this, it works for all three of these pathways. It does, because they’re talking to each other.

David Sinclair (20:27):

And the reason we’re gonna focus on the sirtuins is, in part, because I’ve been working on them in my lab, but also because they become central to brain health. And so we’ll cover both. And also what’s important about the sirtuins, as opposed to these other two buckets, is that the sirtuins respond to a whole variety of environmental pseudo-stresses. We call them adversity mimetics. We’re gonna talk about food, talk about exercise and supplements. We’ll talk about exercise and supplements that you can take that should activate these three pathways quite effectively. And we think, based on animal studies as well, and human studies, should slow down brain aging and even potentially reverse it.

Matthew LaPlante (21:05):

There’s several types of sirtuins, but one in particular, there’s a couple that are important to brain aging. One in particular is called SIRT1.

David Sinclair (21:13):

Right, so there are seven of these genes in every cell in our body. The brain makes a lot of SIRT6 and SIRT1. And over time, the levels of both go down with aging, as well as the fuel that those enzymes need, called NAD. But we’ll focus on SIRT1 mostly, because that’s what seems to be the most important for controlling brain aging.

Matthew LaPlante (21:32):

Let’s talk about the role of sirtuins when it comes to aging in the brain.

David Sinclair (21:38):

Well, remember this clock is ticking away because the loops and the bundles of the DNA are getting messed up. The bundles become loops, the loops are becoming bundles. We’ve linked the sirtuins to that process. What happens when a cell is overstressed, overbroken, over damaged, is that the sirtuins have two jobs. They have to create these bundles of DNA and make sure the cell has its identity. So the genes are read like a proper compact disc or software in a computer. But when chromosomes break or you crush a cell, there’s a panic attack. And the sirtuins rush away to help with that stress and repair the broken DNA. But then they have to find their way back to where they came from and reestablish that structure of the epigenome. And they do a pretty good job. 99.9% of all of those structures go back to how they were, but that 0.1% never goes back and over time accumulates. And these are the scratches that cause aging.

Matthew LaPlante (22:32):

And in order to mitigate that, what we wanna do is upregulate the sirtuins, and we can do that through NAD boosters.

David Sinclair (22:41):

Right, well, in the mouse in 2008, we published that just upregulating SIRT1 gene in the nerve cells of a mouse’s brain was sufficient to slow aging and prevent those loops and bundles from changing. And that was the first evidence you could slow down a mouse’s brain age. But you can’t modify our brains genetically just yet. So we need to find safe ways you could take a chemical, a pill, hopefully rather than an injection, that will increase SIRT1’s activity. The ones we know of are resveratrol and NAD boosters. We’ll talk about those in a second. And then they give the benefit of a good diet and exercise. And in combination, even better.

Matthew LaPlante (23:23):

Well, let’s talk about those things first. Let’s talk about diet and exercise, because that’s gotta be sort of like the foundation on which we build all this other stuff.

David Sinclair (23:33):

Well, absolutely. We’ve talked previously about the Mediterranean diet. And one of the reasons is that it’s very clear in over a dozen studies that a Mediterranean-type diet protects the brain from aging and can even reverse aspects of aging in the elderly with mild cognitive impairments.

Matthew LaPlante (23:49):

Yeah, there’s a study earlier this year from a really large international research group that was led by Tommaso Bellerini. It showed higher adherence to a healthy diet. In this case, the Mediterranean diet is associated with less amyloid beta, less tau, larger gray matter volume. If some of these words are sounding familiar, it’s because they’re all associated with Alzheimer’s disease.

David Sinclair (24:10):

And there was a second study that I found fascinating. This one was by Anastasio et al, 2017. And it was over 1,000, actually close to 2,000 people. And there was a 10% reduction in dementia risk for people on the Mediterranean diet.

Matthew LaPlante (24:25):

There’s actually a 10% risk reduction for each Mediterranean diet score, which means the more Mediterranean your diet, the better you were doing.

David Sinclair (24:35):

Right, and so that includes olive oil in the diet, red wine, and not a lot of red meat.

Matthew LaPlante (24:41):

Yeah, and not surprisingly, this is a research team from Greece. They’re really like the Mediterranean diet for obvious reasons.

David Sinclair (24:48):

Yeah, what I want to get into later, and hopefully we will, is what is it in that diet chemically that can help the brain?

Matthew LaPlante (24:54):

Well, I don’t know that we need to wait too long to get into that. Let’s talk about that. Like, what is it in that diet chemically that can help the brain?

David Sinclair (25:01):

Well, there are a number of things. I would put them into a few different buckets, that there are vitamins that can be deficient, that we need to talk about about the clock later. But first up, there’s red wine, which has polyphenols. Resveratrol is one of those, and my lab has been working on resveratrol for many years. And that directly activates SIRT1. It makes the enzyme, it’s like a Pac-Man, and it’s controlling genes, and it works faster. So resveratrol from red wine has clearly been shown to be beneficial, and also prevents cancer, and not just has metabolic and brain-enhancing effects. The other component of Mediterranean diet that works on SIRT1 is olive oil. And Doug Masinek recently showed that if you add oleic acid, which is a major component of olive oil, toslofen and avocados and other good foods like that, can also directly activate the enzyme by sticking to it and making this Pac-Man, I don’t know if everyone knows what a Pac-Man is, this little puppet creature on an electronic game, chomp faster. And there’s probably other molecules. We talked previously in another episode about xenohormatic molecules. Plants make these molecules to survive stress, and when we eat them, we get the benefits of that stress, because we worry, our bodies worry that our food supply might run out.

