Nutrigenomics, Epigenetics, and Stress Tolerance (IHMC Talk #1)

Well, we're going to talk about quite a few things this evening. As Ken mentioned, my name is Rhonda Patrick, and I plan on discussing a few things with you, including how micronutrients interact with your genes. and this is known as nutrigenomics. How your diet and your lifestyle can change the expression of your genes, this is known as epigenetics. And how we can use this information to design a lifestyle strategy that allows us to become more resilient to the stresses of aging. So this is a snapshot of some of the biochemical pathways in your body. And we're going to go through each and every one of these this evening. Just kidding. But we will go through a few of these pathways these pathways are generating energy in your cells, and energy in all various cells in your body.

Energy is required to maintain immune function, it's required for your immune cells to fight off viruses, fight off bacteria, to fight off cancer cells. It's required for the neurons in your brain to learn and process new information. Well, these biochemical pathways largely are run by something called enzymes. Enzymes. And enzymes are specialized proteins that can convert the food that we eat into energy so that our cells can use them. Many enzymes in the body require micronutrients as cofactors. In fact, 22% of all the genes that encode for enzymes require a micronutrient as a cofactor. What that means is they require it to function properly. So without micronutrients, the enzymes don't work properly. They work suboptimally.

So micronutrients are about 30 to 40 essential vitamins, minerals, amino acids, fatty acids that we must get from our diet. And we have to get these from our diet because our bodies don't make them. So you may have heard of the RDA, Recommended Daily Allowances, for a variety of vitamins and minerals. Well, these RDAs are set to ensure that we have adequate levels of these micronutrients. But these RDAs are set on the normal population. However, we're all different. Gene polymorphisms refer to alternative forms of genes. And single nucleotide polymorphisms change just one nucleotide in DNA, and that can alter the function of a gene in a good or in a bad way. So gene polymorphisms are different from mutations because they occur in a sizable percentage of the population.

And mutations occur randomly, but still occur in a, you know, you still can get some mutations that occur, you know, more common than others. And so polymorphisms make us members of a certain group. For example, people that have blue eyes versus brown eyes, or blonde hair versus brown hair. Well, gene polymorphisms also affect disease risk. like cancer incidence and Alzheimer's disease. They affect the way our body metabolizes micronutrients and absorbs certain micronutrients. And we can actually test for a variety of very common gene polymorphisms. There's some common tools out there that are available to do this, including 23andMe genetic tests, which allows you to test for gene polymorphisms that are common to see which ones you have.

And there's other tools available like Promethease that allows you to interpret some of that data. You don't have to write that down. I'll get to that again at the end of this talk. Okay. But the thing to keep in mind is that these gene polymorphisms, even if there's a bad function associated with it, oftentimes you'll often find there's also a good function associated with it. And that's because these polymorphisms are thought to have been selected for, for a reason. Nutrition, for example, is thought to have selected for certain polymorphisms because people lived in different parts of the country, they had, you know, different minerals in the soil, access to different types of food, etc. So let's talk about some gene polymorphisms, but first I want to show you your mitochondria.

So these mitochondria are generating all the energy inside of your cells, and they require many B vitamins. So the enzymes in these mitochondria require B vitamins as cofactors, like I mentioned. Many enzymes require cofactors to function properly. Well, your mitochondria are generating energy from the food you eat, and in order to do that, they also require certain— B vitamins. vitamins in order to do that properly. So I'll give you an example. This is ornithine aminotransferase. It's an enzyme inside of your mitochondria. Ornithine aminotransferase requires vitamin B6 to work properly. It converts ornithine into proline. And all that is, is it's basically a way of getting rid of excess nitrogen in your body, so when you're processing protein.

There's a certain mutation, which is different from a polymorphism because a mutation doesn't occur in more than 1% of the population. There's a mutation that exists that people have in the gene that encodes for this enzyme that changes the way it interacts with vitamin B6 so that it can't bind to vitamin B6. So it doesn't work very well. And what happens is ornithine builds up inside the mitochondria. And that leads to progressive blindness because it leads to atrophy of the retina in the eye. However, it's been shown that taking very, very high doses of vitamin B6 can overcome that deficit and can interact with that enzyme again and can convert the ornithine into the proline so you don't have a buildup in ornithine, and that prevents the progressive blindness. That's a mutation.

Let's talk about a polymorphism. So polymorphisms occur in at least 1% of the population. There is a couple of very common polymorphisms in the vitamin D pathway. So vitamin D gets converted into a steroid hormone that regulates the expression of over 1,000 different genes in the body. So if you think about that, that's roughly 5% of all the protein-encoding genes in the body, which is pretty significant. So vitamin D gets converted into the steroid hormone, but first it gets converted into something called 25-hydroxyvitamin D in the liver by an enzyme called CYP2R1. And then the 25-hydroxyvitamin D gets converted into the active steroid hormone in the kidneys.

