Welcome to the Life Span 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 Polish, 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 I'm all episodes. So far at least five are at least. Yeah. Well, we just, I don't know. Just I'm enjoying. This is 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 back. I'm really terrified. Now. It like we're coming up on episode 8 and I'm not going to be here for season 2.
Well, we gonna do a season 2 No Doubt.
And I would not do this without you by my
side Rob. Can we make sure that that part of like that? I will not do this without you by my side. We really want to make sure that that gets
broadcast though. I've been known to change my mind.
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 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 all so healthy.
In their mind, I've 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, hard drugs
increasingly over the years. We've gotten better and better and better,
right? We're living longer, but 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.
In fact, it's so currently about 6.2.,
Million Americans, who are over the age of 65 or 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 the 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 that. There's a recent drug, that was approved, but it barely works and make some money different. So we have to make a breakthrough and what we're going to 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, but also that 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. Some nerve cells become.
Alexa consoles, there's another process that's important during aging that will touch upon and particularly about its reversibility and that's loss of blood flow.
And this is really important, because a lot of people, 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. These are, this is about
Making our mental, our intellectual lives better right
now. Well, the, the biological clock is ticking all the time. I'm not talking about a female's biological clock. If you've listened to previous episode, you know, we're talking about what's called the epigenetic or Horvath 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, just slow down that clock
before we can get to that, we've got to thank our
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Sinclair. 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, right? Well, you won't read a lot of this in textbooks. This is new
science. You won't even read the word X
differentiation. This is something that comes out of our work. Yeah, and 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. Is that there's actually a program that begins at Birth. What happens during birth and and prior to that is that sells gain an identity. We start as a stem cell that's fertilized and it gets the cells get different identities brains.
All skin cells liver cells everything. It 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. So from a genetic signalers, this called epigenetic that 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 for 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 what we can now do, instead of 20 songs, there's 20,000 genes and put the reader is the epigenome and overtime by that analogy aging is due to scrapped due to scratches on the CD. And you cannot read the right songs at the right time and a brain cell overtime 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 in the last episode. We said that
In 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
that the brain ages slower than the rest of the body.
Like significantly slower. Your brain is biologic. Very good chance that your brain is biologically younger than you are.
Well, thank goodness because it's the most important organ without a functioning brain. We're really quite
useless. So one of these
Dee's was lead. Actually a couple of these studies was led by your friend and sometimes collaborator Steve Horvath.
All right, before I get into Steve Horvath work on the cerebellum important stuff. Hmm. Let's talk about how that clock is actually measured because that will 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 your cells have their identity and play the right genes for the rest of your life. The problem is with aging that changes.
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 but you could look at the liver and you can see that the liver is actually 55, and you can look at the skin and say, oh, the livers actually 62 in equivalent numbers Horvath. And his associate looked at tissue samples from a hundred and twelve year old woman and they measure the clock and all these different parts of her body. And
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. Well, there's a practical in an evolutionary explanation for those the Practical one is that a brain is protected. There's a blood-brain barrier. It doesn't get hit by
Relied like our skin dogs of these big thick skulls. We're 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 two cells that don't divide including neurons. The nerve cells in our brain,
one thing to note is that cellular turnover is relatively low in the brain. So even though these
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. 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, we call it, but mostly those nerve cells are going to 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. 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 out living in some cases, our brain. The average onset of dementia is 80 years old, and in most
advanced Nations. Now, the average life span 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 other cognitive impairments. That's a terrible fate. That's something that we should all be working to
prevent. 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 a
Ding. We can keep the whole body young including the brain, which is really what we want to do. If you want to have maximal gains in longevity and health, and mental capacity, right up to the
end. And again, there's not, you know, 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 that too, that too because everybody suffers some cognitive decline. This is a little terrifying, the volume of the brain.
Rain, after the age of 40, reduces about five percent per decade. And that's got cognitive implications for all of us as we enter. What's, you know, that used to be called our middle years?
Well, yeah, I'm 52. I can already feel it happening. But I'm doing certain things in my life style. We're going to tell people about some of those things you can do to slow that process down and even reverse it later in
life. So a lot of people might think like, well, okay. What is, it doesn't make a lot of evolutionary sense that the brain starts.
To, you know, have struggles that 30 40 50, but for one thing for a
long period of our
history, people didn't actually lasts that long on general in
general. 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 eighty-year-old, same for women.