Matthew LaPlante (26:12):

And that’s sort of the overarching nature of a plant-based diet, whether it’s Mediterranean diet or some other diet, is that it is mimicking adversity. Your body’s gotta work a little harder to get everything that it needs. That’s sending the signals that maybe times aren’t so great, and we need to activate these longevity pathways.

David Sinclair (26:31):

Well, that’s the difference between a Mediterranean diet and a high-fat, a carnivorous diet, and a typical Western diet. They’re full with calories, full with a whole bunch of stuff that tells the body times are good. It’s a bounty, no need to protect ourselves. Let’s just burn the candle at both ends and forget about life later. And that’s not what you want. What you wanna do is to have the perception of adversity, and the Mediterranean diet, as well as in Japan, what’s called the Okinawan diet, which has low levels of protein and mostly plant-based, those two trick the body into thinking that the food supply sucks and could run out any minute.

Matthew LaPlante (27:09):

And these diets aren’t perfect, right? Let’s talk about some of the things that you need to make sure that you’re getting enough of if you are eating this plant-based diet.

David Sinclair (27:19):

Right, well, one of the first things to worry about if you’re just focusing on plants only is a deficiency in folic acid. This is vitamin B12.

Matthew LaPlante (27:29):

This is the supplementation that they give to pregnant women because they’re often low in folic acid.

David Sinclair (27:33):

Yeah, and there’s a good reason why, which I’ll get to in a second. There are other B vitamins that are also important to make sure that you have enough of vitamin B6 and B3. We’ve talked about B3 as an early component that’s building up that NAD for the sirtuins. So B vitamins, especially if you’re on a plant-based diet, but for everybody, don’t be deficient in these. Why? Because the B vitamins are the ones that make sure you have the methyls that are added and subtracted from the DNA that controls the DNA methylation clock. If you have low levels of B12, it’s known that you have deficiency in the ability to methylate DNA and that will mess up your epigenome and very likely it can cause a lot of problems and actually accelerate the clock in a way that causes aging. And there are a lot of studies that have shown that deficiencies in B12 accelerate a variety of diseases. Heart disease is the major one, but also dementia in the brain. And the main reason, I think, what’s going on is that aging is being accelerated when you don’t have enough of these B vitamins.

Matthew LaPlante (28:29):

And the result of low B vitamins is an elevated level of homocysteines.

David Sinclair (28:34):

Well, that’s a Marcus, yeah, exactly. Often your doctor, but not all the time, measures homocysteine levels because it’s been shown to go up as a predictor of heart disease and dementia. And high levels are particularly dangerous. Most doctors would want you to have less than 10 micromoles per liter. Some people go as high as 100. If you’re that high, you’re certainly gonna die in the next few years of cardiovascular events. So you try to keep homocysteine levels down. And the best way to do that is to make sure B12 levels are optimal. Not too high, because that can also cause problems. Again, you have to measure it. I use Inside Tracker to measure my B vitamins. But also you want to avoid too much alcohol. Definitely don’t smoke. Menopause will also affect your homocysteine levels. Certain types of cancer will. And aging itself leads to increases in homocysteine.

Matthew LaPlante (29:24):

And this all materializes as plaque?

David Sinclair (29:27):

Well, it does, but homocysteine itself, I don’t think is the problem. It’s that the methylation pattern on the DNA is getting messed up. The sirtuins can’t cope, so one’s not good at going back to where it came from. And your body will get older. And when your body is older, it has more inflammation, can’t get rid of plaque, builds up calcium in the arteries instead of being in your bones. And that we call diseases. But that’s actually aging going on.

Matthew LaPlante (29:48):

I think a lot of people think about elevated homocysteines in terms of what’s going on in like their blood vessels throughout their body. But we’re having a conversation here about our brains. It’s important there as well, maybe even more so.

David Sinclair (30:01):

Well, yeah, it’s known that high homocysteine levels, which is a version of an amino acid, do correlate with increased susceptibility to dementia. And the reason probably is that we have vasculature in our brain and that these are very small vessels that are needed to bring oxygen and take away toxins. And they clog up really quickly. And with high homocysteine levels, as an indicator, we’re getting plaque also building up. And not only that, the endothelial cells that are like the lining of the blood vessels, they literally are, but they need to remain flexible like rubber bands. They become defective, they age and they become stiff. And then they start to accumulate this cholesterol and then you get occlusions. And that can ultimately end in a stroke. But even before that, those occlusions are limiting the amount of oxygen your brain gets leading to, of course, losing your ability to remember things even at my age. But ultimately what’s called vascular dementia.

Matthew LaPlante (30:54):

There’s a pretty simple way to monitor that accumulation.

David Sinclair (30:59):

Yeah, you just look in your eye. Well, you don’t look in your eye.

Matthew LaPlante (31:02):

It’s really hard. I actually tried earlier.