Well, there's a couple of common polymorphisms in the gene that encodes for CYP2R1 that changes the function of this enzyme so it can't convert vitamin D3 into 25-hydroxy vitamin D very well. And what this means is that people with this polymorphism, it's actually pretty common, I've already met a couple of people that have this polymorphism, they have lower circulating levels of 25-hydroxy vitamin D. And studies have been published that have shown that in addition to having lower circulating levels of 25-hydroxy vitamin D, they also have a higher all-cause mortality. which means they die earlier of all different types of age-related diseases like cancer and cardiovascular disease and stroke, which is not surprising because vitamin D is a hormone and it's regulating 5% of the human genome.

It's doing some important things. So how do you know if you have this gene polymorphism? Well, 23andMe, which I'll talk about again later, helps you identify whether or not you have this specific polymorphism associated with this CYP2R1, but also you can get your vitamin D levels measured. So generally speaking, vitamin D deficiency is considered to be— have 25-hydroxy vitamin D levels below 20 nanograms per milliliter. Inadequacy is considered to be below 30 nanograms per milliliter, and adequacy is considered to be between 30 and 60 nanograms per milliliter. And studies have shown that people that have vitamin D levels between 40 and 60 nanograms per milliliter have the lowest all-cause mortality.

They have the lowest incidence of cancer, cardiovascular disease, stroke, and they have the longest telomeres, which we'll get to a little bit later. About 1,000 IUs of vitamin D a day can raise serum levels of 25-hydroxyvitamin D by around 5 nanograms per milliliter. That's in people that don't have this gene polymorphism. People that have this polymorphism may require much higher doses of vitamin D, and the only way to know that is to test and get your levels measured. Okay. I'm not gonna spend all night talking about vitamin D, but I do wanna talk about it for a couple more minutes because it's very important and because I just published a couple of papers on it. So there are a variety of factors that regulate vitamin D levels in your body because the sun is the primary source of it.

Anything that blocks out UVB radiation can also inhibit your skin from producing vitamin D. So sunscreen, melanin, age, those all decrease the ability of your skin to make vitamin D. Living in a northern latitude, because UVB doesn't— rays don't get to the atmosphere during many months out of the year, People that are living in really northern latitudes— that's not a problem here in Pensacola— also are not making enough vitamin D in their skin. And body fat also regulates vitamin D levels. So because vitamin D is fat soluble, it acts as a sink for vitamin D. And so less vitamin D is bioavailable to be released into the bloodstream and get converted into the active hormone. So vitamin D does regulate the aging process. These mice here are the same age.

The mouse on the left has had its vitamin D receptor just wiped out, which means it can't respond to vitamin D at all. So it's almost like there's just no vitamin D in the mouse. The mouse on the right has had normal levels of vitamin D, it's just a normal mouse. Well, these are the same animals 4 months later. So vitamin D receptor deficient mouse has a premature aging phenotype, which is not too surprising because vitamin D is regulating about 5% of the protein encoding human genome. So it's regulating many, many different processes, many of them involved in aging. And I'll talk about a couple of those a little bit later.

Not only is it important for aging, but I published a paper last year where I found that vitamin D increases the amount of a gene that's made in your brain that produces an enzyme called tryptophan hydroxylase 2. And this enzyme converts tryptophan into serotonin. And most of you may be familiar with serotonin as being a neurotransmitter that regulates mood. Well, actually, it does much more than that. During early brain development, serotonin is known as a brain morphogen because it shapes the structure and the wiring of the brain. And when you have low serotonin during early brain development, you get abnormal structure and wiring of the brain, and you also can get— Brain damage. Behaviors that are very similar to autism.

So because the developing fetus depends on the mother's levels of vitamin D, the maternal levels of vitamin D, it may be that low maternal levels of vitamin D leads to low serotonin in the developing fetal brain, and that can then lead to abnormal structure and possibly autistic-like behaviors, particularly in combination with other gene polymorphisms that increase autism risk.

I published a paper last month which was a follow-up of that study where I elaborate a little bit more on the other functions of serotonin including its role in social behavior, in impulse control, in executive function and decision-making, particularly in long-term planning, in aggression, anxiety, and memory, and how many of these cognitive functions and behaviors are aberrant in neurodevelopmental and neuropsychiatric disorders like autism, ADHD, bipolar disorder, schizophrenia, and how low vitamin D during both brain development and throughout life, particularly in combination with other types of trauma and stress and other gene polymorphisms that predispose individuals to these neuropsychiatric and neurodevelopmental disorders, may precipitate brain dysfunction and mental illness.

So vitamin D is very important. Of course, you don't want too much vitamin D. Because too much vitamin D can also be toxic. Having levels above 60 nanograms per milliliter is associated with also a higher all-cause mortality. So you wanna have that sweet spot between 40 and 60 nanograms per milliliter. So why is this relevant? Well, 70% of the population in the United States according to our last survey doesn't have adequate levels of vitamin D. So what do you do? You get a blood test and you make sure you have adequate levels of vitamin D. There are common gene polymorphism— polymorphisms in the folate metabolism pathway. So folate is found in dark green leafy vegetables like spinach and kale. And it serves 2 very important functions inside the body.