Well, and we didn't need a really super sophisticated executive functioning to survive. Even when we were in our 30s and 50s. What?
30s 40s and 50s. They like, if you made it that far, your life was going to be pretty much the same on Monday as it was on Sunday. And it was going to 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,
right? As we talked about, in the last episode, getting gray, losing your hair with 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.
You 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. And this is what we call a blastic environment and ever-changing environment. And that has implications in terms of how our brains develop and the plus plasticity that we need to respond to these changes over
time. Yeah. I watched my grandmother who passed away and we wrote about in life span. 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 I she's a very dear spot in my heart, what I saw happen to her as she got older was she should just shut down. She didn't care about life, but you also didn't care about change. And so she didn't worry about computers. She didn't bother learning how to use that. You didn't bother learning how to, to play a compact disc and the last 25 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, you know.
Covid-19 and the pandemic.
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 during the shutdown's during
the pandemic. Yeah. I was just at the Apple Store getting a new phone, just a couple of days ago and I was there as a lot of young people. But then in came an older person, she was probably 85 the way she looked in the way she
Wasn't walking that well, but you 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
grandmother link this to my smart Walker.
Yeah, exactly. And I find also in our generation. So you're in your forties. I'm in my 50s. We cannot slow down either. We can't say. All right. I'm just gonna deal with my compact disc or record collection. We have
Be Spotify to talk to our kids. We share files. But you know social media, if you need dates, you need to figure out that jobs job. The job markets, changing. Totally. We used to have one or two jobs in our lives. Now. We might have three jobs where mobile we work remotely and it's turning over all the time. That requires a brain that is highly highly adaptable.
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.
I'll Decline. And we don't suffer cognitive decline through the 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, you younger and healthier, you know, it's really about keeping the brain younger and healthier to that comes down to some of the same things that we've been talking about throughout this podcast. These three longevity Pathways.
Yeah. So those would have been with us will know that there are three main.
Buckets of longevity factors that respond to adversity and these have evolved have evolved to sense the environment. When times are tough, we call them adversity, memetics the turn on these. These three things are the buckets are mtor, which respond to low amounts of amino acids, particularly leucine, isoleucine valine. There's the am PK pathway and PK sensors, low energy, low glucose levels and makes more energy. More mitochondria, boost Danny D. And that's important for the third Group which are the sort of to ones that require any D and Vicky.
Can be activated by certain chemicals, importantly, they all work together. We'll talk about later, that sort of turns can activate a and Piqué and Piqué can activate sirtuins and mtor. What they do. Downstream is complicated. We're not going to 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. We dive a little into mtor going to talk mostly about
But there's there's a real key role that a play is in a topology.
Well it does. They all play a role in autophagy but mtor is the most potent. One mtor response to insulin signaling and fasting. And in response. It mobilizes proteins to be recycled and made into new proteins when you're 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 we get older, there are these misfolded proteins in the eye, they called life of huskins. And
Then into Alzheimer's are 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 Returns on those recycling Pathways, really effectively. We're not going to talk so much about that, though. We are going to 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.
And even though we're really mostly going to 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 talking to each other. And the reason we're going to 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 will cover both. And also what's important about the sort of tunes as opposed to these other two buckets is that the sirtuins respond to whole variety of environmental pseudo stresses. We call them adversity. Memetics. We
In to talk about food, talk about exercise and supplements. 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. There are several types of sirtuins, but one in particular, there's a couple that are important to brain. Aging one in particular is called
sirt1, right? So there are seven of these genes in every cell in our body. The brain makes a lot of sort 6 and sirt1, and over time the levels of
Both go down with aging as well as the fuel, that those enzymes need called NAD, all focus on sort one. Mostly because that's what seems to be the most important for controlling brain aging. Let's talk about the
role of sirtuins. When it comes to Aging
in the brain will remember, this clock is ticking away because the loops and the bundles of a DNA are getting messed up. The bundles become Loops 2 Loops are becoming bundles. We've linked the sort to instead that process what happens when a cell is
Over stressed over broken 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 red 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 this will to ins Russia way 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 re-established 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 point one percent never goes back and overtime accumulates, and these are the scratches that cause aging
and in order to mitigate that what we want to do is up regulate the sirtuins and we can do that through NAD
boosters, right? Well in the mouse and 2008. We published that just up, regulating sort one 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 even should slow down a mouse's brain age, but you can, 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 injection that will increase sort ones, activity. The ones we know of our Resveratrol and NAD boosters will talk about those in a second and then they give the the benefit of a good diet and exercise.