David Sinclair (31:04):

Yeah, a doctor, an ophthalmologist, or even an optician will look in there and have a look at the back of the eye, the retina. And they can see very clearly, and they’ll take photographs. They can show you of whether you’ve got a perfect blood vessel lining. These blood vessels sit on top of the nerves, which is a bad design. That’s how we are designed. They will see those blood vessels. And if they’re occluded, that’s a really, really bad sign. We’ve actually known for many decades that if you see one of these occlusions and a lot of plaque, you basically are gonna suffer from a heart attack and die pretty soon.

Matthew LaPlante (31:36):

Yeah, you have like a 15% chance of death within a year. And then it goes up from there in really scary measure.

David Sinclair (31:44):

Exactly. In 1959, Dr. Robert Hollenhorst found that these plaques, these little occlusions that he could see in the back of the eye with his lens predicted survival. It got really bad. In fact, what’s now known, if you see these, you got a 50-50 chance of being alive seven years later. And that’s really scary.

Matthew LaPlante (32:03):

That’s really scary. So obviously, like staying ahead of this, not letting that accumulate at all is preferential, even to catching it early.

David Sinclair (32:13):

Right, and think of this, your eyes are a window into your brain. In fact, your eyes are your brain. They’re extensions of those nerves with balls of green.

Matthew LaPlante (32:18):

I know this creep, you told me that before and I got creeped out. Yeah, when you look at someone

David Sinclair (32:21):

in the eye, you’re actually looking at their brain. Pretty cool. But what’s great about it is you can see into your brain and that’s what we’re talking about here is getting an indicator of how much occlusion and plaque there is building up inside your skull.

Matthew LaPlante (32:33):

Let’s talk also about fatty acids and the importance of really making sure that you’re getting the right and the right kinds of fatty acids, particularly if you are on a plant-based diet and you’re concerned about brain health, which we all should be.

David Sinclair (32:48):

Right, even with a normal diet, you often don’t get enough of these omega-3 fatty acids, which are the types that we don’t make ourselves. If you’re only meat and you don’t eat fish, you eat animals besides fish, you’re not getting a lot of them. And they’re the building blocks of the brain. So we need a lot of them. And they’ve been shown in a number of studies to help with many different things from wound healing and of course depression. Now, what are the sources? Well, if you eat fish, you’re probably in good shape. You’ve got salmon and mackerel, krill, sardines. These are good sources of omega-3s.

Matthew LaPlante (33:20):

And these are giving us the DHAs and the EPAs, because there’s three different kinds of these, right?

David Sinclair (33:24):

Well, there are lots, but the three main ones that people talk about are EPA and DHA. The EPA is the more important one. You want to get at least a gram of that. Sometimes people say get 1.6 grams of this ratio of EPA to DHA and women about 1.3 grams. And that’s been shown to greatly improve memory and counteract depression. Now, if you’re a plant-based diet, now that if you’re a plant-based person, you can’t obviously get as much. You have to focus on other types of food that have what’s called alpha-linolenic acid or ALA, which is converted slowly, not efficiently, about 10% of it gets converted by the body into the two types we just mentioned that are important, the DHA and importantly, the EPA.


Focus then on flax seed, walnuts, chia seeds. That’s where you get your ALA. Linseed oil is where it was first discovered, ALA, linoleic acid. I use that to polish certain things, keep wood looking good, cricket bats, you put it on there. But you can also, you can consume a little bit. There’s a lot of it in there as well. And there’s one other thing I want to mention that isn’t in that list of three, which is a monounsaturated fatty acid called oleic acid, which is really important. And I mentioned it earlier, it’s a component of olive oil and avocados. And I have that included in my supplement every night along with these other components.

Matthew LaPlante (34:41):

As a recent convert to seaweed salads, I would be remiss not to note that you can actually get, if one of the few plant sources that you can get DHA and EPA from is from seaweed. Is that right?

David Sinclair (34:52):

It is right. Well, I don’t know if you get enough of it. I think it’s really a good thing to consider and talk to your doctor about it to take at least a gram of these omega-3 fatty acids every day.

Matthew LaPlante (35:02):

So we know we should be consuming these omega-3s, but why? What are they doing in our cells?

David Sinclair (35:07):

So it turns out these omega-3s actually form a structural component of the brain. They insert along with other fats in the brain. So fat is actually good for the brain. A lot of our brain is made up of these fats. The reason is that the nerves aren’t naked, much like an electrical wire. You don’t have them lying around your house naked. They actually wrapped with insulation tape or insulating material. And that’s what these fats do. And these are membranes that wrap around. It’s called the myelin sheath. And these fats actually, some of them are omega-3s. And the more omega-3s you have in your diet, the more you’ll have in those membranes. And that protects from inflammation and damage and helps the nerves function and repair if they get damaged.

Matthew LaPlante (35:46):

We have to eat for brain health because what we eat, what we consume helps make up the parts of our brain that keep our brain healthy. We also have to exercise for brain health. We can’t neglect that part. And we can’t think that exercise just affects us from here down. It doesn’t.