First, it gets converted into 5,10-methylene tetrahydrofolate. And that serves as a precursor for thymine, which is a DNA nucleotide, which is needed to make new DNA. And when do you make new DNA? You make new DNA every time you make a new cell. So every time you're making a new sperm cell, if you're a guy, and it's happening all the time, anytime you're making a new liver cell, you need DNA, which means you need folate. So folate's very important for that. The other thing it's very important for is for making something called 5-methylfolate, which is an important methyl donor to convert homocysteine into methionine. And to— so homocysteine gets methylated and then it's converted into methionine. Right.

And this methionine then has this methyl group sticking off which ultimately serves as a source for epigenetics, which we'll get to in a minute. There are a cluster of very common gene polymorphisms in a gene that encodes for an enzyme called MTHFR. And MTHFR is the enzyme that's necessary to convert the precursor, the folate, into 5-methylfolate. And people with these, there's a whole cluster of them, it's very, very common. And people with this cluster of polymorphisms have reduced capacity to do that anywhere between 30% to 90%. So they basically have— this leads to high levels of homocysteine because they're unable to convert the folate into the methylfolate and therefore they're unable to convert homocysteine into methionine.

Now these polymorphisms are so common that my mother has a very severe form and my mother-in-law who's here this evening. has a very severe form of it. They both have to supplement with something called L-methylfolate. It has a variety of different names, but L-methylfolate in a combination with other B vitamins can overcome that deficiency because you don't need to get the folate converted into it. It's already in that form. And studies have shown that people that supplement with this form can lower their homocysteine levels and can then reconvert homocysteine to methionine, and then this is you know, our epigenetic precursor. So the 23andMe that I mentioned earlier, this genetic test allows people to test for these common polymorphisms.

That's how I found out my mother had it, and my mother-in-law found out she also had it. So there's a lot of— there's other consumer-available tools out there that also allow you to test for these common polymorphisms. You can get your homocysteine levels measured. If it's really high, that may be a warning sign. But I want to talk a little bit about the epigenetics. And why that's important. So epigenetics refers to changes in gene expression without actually altering the DNA nucleotide sequence. That's very different than the polymorphism. Polymorphism altered the DNA nucleotide sequence. Epigenetics does not do that. What epigenetics does is it has these factors like the methyl groups that are generated from the folate metabolism pathway.

You also generate them from another pathway involving choline, we're not going to talk about that this evening, and also acetyl groups which are generated from normal energy metabolism whether you're metabolizing glucose or fatty acids, you generate acetyl groups. These methyl groups and acetyl groups, I call them epigenetic factors, they sit on top of your DNA and they'll turn a gene on and when the gene is turned on, the gene is active, it's doing a function, it's doing what its function is and it's doing it more often. And it can also turn a gene off. So it can, you know, even though the gene is there, the gene is not doing its function, so it's almost like it's not there. And we usually call this expression. Genes being expressed are active, they're doing a function.

The genes that are not expressed are not active, they're not doing a function. And what's really interesting about these epigenetic factors is they're regulated by our diet, by how much B vitamins we take, by how much we eat, by how little we eat, by how stressed we are, by how much sleep we get, how much exercise we do. They all change the patterns of these epigenetic factors. And what's really interesting is that we can pass these epigenetic factors on to our children and to our grandchildren. So these epigenetic factors will hitchhike onto your DNA, your sperm and your egg DNA, and they'll get passed on to your children and grandchildren. So in some cases, your bad lifestyle can affect your children and grandchildren. I'll give you an example of that. Okay.

So researchers have done multiple iterations of this study, but this is a male mouse. And as you can tell, he's a little bit obese. The reason he's obese is because researchers have been giving him a diet that mostly consists of corn oil, which causes— it's a high-inflammatory diet. So this little dude's been eating a diet that's mostly consisting of corn oil. He becomes fat and he also gets type 2 diabetes, which isn't that surprising. But what was really interesting is that this male mouse has offspring, female offspring, that were fed a normal diet. So they were not fed a high corn oil diet, but the female offspring— so they were thin, but the female offspring grew up and they got type 1 diabetes.

And the reason they got type 1 diabetes is because the high corn oil diet in the male mouse, it silenced a gene in the sperm DNA that's involved in producing insulin in the pancreatic islet cells. And that was passed on to the daughter. And so she then, the offspring, had trouble then producing insulin because that gene that's supposed to help produce insulin was silenced. So what about good factors that are passed on? So this is a classic study that was done at Duke University. So Duke researchers took these female mice that have yellow fur. And having yellow fur when you're a mouse is not a good thing because the gene that encodes for the yellow fur also predisposes these animals to obesity. As you can see here, she's quite obese. To type 2 diabetes and to cancer.