And in combination even
better. Well, let's talk about those things first. Let's talk about diet and exercise because that's got to be the sort of like the foundation on which we build all this of other stuff.
Well, absolutely. We've talked previously about the Mediterranean diet and one of the reasons is that it's very clear and over a dozen studies that a Mediterranean type diet. Protects the brain from aging and can even reverse aspects of Aging in the old Lee with mild cognitive
impairments. There's a study
Earlier, this year from a really large International research group is led by a Tomaso ballerini. It showed higher adherence to a healthy diet. In this case. The Mediterranean diet is associated with less amyloid-beta, lest our larger gray matter. Volume. If some of these words are sounding familiar it's because they're all associated with Alzheimer's disease
and there was a second study that I found fascinating. This one was by Anastasia Adele, 2017, and it was over 1,000, actually close to 2,000 people and there was a 10% reduction.
Dementia risk for people on the Mediterranean diet and the
actually 10% risk risk reduction for each Mediterranean diet score, which means the more Mediterranean your diet, the better you were
doing, right? And so that includes olive oil in the diet, red wine and not a lot of red meat. Yeah,
and not surprisingly. This is a research team from Greece there, really like the Mediterranean diet, for obvious
reasons it what, I want to get into later and hopefully
We will is, what is it in that diet, chemically? They can help the
brain. 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 it in that diet? Chemically that can help the
brain. 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 her want it.
The enzyme. It's like a pacman and it's controlling jeans and it works faster. So Resveratrol from red wine. It's clearly been shown to be beneficial and also prevents cancer and not just his metabolic and brain enhancing effects. The other component of Mediterranean diet, that works on sort one is olive oil. And Doug Masonic recently showed that if you add oleic acid, which is a major component of olive oil, to also found in 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 that a Pac-Man. Is this little puppet creature on another trying to game chop faster and there's probably other molecules. We talked previously in another episode. About Xeno hermetic, molecules plants, make these molecules to survive stress. And when we eat them, we get the benefits of that stress because we worry a bodies worried that our food supply might run out
one of the, the 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 got to work a little harder, to get everything that it needs that sending the signals that may be times aren't so great. And we need to activate these longevity
Pathways. Well, that that's the difference between a Mediterranean diet and a high-fat carnivores diet and a typical Western diet, they full with calories full with whole bunch of stuff. That tells the body times a 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
You want what you want to do, is to have the perception of adversity, and the Mediterranean diet as well as in Japan, that What's called the Okinawan diet, which has low levels of protein and mostly plant-based those to trick the body into thinking that the food supply sucks and could run out any minute and and
these 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,
right? Well, one of the first
I'm still worried about if you're just focusing on Plants only is a deficiency in folic acid. This is vitamin B12, Lola, the
supplementation that they give to pregnant women because they're often low in
folic acid. 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 + B3. We've talked about B, 3 as a early component that's building up that NAD for the sweet Tunes. So beef item ins especially for on a plant-based diet, but for everybody don't be deficient in these.
He's why? Because the B vitamins are one, are the ones that make sure you have the metals 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 a deficiency in the ability to methylate DNA and that will mess up your epigenome and very likely 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. It is the major
21. But also dementia in the 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 and the result of low, B. B vitamins, is an elevated level of homocysteine.
Well, that's a Marcus yet. Exactly. So 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
Would want you to have less than 10 Micro moles moles per liter. Some people go as high as 100. If you have that high, you're certainly going to 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 your menopause will also affect your homocysteine levels. Certain types of cancer will
And aging itself leads to increases in homocysteine,
and there's all
materializes as plaque. 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. This returns can't cope. So, that one's not good at going back to it. Came from and your body will get older. And when your body is older, 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. I think a lot of people think about elevated homocysteine.
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 well, yeah, it's knowing 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, they become stiff, and then they start to accumulate this cholesterol and then you get a Cluj ins and that that can ultimately end in a stroke. But even before that, those exclusions are limiting, the amount of oxygen, your brain gets leading to, of course, losing your ability to remember things even at
Age. But ultimately what's called? Vascular dementia.