David Sinclair (36:03):

Well, that’s actually known in dozens of studies has been showing that if you do aerobic exercise or even just walk, that’ll improve your chances of having a better memory and cognition as you get older. The reason we think that is, is that there’s two reasons. One is better blood flow and also better neuronal activity and slowing aging of those cells. That involves the sirtuin. That involves the sirtuins, this third protective survival pathway that can be activated, of course, by the food and also by exercise.

Matthew LaPlante (36:28):

We’ve seen this in a number of both human and animal studies.

David Sinclair (36:32):

Well, that’s right. There are a number of studies that we could talk about. The one that stood out for me in our research was the one that involved 160 sedentary, sitting down, non-exercising adults that were told for six months to do extra aerobic exercise.

Matthew LaPlante (36:45):

To do some aerobic exercise. Yeah, they were actually, they were led through this process because you can’t just tell humans to do anything. They’re just not going to do it, right?

David Sinclair (36:51):

They had a cattle prod and they were pushed onto a treadmill, something like that.

Matthew LaPlante (36:54):

I don’t think it’s that highly regulated, but they do make sure they actually do the exercises.

David Sinclair (36:60):

So Blumenthal and his colleagues found, what was it, 2019, that this greatly improved executive function.

Matthew LaPlante (37:07):

Executive function? Yeah. That’s the function that’s like co-equal to the judicial and legislative function?

David Sinclair (37:13):

It’s kind of like that, but kind of different, which is, so you know a lot of kids don’t have executive function. They can’t focus, they can’t do tasks, right? That’s what executive function is. Concentration, focus, do some tasks.

Matthew LaPlante (37:22):

And so just a little bit of exercise. Six months of exercise improved for these people, they’re all over the age of 55, improved dramatically their ability to do these things.

David Sinclair (37:35):

Well, they did. And I think that that’s one of the main reasons for exercising. You might want to do it not just because you feel better, but you will think better too.

Matthew LaPlante (37:42):

It’s hard to take people who have Alzheimer’s, Parkinson’s disease, other cognitive problems through things like that, because it’s just at a certain point, you lose the ability to get them to respond to you. But there’s also lots of evidence in mice for this. There was a study this year out of Brazil that showed that exercise had a really significant effect on mouse models of Alzheimer’s and Parkinson’s.

David Sinclair (38:06):

Right, so it’s not just aging that exercise works on. What you’re saying and what’s in the literature is that diseases of aging, and also including Parkinson’s, which is age-related, are benefited as well. There’s another study. It doesn’t have to include aerobic exercise. There’s one where there’s strength exercise. So if you don’t like running, pick up some weights, because what’s been found in this study, this is 2013, Pereira and colleagues found that in an elderly cohort, they had 451 people, just 10 weeks of strength training increased the level of factors that grow new brain cells, new nerves. This marker is called BDNF, or brain-derived neurotrophic factor. And we use that as a way of indicating the youthfulness of the brain and regrowth of new nerve cells.

Matthew LaPlante (38:49):

And the takeaway here is that at a time in many people’s lives when they’re becoming less active, it’s actually more important than ever before to become more active and to stay active.

David Sinclair (38:59):

Before it’s too late, it’s very hard to get a very elderly grandparent or parent to get on a treadmill or lift weights. So what we want to do for ourselves and for our parents and grandparents is to get them moving early on before it’s too late.

Matthew LaPlante (39:12):

Even if we’re eating well, even if we’re exercising, I mean, presumably our ancestors did these things too. If they hadn’t, we wouldn’t be here. They faced these sorts of adversities all throughout their lives. And that’s what we’re trying to mimic through our diets and our exercise. It still might not be enough, because we do live these lives of incredible comfort and we eat a lot of food. So we might need a little additional help when it comes to keeping our brains healthy. This is where supplementation comes in. And one of the supplements we want to talk about is metformin. A lot of people are going to say, oh, wait, that’s an AMPK activator. You guys said you were talking about CERT, but we’re actually kind of talking about both.

David Sinclair (39:58):

Well, yeah, there’s crosstalk between these various defenses. The AMPK pathway talks to the NAD Sirtuin pathway. When you take metformin and you get this mitochondrial hormesis, mitohormesis, that will raise NAD levels. It’ll stimulate the production of the enzyme that turns NMN, a precursor of NAD, into NAD itself and raise NAD levels and get the sirtuins active as well in the brain.

Matthew LaPlante (40:21):

Okay, and we know that metformin is good for brain health from a variety of studies. One we want to start with today is this fish study, which I did not know that they did cognitive studies on fish.

David Sinclair (40:34):

fish are actually used quite often in labs. And most of them live about two years, as long as a mouse, which doesn’t make them that much more advantageous. But there are short-lived fish. There’s one called Northobranchus fusuri that lives only a few months. There’s one, in this study, they used red-tail notho, which is ganthuri, Northobranchus ganthuri. And it comes from Zambia. It lives a bit longer. Its environment isn’t as harsh as the other one. And over that year, what it does is it breeds very quickly. It lays eggs that become encased in a shell. The fish then dies, and those eggs will survive until the rains come again. But it’s a great model for aging because it goes through its life cycle super quickly, but it’s built of the same stuff that mice and we are.

Matthew LaPlante (41:17):

And how do you tell that a fish is having cognitive impairment or cognitive success?