So these mice really have it bad. When they have the yellow fur, the gene that encodes for that yellow fur really makes them have a terrible outcome in terms of their life. So So what researchers at Duke did is they fed these female mice a diet that was high in B vitamins. So they gave them supplemental folic acid and supplemental vitamin B12 a few weeks before they became pregnant. And what they found was that these female mice had offspring that no longer had yellow fur. They were no longer predisposed to diabetes— type 2 diabetes or to cancer or obesity. And the reason for that is because the high B vitamin diet generated methyl groups that silenced the gene in the egg DNA in these female mice and turned off that gene.

It's called the agouti gene that makes these animals have yellow fur. So even though these, you know, the offspring doesn't have any yellow fur, they still have the gene. They still have the gene that's bad, but they turned it off. They turned it off because of the methylation groups that were able to turn off the gene. Okay. What's also really, really interesting about epigenetics is that these methylation patterns and these acetylation patterns, mostly methylation patterns, they follow a distinct pattern with age. So at UCLA, researchers have gathered over 22,000 samples from blood, from saliva, and other tissues. And they've looked, using machine learning, they've looked at these methylation patterns in people ranging age from 19 to age 101.

And what they found is that there's a certain pattern of this epigenetics that follows a distinct pattern with age. And it's so accurate that researchers can take blood cells from an individual, look at this pattern, and identify a person's age with 96% accuracy, plus or minus 4 years, which is pretty good, without knowing their age. So it really suggests that these This epigenetic pattern may be a biomarker for aging, much like telomere length is, which we'll talk about in a little bit. So, in addition to the changes in epigenetic factors with age, there's also changes in the expression of genes with age, which makes sense because, as I mentioned, epigenetics regulates how genes are expressed, so you'd expect them both to change with age.

And we can actually measure gene expression by doing something called gene profile analysis. So this is an example of a microarray, and every little rectangle on this microarray represents a gene. And a gene that is indicated in red, that gene is turned on, so it's active, it's doing a function more readily, and it's being expressed. The gene that— genes that are indicated in green, those genes are not active, they're being silenced. So the gene is still there, but it's just not active. So it's almost like it's not there. We know that changes in gene expression occur with age. And they also change with a diet. We can take certain— make certain dietary changes and change that pattern of gene expression. Certain lifestyle changes can change that pattern of gene expression.

So what is it that's changing? Where are these changes occurring in the human genome? So we know that these methylation patterns are clustering around genes involved in DNA repair. And they're turning these genes off. DNA repair is very important because it repairs damage that's done to the DNA to prevent mutations from occurring. We also know they're occurring around genes that are involved in stem cell function. So they're decreasing the activity of genes involved in stem cell function, which is a bad thing because stem cells are really important for replenishing a cellular population in a certain tissue. For example, our white blood cells. We need to keep making more white blood cells.

As we age, we don't make as many white blood cells, therefore can't fight off infections as well as we did when we were younger, fight off cancer as well. But we have hematopoietic stem cells in our bone marrow that can generate more white blood cells, which is really important. So you want to actually increase stem cell function— genes that are involved in stem cell function with age. They also make more stem cells. These epigenetic factors are also clustering around genes involved in metabolism, genes that are related to antioxidant activity, also stress resistance in general, and Alzheimer's disease and cancer. So we know that these epigenetic factors are clustering around these genes. These genes are also turned off as we age as well.

So the question is, is there anything we can do to slow these changes in epigenetics as we age? So there's one paradigm— 2 paradigms, but limiting food intake in general has been associated with increasing lifespan in a variety of different species, in worms and flies and mice. Yeah. dogs and monkeys. And there's 2 paradigms that can be done to limit food intake. One is called caloric restriction. And this is where generally you eat 30% less food than you would normally eat while still maintaining all your adequate micronutrient intake. So you still need to get all your vitamins and minerals and essential fatty acids. That's important. The second paradigm is called intermittent fasting.

And this involves a variety of different protocols including alternate-day fasting, I've seen 16-hour fasting, 8-hour fasting, or 48-hour fasting protocols. There's a lot of overlap between these 2 paradigms for limiting food intake. I think intermittent fasting is a lot easier for people to do. They change gene expression in the opposite way that epigenetic aging does. They actually activate all those good genes. We'll talk about that in a minute. But there's also some differences between the 2. I end up sometimes just following an intermittent fasting protocol like where I'm not eating for 8 hours or, you know, I don't eat for 8 hours and it just happens because I'm busy. So I think that intermittent fasting is a lot easier for people to try if they're gonna try limiting food intake.

So for an example, these monkeys here are the same age. The monkey on the left has had unlimited access to food. So it's been allowed to eat as much as it wants to eat at all times during the day. The monkey on the right has had 30% less food throughout its life while still maintaining adequate micronutrients. So they were given supplemental vitamins and minerals to make sure they had enough micronutrients. I mean, clearly the monkey on the right looks much younger. I mean, that's a no-brainer. But we know that those monkeys also had less cancer incidence, they had less cardiovascular disease incidence, they had better glucose metabolism, they had less brain atrophy. So they were aging better, they were getting diseases less frequently than their well-fed counterparts.