There's a pretty simple way to monitor that. That
accumulation. Yeah. You just look in your eye. Well, you don't look in
your eye. It's really hard. I actually tried earlier.
Yeah, you a doctor. An ophthalmologist or even enough. Trish Trish in will look in there and have a look at the back of the eye, the retina, and they can see very clearly. 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.
Design, 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 exclusions and a lot of plaque you basically are going to suffer from heart attack and die. Pretty
soon. Do you have like a it's like a 15% chance of death within a year. And then it goes up from there in really scary measure.
Exactly in 1959. Dr. Robert Hall and Hast found that these plaques, these little Igloo conclusions. He could see in the
Actually, I 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.
That's really scary. So, obviously liked staying ahead of this. Not letting that accumulate at all, is preferential even to catching it
early, 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 Boulders. Drink. You told me that before and I
When you look at someone 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 plaque. There is building up inside your skull.
Let's talk also about fatty acids and the importance of really making sure that you're getting the right in 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
right, even with a normal diet you off.
Don't get enough of these omega-3 fatty acids, which are the types that we don't make ourselves. If you're only meeting, you don't eat fish 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
threes and these
Giving us the DHA and the EPA is because the three different kinds of these,
right? Well, there are lots, but the three main ones that people talk about our EPA and DHA. The EPA is the more important one. You want to get at least a gram of that. Sometimes people see, go 1.6, grams of this ratio of EPA, to DHA and women about one point three grams and that's been shown to greatly improve memory and counteract depression. Now that if you're a plant-based person, you can't obviously get as much. You have to focus on.
Types of food that have what's called Alpha linoleic acid or a la, which is converted slowly not efficiently by 10% of it. Gets converted by the body into the two types. We just mentioned that are important that the DHA and importantly, the EPA.
Focus then on flaxseed. Walnuts, chia seeds. That's where you get your EST. La linseed oil is where it was. First discovered a la linoleic acid. I use that to polish certain things are 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 avocado.
His and I have that included in my supplement every night along with these other components
as a recent convert to seaweed salads. I would be remiss not to know that you can actually get it. One of the few plant sources, you can get DHA. And EPA from is is from seaweed. Is that right? 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. So we know we should be consuming these Omega-3s, but why, what are they doing?
On ourselves.
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 actually wrapped with insulation tape or insulation insulating material and that's what these fats do. And these are membranes that wrap arounds 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, 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 of me. Can't think the exercise just affects us from here down. It
doesn't. 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 sirtuins this third, protective survival pathway. They can be activated. Of course, by this the food. And also by
exercise, we've seen this in a number of both human and animal
studies. 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 to do some
aerobic. 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? They had a cattle prod, no pushed onto the treadmill, something like that. I don't think it's
that highly regulated, but they do make sure they actually do the exercises.
So Blumenthal and his colleagues found. What was it 2019 that this greatly improved?
-
function executive function. Yeah, that's the function. That's like co-equal to the judicial and legislative function. 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. And so, 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.
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 because you will think better to 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's a study this year out of Brazil that showed the exercise had a really significant effect on Mouse models of Alzheimer's and
Parkinson.
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 our benefit 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.
Factors that grow new brain cells, you nerves. This micro is called, bdnf. Brain-derived neurotrophic factor and we use that as a way of indicating the youthfulness of the brain and regrowth of new nerve
cells. And the takeaway here, is that at a time, and many people's lives, when they're becoming less active. It's actually more important than ever before to become more active in the stay active
before. It's too late. It's very hard to get very elderly grandparent or parent to get on 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.
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 face these sorts of adversities all throughout their lives. And that's what we're trying to mimic through our diets. In our exercise. It still might not be enough because we do live these lives of incredible comfort and
We eat a lot of food. And 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. Well, yeah, there's crosstalk between these various defenses. The am PK pathway talks to the NAD, sirtuin pathway when you take Metformin.
And you get this mitochondrial, hormesis might hormesis, that will raise energy levels. It will stimulate the production of the enzyme that turns nmn, a precursor of NAD into NAD itself and raise energy levels and get the sirtuins active as well in the brain.
Okay, and we know that metformin is good for brain health from a variety of studies. When we want to start with today. Is this this fish study, which I did not know that they did cognitive studies on
fish fish or actually use 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 north of bronchus for Zuri that lives. Only a few months. There's one in this study. They used red tail know though, which is good theory. Not the bronchus Cantore and it comes from Zambia. It lives a bit longer. It's 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 lifecycle super quickly, but it's built of the same stuff that mice and we
are. And how do you tell that a fish is like having cognitive impairment or cognitive success?