David Sinclair (41:24):

So it sounds crazy measuring memory in a fish, but they do have good memories. You can test it in a variety of ways. You can put food and a light and see if they remember that the light is where the food is. They come to the light if they have a good memory. You can put them through mazes, like a mouse. They swim through if they’ve got a good memory, and they know where the food is at the other end. And the third one is where you test their fear conditioning, its reaction and memory of fear. And you shine a red light in the tank, and then you get a stir like you would a cocktail and swizzle it around. And they should, if they remember that, next time they see the light, they should run away, or swim away, I should say. And so what they did was, in the study, was they found that by treating these fish with metformin, put a little bit of metformin in their food, those fish were able to remember those tasks much better as they got older.

Matthew LaPlante (42:08):

And so the Ted Lasso quote about being a goldfish and, like, immediately forgetting things, that’s not true.

David Sinclair (42:14):

No, fish have a really good memory, actually, and they have brains that are quite similar to mammals.

Matthew LaPlante (42:20):

So when you give these fish the metformin, what’s happening, like, cellularly?

David Sinclair (42:26):

Molecularly, what’s happening is that the metformin molecule gets inside the cell and into the mitochondria, where there’s what’s called the electron transport chain. This is a series of bundles of proteins, five in all, that pass electrons between them, like a hot potato, and generate chemical energy. Metformin disrupts that first step, and in doing so, releases free radicals. Superoxide anion is one that goes off and damages parts of the cell, and we call this damage mitohormesis, which is a little bit of damage makes, actually, the cell stronger. One of the main things that happens is that the cells react and say, oh my goodness, we don’t have enough energy, make more mitochondria, more battery packs, more energy for the body. That’s always a good thing with aging and health and longevity. The other thing that happens is that this signal sends a protein called GLUT4 to the outside of the cell, in the membrane, to suck more sugar out of the bloodstream, and having lower blood sugar protects the body from this caramelization process that also causes many diseases, including dementia, by clogging up the arteries.

Matthew LaPlante (43:24):

So high blood sugar is not good for brain activity.

David Sinclair (43:28):

No, it’s not good for any tissue. What happens is this glucose that’s in your bloodstream, if it gets too high, it actually binds to proteins. About 10%, five to 10% can be covered in this glucose molecule. That’s bad for their function. It’s often hard to remove, and it leads to dysfunction, particularly of the cardiovascular system.

Matthew LaPlante (43:46):

We’re not just seeing improvement in cognitive function with metformin in fish. There’s been studies on mice. There’s been studies on rats. There’s been studies on humans.

David Sinclair (43:58):

Yeah, there’s a bunch. Our researchers did a great job, and they’re all fairly recent, 2014 to 2019.


The one that I want to bring up is Koenig and colleagues in 2017, a really good study. It’s randomized, placebo-based, controlled crossover, that’s what you always look for. Metformin improved, again, this executive function, the ability to focus by treating 20 non-diabetic normal subjects. And they had mild dementia when they started, and they improved, which means that dementia is somewhat reversible with this drug. It also means that if you’re starting to lose focus in your job, daily activities, either taking metformin may help or just keeping your glucose levels steady, which is what a lot of us do, and we measure that daily with monitors on our arms. That is also a way to stay focused.

Matthew LaPlante (44:46):

And that’s a small, really well-controlled study. There’s also a really big, less well-controlled study, but nonetheless, really impressive study from 2019. They took a really huge cohort of diabetic patients, tens of thousands of them. Dementia incidence for the metformin users, 55% lower.

David Sinclair (45:06):

So actually it was preventing the onset of dementia by what? 55%? Right. That’s a massive number. When we talk about these numbers, often it’s a 5% to 10% decrease in disease. 55% is a massive number that we should definitely pay attention to.

Matthew LaPlante (45:19):

There’s been some suggestion that metformin, in addition to acting on AMPK and then the chain of custody moves its way down, and AMPK acts upon NAD. Metformin actually might impact NAD directly as well.

David Sinclair (45:37):

Yeah, so that study was super interesting from a few years ago that metformin could directly interact with, bind to the enzyme, and make that muppet, that Pac-Man creature go faster, in the same way that resveratrol has been shown to. But that was only done in one study. And of course, in all science, we need to reproduce it, and we’re still waiting on those results. In my lab, we’ve tried it. We haven’t had perfect results yet, but we’re still trying.

Matthew LaPlante (46:00):

In the meantime, there are more direct ways to impact NAD levels, and that’s through NAD boosters. There’s been lots of animal research on this. It elevates cognitive functioning. It promotes recovery after brain injury, all good stuff.

David Sinclair (46:15):

Yeah, why would you want to supplement NAD in the first place? Well, it’s known, just like the rest of the body, that in the brain, NAD levels go down for a couple of main reasons. One is that we don’t make as much, that NAMPT enzyme that’s activated by metformin and exercise goes down, so you don’t make as much. But also, it was shown by Jeffrey Milbrandt at Washington University in a couple of high-profile papers just in the last few years that there’s an enzyme that gets turned on in nerve cells when they’re damaged called SARM1, and it depletes the cell rapidly of NAD. So what you’ve got is a decrease in the production level of the production of NAD, also with an increase in the degradation of NAD. So supplementation, we think, is important to not just get the youthful levels back, but go beyond that to mimic exercise and mimicking a perfect diet, especially for the elderly who cannot always do those things.