We also know that those animals were not— there was no negative effects associated with limiting food. Their steroid hormone levels were normal. Their reproductive organs were working normally. You know, when you're limiting food, there's a window that you wanna limit your food intake. You don't wanna do it too much where you start to mess around with your hormones, your thyroid hormone, and things like that. So, So 30% less food seems to be within that sweet spot. So what is it about the caloric restriction and the intermittent fasting that allows these monkeys, these mice, and worms, and flies, and not to age better? We know one thing it does is it activates a global epigenetic program, and that program is known as SIRT1. So you may have heard sirtuin-1.

And that program is activated when— during the fasting state, when you're fasting. And the reason for that is because it senses what's called NAD levels. And NAD is a cofactor for many, many different metabolic enzymes. All those reactions I showed you in the first slide, lots and lots of them require NAD. So anytime you eat, whether you're talking about fat or talking about carbohydrates, you use up NAD and you use it up because it's needed as a cofactor for enzymes. to work. So NAD levels drop. But when you're fasting, those NAD levels build up and that serves as a molecular switch on for sirtuin.

And sirtuin-1 is a global regulator of epigenetics and the reason for that is because SIRT1 binds to these acetyl groups, which are epigenetic factors that sit on top of histones, which are how— it's how your DNA is wound up inside your cell. is a protein-DNA complex. And they remove these acetyl groups, and this changes gene expression in, you know, hundreds of genes. There's lots of different things going on here. So sirtuin then activates one important gene that's involved in longevity that's called FOXO3. And FOXO3 is called the longevity gene for a variety of reasons. So what is FOXO3 doing? Well, FOXO3 is a master regulator of a lot of genes also. So when FOXO3 gets activated, it's activating all these other genes as well.

It's activating genes that are involved in DNA repair, the same ones that are going off when you're aging. FOXO3 is turning those on. So DNA damage happens, it's happening right now to you and I, it's happening just from normal metabolism. Anytime you eat food, you have to convert it into energy, it creates reactive products that can react with your DNA and damage it. And when you damage your DNA and if you don't repair it, This damage also happens, by the way, from normal immune function. So just normal immune activation creates this, a similar type of reactive product that damages DNA. So this is happening all the time. Our immune cells are getting active, they're active right now, we're metabolizing, so we're getting DNA damage all the time.

If it's not repaired, this may lead to a mutation, and the mutation can occur in a random part of the genome that may lead to cancer. So you don't wanna get mutations. Repairing that damage is important because it leads to— it prevents mutations from occurring. FOXO3 activates those genes. In addition, FOXO3 activates genes that are involved in making sure a cell that has been damaged dies. It's like, okay, well, if you got this damage, I can't repair it, I don't want it to live because I don't want it to give me a mutation that could cause cancer, I want it to die. So FOXO3 activates some of those genes and that's part of the way it can protect against cancer. So FOXO3 is activating those really good genes.

In addition, FOXO3 is activating genes that are involved in keeping your protein— proteins inside your body having the right 3-dimensional structure. So proteins are doing everything in your cell. You can think of DNA as the blueprint. DNA makes RNA, RNA makes proteins, proteins are doing everything. So these proteins have a certain 3-dimensional structure, and that 3-dimensional structure is essential for their function. But proteins also get damaged. They're susceptible to the same type of damage your DNA is, the damage that you and I are making every day. And that's just talking about normal living. I'm not talking about smoking and all the external things that can also play a role in causing DNA damage.

So what happens when a protein gets damaged is the 3-dimensional structure of that protein is messed up. And when that 3-dimensional structure gets messed up, what happens is that protein can't function properly, which is in and of itself a bad thing. But what also happens is then it can start to aggregate with other proteins, that are not folded and don't have their proper 3-dimensional structure. And that leads to little aggregates. An aggregation of protein can mess up the way a cell functions. Aggregated proteins are associated with a variety of neurodegenerative diseases. Alzheimer's disease, Parkinson's disease, Huntington's disease are all associated with aggregated proteins.

So FOXO3 turns on genes that once you have a protein that's damaged, it fixes it, so it repairs that protein to make sure it has its proper 3-dimensional structure. So that's really important because that also decreases with age. In addition, FOXO3 turns on genes that are involved in general stress resistance, the same genes that get turned off with aging. And so the same damage that can affect your DNA, the same damage that affects proteins in your cell, also affects your cell in general. And when you have a damaged cell, it can lead to what's called senescence.