So it sounds crazy measuring memory and 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 put them through mazes like a mouse. They swim through if they've got a good memory in, 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 asteroid 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 little bit bit of Metformin their food, those fish were able to
Remember those tasks much better as they got
older? And to the the Ted lasso, quote about being a goldfish and like immediately forgetting things. That's not true.
No Fischer have a really good memory actually. And they have brains that are quite similar to to mammals.
So when you give these fish, the metformin, what's happening in Libya,
cellularly molecular Lee, 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
Means 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. Might hormesis, 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.
Petit. The other thing that happens is that this signal sends a protein called gluten, for 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
high blood sugar is not good for brain
activity. 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
Sent five to ten percent can be covered in this glucose molecule. That's bad for their function is often hard to remove and it leads to dysfunction particularly of the
cardiovascular system. We're not just seeing Improvement in cognitive function with metformin and fish. There's been studies on mice, there's been studies on rats. There's been studies on humans.
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 Kearney and colleagues in 2017. A really good studies, randomized placebo-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's also means that if you're starting to lose focus in your job daily activities, either taking
Foreman may help or just keeping your glucose levels steady, which is what a lot of us do. And we measure that daily with with monitors on our arms that is also a way to stay
focused and that's a 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 took a really huge cohort of diabetic patients. Tens of thousands of them. Dementia incidents for the metformin users 55%
Lower. 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 five to ten percent decrease in disease, 55% a massive number that we should definitely pay attention to.
There's been some suggestion that metformin in addition to acting on ampk and then like, you know, then the chain of custody moves, its way down a name PK acts upon NAD, metformin actually might impact
NAD directly as
well. Yes, so that that study was super interesting from a few years ago that metformin could directly interact with bind to the enzyme and make that 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
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. Yeah. Why would you want to supplement an 80 in the first place? Well, it's known. Just like the rest of the body that in the brain. In a D levels go down for a couple of main reasons. One is that we don't make as much that nem PT enzyme that's activated by metformin and exercise goes down so you don't make as much but also it was shown by Jeffrey Mill, brand 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 are damaged called someone and it depletes the cell rapidly of any D. So what you've got is a decrease in the production of NAD. Also with an increase in the degradation of any D. 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, perfect diet, especially for the elderly. Who cannot always do those
things. And we've got a long history now. Research going back almost 20 years.
Years of NAD, supplementation on brain health. It was a study in 2004 that showed treatment with nadh slowed Alzheimer's. A lot of people hear about nad+ nadh, might be a little
unfamiliar. Nadh is basically NAD with and hydrogen atom attached to it nad+ has a positive charge like the end of a battery. And then if you stick the hydrogen ion to the vitamin B3, part of the NAD, then that's going to be called nadh and that's important in a Cell because that's the other major function of
And he d 1 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 hydrogen's and moves it from one place to another.
So why would any DEH work if nad+ is what what's the standard?
Well, what I think is going on here is that so NAD activates or two ins in a test tube and in the cell nadh actually has the opposite effect so you don't want high levels. So 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 just giving the components in a concentrated form by taking
nadh, another more, recent result, a combination of n r, which is another kind of NAD booster that we talked about a few episodes back and pterostilbene, slowed down the progression.
Of
ALS, so NR is different from any man. Let's go through that again. When you want to make NAD NAD, what the cell does? It takes vitamin B3 or nice or nicotinamide turns it into n r. So the nicotinamide gets now a sugar ribose and then to make an amen, it puts a phosphate, which is phosphorus and oxygen and then it combines that together to form any D. So those are the very steps. Now, what NR is it's a couple of steps back from NAD. And so when you take in are Italy, it's me.
It into any man-made into any D. But you can, it's been shown in humans by taking large doses about a gram of NR. You'll make any man you make higher levels of NAD, which is 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 Tara still being and the Terrace still being 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 or as
Troll plus an NAD. Booster.
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 Lindy guarantee 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 for patients who are dealing with a real.
Really, really debilitating
disease for which there is no cure or, 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 2, so they made it further than most, but of course is a very difficult disease. ALS Stephen Hawking is just a terrible debilitating disease, very hard to treat, but fingers crossed for this one. Hopefully those patients will continue to do better.