Matthew LaPlante (47:01):

And we’ve got a long history now of research going back almost 20 years of NAD supplementation on brain health. There was a study in 2004 that showed treatment of NADH slowed Alzheimer’s. And a lot of people hear about NAD+, NADH might be a little unfamiliar.

David Sinclair (47:19):

NADH is basically NAD with a hydrogen atom attached to it. NAD plus has a positive charge, like the end of a battery. And then if you stick the hydrogen onto the vitamin B3 part of the NAD, then that’s gonna be called NADH. And that’s important in the cell because that’s the other major function of NAD. One is to turn on the sirtuins and DNA repair and all that good stuff. But it also is known as a hydrogen carrier molecule that takes hydrogens and moves it from one place to another.

Matthew LaPlante (47:47):

So why would NADH work if NAD plus is what’s the standard?

David Sinclair (47:55):

Well, what I think is going on here is that, so NAD activates sirtuins in a test tube and in the cell. NADH actually has the opposite effect. So you don’t want high levels. What’s probably happening is that NADH gets into the bloodstream, gets degraded into its various components, vitamin B3, there’s a phosphate, there’s a part of DNA called a nucleotide, the A letter, and they get reassembled back into NAD+. You’re just giving the components in a concentrated form by taking NADH.

Matthew LaPlante (48:23):

Another more recent result, a combination of NR, which is another kind of NAD booster that we talked about a few episodes back, and a pterostilbene slowed down the progression of ALS.

David Sinclair (48:37):

So NR is different from NMN. Let’s go through that again. When you wanna make NAD, what the cell does is it takes vitamin B3 or niacin or nicotinamide, turns it into NR. So the nicotinamide gets now a sugar, ribose, and then to make NMN, it puts a phosphate, which is phosphorous and oxygen, and then it combines that together to form NAD. So those are the various steps. Now, what NR is, it’s a couple of steps back from NAD. And so when you take NR, it’s made into NMN, made into NAD. But it’s been shown in humans by taking large doses, about a gram of NR, you’ll make NMN, you’ll make higher levels of NAD, which has shown to be important in this study in ALS patients. Those ALS patients actually benefited greatly from the supplementation. The other component I forgot to mention is pterostilbene, and the pterostilbene part of it is resveratrol. It’s resveratrol with three methyl chemicals on it. It’s essentially a way of delivering in a pill form resveratrol plus an NAD booster.

Matthew LaPlante (49:37):

This was a pretty short-term study. It showed sort of like immediate returns for ALS patients when they took this combination of NR and pterostilbene. But Lenny Guarinti, who’s running the study out of his lab at MIT, your former mentor there, we chatted with him this morning. He said, actually, they’re now looking at a year-long study so that they can see if these results continue on for a longer term for patients who are dealing with a really, really debilitating disease.

David Sinclair (50:08):

For which there is no cure or even effective treatment. So this would be a big deal. And most of these trials fail in the first stage, phase one. They’re in phase two, so they’ve made it further than most. But of course, there’s a very difficult disease, ALS, Stephen Hawking, it’s just a terrible debilitating disease, very hard to treat. But fingers crossed for this one, hopefully those patients will continue to do better.

Matthew LaPlante (50:31):

Can we talk a little bit about this idea of increasing blood flow and what NAD boosters do for blood flow? One of the studies that you were involved in showed vascular improvements in mice that were put on these boosters. But vascular flow isn’t just important in our bodies. It’s, well, frankly, it’s more important in our brains, right?

David Sinclair (50:58):

Right, we forget about our brain needing blood flow and oxygenation because we don’t really see it. It’s not part of our daily thoughts. But it’s just as important, if not more important, than the rest of the body. We found not only does NMN and SIRT1 activity maintain the youthfulness and ability to grow new blood vessels in the mouse’s muscle, but we collaborated with Zoltan Angvari at the University of Oklahoma to show that mice, even in their brains, benefit from NMN by building new blood vessels. And those elderly mice not just had better blood flow, but could think and remember things better.

Matthew LaPlante (51:34):

And we think that’s because of the improvement in vascular tissue.

David Sinclair (51:39):

Well, almost undoubtedly, that’s what was going on in those mice because we could block the effect. We could actually downregulate the SIRT1 specifically in those endothelial cells that line blood vessels, and then the benefit of NMN went away.

Matthew LaPlante (51:51):

And this turns mice with older brains into mice with younger brains?

David Sinclair (51:55):

That’s essentially what happens when mice and people get their ability to learn. Again, that’s reversing an aspect of aging.

Matthew LaPlante (52:02):

So before we move off of the topic of sirtuins in the brain, it’s not just blood vessels that are being affected. It’s not just the cerebellum. There are other parts of the brain that are also really well impacted by SIRT.

David Sinclair (52:17):

There are a few things I want to mention about SIRT1 before we leave this topic. One is that overexpression, turning up SIRT1 in all of the nerve cells in the brain, extends a mouse’s lifespan and protects them against these diseases that we induce in them, ALS, Huntington’s, and Alzheimer’s disease. The other thing is there are a couple of regions that are of note. One is the hippocampus, which secretes hormones into the bloodstream, and that can actually reduce blood glucose levels by talking to the liver.