So the cell is damaged, but it doesn't die, and so it just hangs around and it just stays there, and it's not doing anything except for secreting pro-inflammatory cytokines and molecules and all these bad factors that start to damage other cells. And it's like this vicious cycle where your senescent cell secretes bad stuff, that then affects the other cells and it just keeps going. So what FOXO3 does is it increases the expression of genes that are involved in preventing that damage from ever hitting the cell, and these are antioxidant genes. And these genes are called antioxidant genes not because they're activated by antioxidants that you eat in your diet, but because they serve a function that's very similar, although it's still different.

Antioxidant genes are very, very important and they trump any dietary antioxidants that you might be taking. So FOXO3 increases the expression of those antioxidant genes. In addition, let's say you already have a cell that's damaged, what do you do? Well, FOXO3 increases genes that make something called autophagy happen. Autophagy is when the cell eats itself. So the cell is damaged, it's like, well, I don't want to be sitting around here doing all this damage to other cells, so I need to— Eat itself. Sacrifice myself, eat myself, and, you know, generates energy in the process. So autophagy is a really important way to get rid of damaged cells, and FOXO3 increases the expression of those genes.

In fact, autophagy was just shown recently by UCLA researchers to be increased with intermittent fasting. So intermittent fasting for 48 hours takes damaged white blood cells and gets rid of those damaged white blood cells through autophagy, and causes hematopoietic stem cells in the bone marrow to make more white blood cells to replace those, and it caused hematopoietic stem cells to make more hematopoietic stem cells. So it's a really good thing. FOXO3 is indeed associated with longevity. In fact, polymorphisms that are associated— humans that have polymorphisms that are associated with making more FOXO3 have about a 2.7 chance of living to be 100, so living to be a centenarian. In fact, my mother-in-law has this polymorphism and so does my husband.

So they're both— I don't have this wonderful polymorphism, but they do, and so they might outlive me. Also, worms that are genetically engineered to make more of the worm equivalent of FOXO3 can increase their lifespan by up to 100%. So you can take a worm and it can go from living 15 days to living up to 30 days. So it's pretty significant. In mice, you can give mice more FOXO and it can extend its lifespan by 30%. So FOXO3 is indeed associated with longevity. It's activated by intermittent fasting, caloric restriction. It's activated by SIRT1. And also it's activated by other dietary factors. EGCG, which is found in green and white tea, activates FOXO3. So does quercetin, which is found in yellow onions. Wow. In addition, heat stress, as in using the sauna, also activates FOXO3.

In addition to heat stress— sorry, in addition to FOXO3, heat stress also activates something called heat shock proteins. So it activates the expression of genes that make heat shock proteins, HSPs. And those are the proteins that help proteins that are misfolded and damaged So it's the same ones I just mentioned earlier that decrease with age. FOXO3 activates. Well, heat stress also activates it. Recently, very recently, a study came out of Finland showing that men that use the sauna 2 to 3 times a week had a 24% lower all-cause mortality, including lower cardiovascular incidence, lower cancer incidence, and stroke. And men that use the sauna even more frequently, so 4 to 7 times a week, had a 40% reduction in all-cause mortality.

So the sauna has been linked to longevity, I think through FOXO3 and heat shock proteins. Also, worms and flies that are given a brief exposure to heat shock can increase their lifespan by 15%. So, you know, the sauna— I love to get in the sauna, but heat stress also occurs when you exercise. When you exercise, you get hot, you increase your core body temperature. So there's a lot of similarities that happen between heat stress from using something like the sauna and the heat you're producing when you exercise. And it just so happens that exercise and heat stress both increase the expression of genes that make something called neurotrophic factors. Neurotrophic factors allow for new neurons in your brain to grow. So this is called neurogenesis.

So it increases the growth of new neurons in your brain. Wow. Both exercise and heat stress and intermittent fasting, caloric restriction, have all been shown to activate these same genes that produce neurotrophic factors. In fact, a study showed that exercising just 4 hours a week was associated with increased neurogenesis in the hippocampal region of the brain, what's the part of the brain that's involved in learning and memory. So that's a great thing. Well, telomeres are also regulated by different environmental and lifestyle factors. and by epigenetics. So telomeres are tiny little caps at the end of your chromosomes. So every cell in your body has chromosomes, and these chromosomes contain your DNA.

Well, telomeres are tiny caps at the end of your chromosomes that protect your DNA from that same damage that I was talking about. And they protect your DNA from unwinding, so they protect— they're like the guardians of your DNA. So every time a cell divides in your body, it has to replicate all the DNA inside the cell, including the telomere DNA. And there's a little structural defect at the end of the telomere DNA that doesn't allow the DNA machinery that copies it to copy it. So a little piece of that DNA doesn't get copied. And that means that the next cell is gonna have just a little bit less of that telomere because it couldn't copy that end. So every time your cell divides, you have a little bit shorter telomeres. And that's why telomere length is often associated with aging.