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 Improvement 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? Right. We forget about our brain needing blood flow and oxygen.
Generation because we don't really see, 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 sort one activity maintain the youthfulness and ability to grow new blood vessels in the mouse as muscle, but we collaborated with salt and I'm very at the University of Oklahoma to show that mice, even in their brains benefit from a demand, by building, new blood vessels and those elderly mice, not just had better.
Blood flow, but could think and remember things
better. And we think that's because of the Improvement and in vascular tissue.
Well, almost undoubtedly. That's what was going on in those mice because we could block the effect, get actually down, regulate the sort one, specifically, in those endothelial cells, that line blood vessels. And then the benefit of any man went away
and it's turns mice with older brains and two mice with younger brains.
That's essentially what happens when mice and people get their ability to learn again.
Reversing an aspect of Aging.
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
served. There are a few things. I want to mention about sort of one before we leave this topic. One. Is that overexpression turning up sort of one 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, sort, one 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
Is that sort one plays an amazingly important role. In delaying. Aging preventing diseases of Aging in a mouse and potentially even in a human will 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.
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. This, there's lots of research on this.
Yeah, even at the molecular,
A level, we understand that start one and NAD, play a fundamental role. In controlling your wake, sleep cycle, sort one in AD or 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 be mail, which is part of the clock, not the hover clock, but the daily clock the Circadian rhythm clock and those genes tell the liver to calm down until the brain to calm down and in the morning, tells everything to wake up again. And so, what is it really important to understand? Is, if you start to lose
Is the function of sort one and have low energy levels. You probably not going to sleep well, but also you're going to age
prematurely 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 exercise as we get older to promote brain
health. Yet 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.
And 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 Anna men, and women is going to raise any D 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.
There's a mother supplements that a lot of people take
magnesium. That's good for sleep. I'll theanine is another one that people try. I've used it teams to help me. But essentially, you just want to calm down at night. Don't do your emails too late, relax your brain.
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 to do right away. When you wake up,
you mean go outside but you got to get,
you got to get light, right? You 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. Well, you can and it 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 and like the other
things we've talked about today as lots, lots of research. We're not like, just
Making this up. Sleep is important. We know
this. Well, yeah, even in flies flies sleep. It's a little known fact, but there were before we get to the humans. I wanted, this is a really cute study. It was a study that was in 2020 and 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 rescued by treating them with an NAD
booster, which is also a way that we've seen that you can rescue human subjects from sleep deprivation, but
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, the night, but I can sleep. Well, the rest of the week, one night of sleep, deprivation, increases amyloid-beta, production by 5%, That's the you don't want to mess with Emma Lloyd beta,
right? Know that that will accumulate in your brains, 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.
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 tell what they found was that in people that had very little sleep. The risk of dying was 30% higher than those, that got her natural normal night. Sleep. Nothing is our
brains are getting so much adversity, right now, right? We talked about a little bit of adversity, being good, but we evolved to have a pretty low constant low level of
He 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. It's
just too much the 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.
The overall message today is we got to 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 illusionary history, which is to last longer than we have. We figured out many of the tricks that are going to Keep Us Alive for longer holistically, but we got to keep our brains healthy for at least one day longer than the rest of us laugh.
It's super important that we look after.
Brains. It's not just about ourselves 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 a particularly keeping our brains younger for
longer. In our next episode. We're going to be talking about a lot of the things that we sort of hinted at throughout the series so far in terms of what's coming.
Being next, maybe was 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 this there, if we get there
healthy. Well, it's a super exciting time though. 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 are being made and the kind of results that are in the lab and
Like going to customers consumers and eventually to patients in hospitals and at home with medicines will be directed towards the lengthening. Life span not just by one or two years but by decades and I can see that coming. We're going to 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 by potentially by
decades. One of the things that I noticed and you 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 at 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 going to say these are kind of far down the line, who knows? They could be here next
Tuesday, 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 going to 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 has happened, thanks to the pandemic. Is that home remedies and home testing has taken off. There are things we can now do at home that were Beyond even the imagination when we wrote the
book. Yes. Fundamentally changing.
What Healthcare is going to look like in this next part of the 21st
century? Well, it's exciting a lot of our health and our Wellness is in our own hands. Now, we have the tools. We will 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 going to 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.
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 patreon.com 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.