The other area of the brain is the hippocampus. This is the part of the brain that consolidates memory, and it was found in old mice if we activated that part of the brain with resveratrol or activated SIRT1 by putting in more copies of that gene and turning it on. Those mice had better memory even in old age. So really what this says is that SIRT1 plays an amazingly important role in delaying aging, preventing diseases of aging in a mouse, and potentially even in a human. We’ll see how those trials continue. But let’s talk a little bit about sleep because the hypothalamus controls the circadian rhythm, day and night rhythms of the body.

Matthew LaPlante (53:18):

Yeah, let’s talk about sleep because, I mean, quite frankly, if you don’t sleep, you’re in a lot of trouble, and you’re going to age faster. There’s lots of research on this.

David Sinclair (53:29):

Yeah, even at the molecular level, we understand that SIRT1 and NAD play a fundamental role in controlling your wake-sleep cycle. SIRT1 and NAD are going up in the morning, coming down later in the day, getting your body ready for sleep. And in doing so, what they do is they turn on a particular gene called BMAL, which is part of the clock, not the HOVAC clock, but the daily clock, the circadian rhythm clock. And those genes tell the liver to calm down. It tells the brain to calm down. And in the morning, tells everything to wake up again. And so what is really important to understand is if you start to lose the function of SIRT1 and have low NAD levels, you’re probably not going to sleep well, but also you’re going to age prematurely.

Matthew LaPlante (54:08):

And the big problem here is that sleep efficiency actually declines with age. So we got to work harder at sleep as we get older, just like we have to work harder at exercise as we get older to promote brain health.

David Sinclair (54:21):

Yeah, another way of saying it is that as you get older, you lose your ability to sleep. And if you don’t sleep well, you’ll lose your ability to fight aging. And it’s just a feed-forward disaster. So you’ve got to intervene. You can intervene with the kind of things we talk about here, which is eating well, exercising, and intervening with the kind of things that you can take perhaps as a supplement. But now let’s talk about what do we do to make sure we sleep well and we have the right rhythm. And one of the key things that I use is NMN. NMN is going to raise NAD levels in the morning. I take a gram of it then. But I also, when I travel, I use it to reset my body. And I definitely feel that I can avoid jet lag if I do that.

Matthew LaPlante (55:01):

There’s some other supplements that a lot of people take, magnesium.

David Sinclair (55:04):

That’s good for sleep. L-theanine is another one that people try. I’ve used it, it seems to help me. But essentially you just want to calm down at night. Don’t do your emails too late. Relax your brain.

Matthew LaPlante (55:15):

And then I think a little counterintuitive, one of the best things that you can do for sleep at night is actually not something you do before you go to sleep. It’s something you do right away when you wake up.

David Sinclair (55:26):

You mean go outside?

Matthew LaPlante (55:26):

Well, you’ve got to get light, right? You’ve got to reset your circadian rhythms. And the best way to do that is put yourself in a situation where your body knows it’s daytime.

David Sinclair (55:35):

Well, you can. But here in Boston, where I live, there’s not a lot of light in winter. So I actually have some blue light that I can shine in my eyes to get my cortisol levels up in a synthetic way, not naturally. But whatever you do, try to get some light early in the morning because that always gives you an energy boost and helps you reset your skating rhythms if they’re not perfectly in sync.

Matthew LaPlante (55:55):

And like the other things we’ve talked about today, there’s lots and lots of research. We’re not like just making this up. Sleep is important. We know this.

David Sinclair (56:04):

Well, yeah, even in flies, flies sleep. It’s a little known fact. But before we get to the humans, I want to, this is a really cute study. It was a study that was in 2020 in fruit flies. They found that if you deprive flies from sleep, they have a lot of oxidative stress in their gut and they also have a short lifespan, which by the way, could be rescue. Which by the way, could be rescued by treating them with an NAD booster.

Matthew LaPlante (56:24):

Which is also a way that we’ve seen that you can rescue human subjects from sleep deprivation, but even just one night of sleep deprivation. A lot of people say, oh, you know, I’ll catch up tomorrow. I’ll catch up the next day, whatever, right? Maybe I didn’t sleep well tonight, but I can sleep well the rest of the week. One night of sleep deprivation increases amyloid beta production by 5%. That’s, you don’t want to mess with amyloid beta, right?

David Sinclair (56:52):

No, that will accumulate in your brain. It’s very hard to get rid of. And I was also shocked to read that it’s not just the brain that ages if you don’t sleep. We already know that if you restrict rats from sleep, they get diabetes within two weeks. In humans, looking at a million people, this study from 2010, Capucho et al., what they found was that in people that had very little sleep, the risk of dying was 30% higher than those that got a natural, normal night’s sleep.

Matthew LaPlante (57:19):

And the thing is our brains are getting so much adversity right now, right? We talk about a little bit of adversity being good, but we evolved to have a pretty low, constant low level of adversity popping up now and then. And right now, in terms of sort of like the insults and injuries that we’re taking in in terms of stresses, daily stresses, everything changing, our brains are being besieged all the time. We need sleep to reset.