Because as you age and your cells are dividing and you're making more cells, your telomeres get shorter and shorter and shorter. Till eventually there's no telomere left. And when that happens, the cell goes into a crisis. What do I do? What do I do? Well, a couple of things it does, and there's other factors that are in that little cell environment that can determine what happens, but what can happen is the cell just dies. And if that happens in a stem cell, that's not a great thing because you want to keep your stem cells, especially when you're aging. The other thing that happens is it becomes senescent. So that same thing that I mentioned earlier, the cell just sits around and it secretes this pro-inflammatory stuff that then damages other cells, so senescent cells aren't great either.

The other thing it can do is it can reactivate this program that's usually not active, that can make it immortal by giving it telomeres again. And if the cell is damaged, that's not a good thing because now you're giving a damaged cell immortality, which means you can lead to cancer. So telomere length is often associated with aging. The longer the telomeres, the younger. The shorter the telomeres, the older. Well, there's also other factors that can accelerate that telomere shortening and things that can slow it down. stave it off. So vitamin D and omega-3 both have been associated with staving off telomere attrition, so they slow telomeres from shortening. And the way they do that is because they lower DNA damage and inflammation.

So vitamin D activates genes that are involved in DNA repair, it activates genes that are anti-inflammatory, omega-3 is anti-inflammatory, it makes sense. The telomeres, because they're trying to protect your DNA, they're hotspots for DNA damage. Right. Because they don't want your DNA to get a mutation, they soak it up, they take the hit. But that means that the telomeres are going to get even shorter than they already would from that problem I mentioned. So anything that lowers DNA damage, that lowers inflammation, is also going to prevent your telomeres from shortening more quickly.

A study that was done in a couple thousand twins, they looked at vitamin D levels in the twins, and they found that those twins with the highest vitamin D levels compared to the lowest had telomeres that are associated— so the ones that had the lowest vitamin D had telomeres that were 5 years older looking than their twins that were chronologically the same age. So you can affect the way your cells age by your diet, by your lifestyle, and so you can look biologically older or younger than your chronological age. Exercise also slows the attrition of telomeres. These women right here are actually really, really old. You wouldn't know that because they run a lot.

But— no, seriously, but exercise also is, you know, lowers inflammation and so— and it also is changing the expression of, you know, good genes as well. So in another study that was also done in twins, it was found that those twins that exercised the most vigorously compared to those that were the most sedentary had telomeres that looked 10 years biologically younger. So exercise is a good thing, you're activating FOXO, you're activating heat shock proteins, neurogenesis, and you're keeping your telomeres longer for a longer period of time. Meditation also increases telomere length.

The way meditation increases telomere length is a little different because meditation can activate the expression of a gene that makes an enzyme called telomerase, and telomerase can actually rebuild your short telomeres. And you'd think, well, that's a great thing, but see, telomerase is not active in most of your cells, with the exception of your stem cells and your reproductive cells. And there's a reason for that, because telomerase, because it can help the cell become immortal by making the telomeres long, it can also help a cell that has a bunch of damage become immortal. So you don't want cells, you know, to just have a ton of telomerase all the time, But still, activating telomerase by meditation can be a good thing if you don't have a lot of damaged cells.

So people that are meditating probably are also having— have a good diet and lifestyle, so. Poor sleep accelerates telomere attrition. So in a study that was done in men, men that had less than 5 hours of sleep had telomeres that were 6% shorter than men that had at least 8 hours of sleep a night, which is not surprising because when we sleep is when we repair damage. So when we sleep, one of the ways we repair damage is by activating melatonin. So melatonin is produced in the pineal gland, which is a small endocrine gland close to the brain, and it produces melatonin when we sleep because it's inhibited by blue light. So we make more of it when we're sleeping. And melatonin actually activates and regulates genes, over 500 different genes.

So that's half as many as vitamin D. It's still doing a lot of really important things. It's activating genes that are involved in repair. It's activating genes that are involved in antioxidant function, like I mentioned. And so it's really important, you know, when you're sleeping, you repair a lot of the damage that you accumulate throughout the day. It's also decreasing genes that are involved in cancer metastasis. It's been linked to decreasing cancer metastasis and incidence in a variety of studies. In fact, A really interesting tidbit of information is that people that are blind, they have higher levels of serotonin— I mean melatonin because actually serotonin gets converted into melatonin in another pathway.

But the reason they have higher levels of melatonin is because melatonin production is inhibited by light. And so when you're blind, you don't have the constant inhibition on the pineal gland. And what's really interesting is that blind people have half the cancer incidence than people who are not blind. But also, when we sleep is when we activate something called the glymphatic system. And the glymphatic system is this system of vessels that extends from the cerebral spinal fluid all the way throughout the brain. And when we sleep, we squirt cerebral spinal fluid up throughout the brain, and our brain swells, and we wash out all the garbage from the day. We wash out the cellular debris that's accumulated. We wash out proteins that are aggregated, we wash out all the gunk and gross stuff.