David Sinclair (57:46):

It’s just too much. There’s too much to remember. There’s too much to cope with, too much anxiety. We just are living through a pandemic. This is really stressful times. And just lack of sleep makes it worse. And physically, we will regret it decades later.

Matthew LaPlante (57:60):

The overall message today is we gotta keep our brains healthy and we have to work to keep our brains healthy. We can’t just expect that they’re going to do what they’ve always done throughout our evolutionary history, which is to last longer than we have. We’ve figured out many of the tricks that are gonna keep us alive for longer holistically, but we gotta keep our brains healthy for at least one day longer than the rest of us last. It’s super important that we look after our brains.

David Sinclair (58:28):

It’s not just about ourselves, it’s about our families. Many families have had to take care of parents and grandparents that have dementia. This is not pleasant for anybody. And we have a responsibility to society, and particularly our family members, to stay healthy for longer, particularly keeping our brains younger for longer. In our next episode, we’re gonna be talking

Matthew LaPlante (58:47):

about a lot of the things that we’re doing about a lot of the things that we sort of hinted at throughout the series so far in terms of what’s coming next. Maybe what’s coming next in a few years, maybe what’s coming next in 10 years, and what, if we can keep ourselves from aging too quickly over the next couple of decades, might be a quarter century away and sort of waiting for us there if we get there healthy.

David Sinclair (59:17):

Well, it’s a super exciting time. The reason we’re doing this podcast now is to bring the audience, the world, along with us, and to experience these changes essentially in real time as they’re being made. And the kind of results that are in the lab and increasingly going to customers, consumers, and eventually to patients in hospitals and at home with medicines will be directed towards a lengthening lifespan, not just by one or two years, but by decades. And I can see that coming. We’re gonna talk about some of these things. It’ll include wearables, monitors, and even age reversal technologies that get that Horvath DNA methylation clock to go back not just a couple of years, but potentially by decades.

Matthew LaPlante (59:54):

One of the things that I noticed, and we’ve talked about this a lot, you and I, many of the things that we talked about in the book that we said, these are a little ways down the line. It’s only been three years since the book, two years since the book was published. And a lot of those things are coming to fruition a lot faster than we had even thought. And so these things that maybe in the next episode, we’re gonna say, ah, these are kind of far down the line. Who knows? They could be here next Tuesday.

David Sinclair (01:00:24):

Right, it’s blowing my mind how quickly things are changing. I didn’t realize the discovery of reprogramming in the eye, which was in the book and we published very recently, has taken the world by storm. There’s billions of dollars being poured into this. So it’s very hard to predict how this is gonna look just a few years from now. Plus the wearables, these things are changing and coming to the public all the time. The other thing that’s happened thanks to the pandemic is that home remedies and home testing has taken off. So there are things we can now do at home that were beyond even the imagination when we wrote the book.

Matthew LaPlante (01:00:58):

Yes, fundamentally changing what healthcare is gonna look like in this next part of the 21st century.

David Sinclair (01:01:03):

Well, it’s exciting. A lot of our health and our wellness is in our own hands now. We have the tools, we’ll have the knowledge to greatly lengthen our lifespan of those of our parents, our grandparents and our kids. And that’s in part what we’re gonna talk about in the next episode of Lifespan. If you’re enjoying this podcast and would like to support us, please subscribe on YouTube, Apple Podcasts and Spotify. On Apple, you have the opportunity to leave us up to a five-star review. Also check out the sponsors that we mentioned at the start of the episode. That’s probably the best way to support the show.


These sponsors not only make it possible for us to get this show to you at no cost, but they offer products and services that we truly believe in and we think that you’ll really enjoy. We also have a Patreon account. It’s at slash David Sinclair. And there you can support this show at any level that you’d like. Thank you again for joining us on this episode of the Lifespan Podcast.

Episode Info

In this episode of the Lifespan podcast, Dr. David Sinclair and co-host Matthew LaPlante dissect the topic of brain aging. They explore evidence suggesting that the brain ages more slowly than other parts of the body and highlight how cognitive function is impacted by aging. Different interventions aimed at preserving brain health are also discussed, including a plant-based diet, exercise, metformin, NAD boosters, and sufficient sleep.

Thank you to our sponsors:

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To stay up to date with David's work to democratize biological age testing and insights, visit


(00:00:00) Introducing Episode Seven: Aging of the Brain

(00:04:39) Thanking the Sponsors

(00:07:38) Ex-differentiation as a Driver of Aging

(00:09:22) The Brain Ages Slowly

(00:14:17) Cognitive Function and Plasticity

(00:17:44) Three Longevity Pathways: mTOR, AMPK, and Sirtuins

(00:23:26) Plant-based Diets and B-vitamins

(00:28:32) Homocysteine, Plaque, and Vasculature

(00:32:35) Fatty Acids

(00:35:48) Physical Activity

(00:39:14) Metformin

(00:46:02) NAD Boosters

(00:50:33) Increasing Blood Flor

(00:53:20) Sleep

(00:58:02) Overall Message: Keep your Brain Healthy

(00:58:50) Next Week’s Episode and the Future of Medicine

(01:01:21) Options for Subscription for Support

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

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

Title Card Photo Credit: Mike Blabac

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