And it's really important because it washes out things like amyloid beta plaques, which are associated with Alzheimer's disease. And the reason we activate this system when we sleep is because it requires enormous amount of energy. And so when we're awake and processing information, that also requires an enormous amount of energy. So when we're sleeping, the energy can be diverted to this glymphatic system. And so the glymphatic system is really, really cool because it's a way of just taking the trash out in your brain from all the stuff that's accumulated throughout the day. So with that said, I've covered a wide variety of topics this evening and I expect you to remember every single one of them.

But I think that— I hope that you take home a few things and that is that we all have polymorphisms, we all have genes that are, you know, different variations of genes and these genes have different functions that may or may not be— have downsides that could be ameliorated with taking certain micronutrients and supplements and just knowing that they exist, knowing that different lifestyle factors can affect them. So you can actually— there's tools available. I mentioned 23andMe is one where it's $99. They send you a kit, you spit in a tube, they isolate DNA and then they look at a variety of common polymorphisms that you have.

They send you back the raw data, and then you can use another tool called Promethease, which is $5, and it's a huge database that has like over 57,000 published polymorphisms, and it matches your polymorphisms to the published one. And so it kind of helps you guide and understand what your polymorphisms mean. And anyone can do this. My mother-in-law has become a genetic expert, and she's got no biology background, and she's just looked at her 23andMe and Promethease and been able to learn that she had MTHFR, for example. So I really like these consumer-available tools. I also talked about how we can change the expression of our genes with different lifestyle factors, with different micronutrients, by limiting food intake, by sleep, by exercise, stress.

These things all affect the gene expression in our body and we can there's a certain pattern of gene expression and a certain pattern of epigenetics that occurs with age, and there's certain lifestyle factors we can intervene to revert those genes back to how they're being expressed when you're younger. So I think with that said, I will thank you and take questions. Thank you. So, right— oh, all right, this gentleman right here in the front row. We recently heard a discussion from Dr. Hollister. He's the vitamin D expert, and he said that he gave his family 5,000 units of D a day. He recommended 2,000 for us. So what's your stand on that? the dosage of D? So I think that it depends on the person. So depending on what your lifestyle is, how old you are.

So if you live in a region like Minnesota where you're not getting UVB rays from the sun a certain percentage of the year, and let's say you're working at your computer all the time so you're not getting out even when there is UVB like in the summer and spring. You know, I think that how— what your body fat is and also how old you are, because there's so many factors that regulate how much vitamin D you make from the sun, that plays a role in how much you need to supplement with. And in addition, there's polymorphisms now which complicates things even more. So I know 3 people now that have a polymorphism that makes them have to take much, much higher doses of vitamin D, so they have to take like 10,000 IUs a day, which is— that's too much for a person like me.

So, you know, I think generally speaking, because people that don't have a polymorphism, they can raise their serum levels by taking 1,000 IUs of vitamin D a day will raise their serum levels by 5 nanograms per milliliter. That's a good thing to start with, like a template to figure out, you know, well— First you have to get a blood test. I think getting a blood test is important, figuring out what your levels are and knowing that having levels between 40 and 60 nanograms per milliliter has been associated with lowest all-cause mortality. It's been associated with having the longest telomeres. I think being within that range is ideal.

So whatever you have to do to be within that range, which means you probably have to get more than one test done because then— and now I'm totally telling you guys to do work here, but I think it's the most scientific way. I think if you really, really want to know how much vitamin D you Because you don't want too much. And then what if you're taking 5,000 IUs and you're like my friend who has this polymorphism and they can't convert D3 into 25-hydroxy very well and they have to take twice as much? He'll never know that if he doesn't get his levels measured. He'll think he's getting enough. So I think that the take-homes here are get a blood test and see where you're at. Know what your lifestyle factors are, your age and how much sun you get and things like that.

I think those are all important. Thank you. Yes, you right here in the front. We've both been tested already by 23andMe, but it's my understanding that they really can't give us any information because of some government situation. Do you have any idea of what the standing is? And since they can't give us the information, how can we go to this Promethease? Right. Okay. So 23andMe used to give you a report that told you exactly what these polymorphisms you have, what they mean, or what they can mean. It's important to keep in mind that it's not like a be-all end-all. You know, these polymorphisms are interacting with each other, and so you often have things that are compensating for loss of function in one region. So it's not like when you see something it's the ultimate.

You know, it's— you have to keep that in mind when you're interpreting this data. Right. But so 23andMe still gives you the raw data. And Promethease, I mentioned Promethease, it's a tool that costs $5, and it exports the 23andMe raw data, and then it runs and matches all the polymorphisms to this huge database, and then it generates a report for you, much like the one 23andMe used to do. Now 23andMe, they're working on, you know, getting around that FDA regulation. But Promethea is, like I mentioned, my mother-in-law who has no scientific background whatsoever has been able to figure out what's going on in her own genes and in her family genes. So it's really, I like these 2 tools together. So maybe someone in the back here, yeah, with this man standing.

I wonder if you could elaborate a little on magnesium and this whole process you talked about tonight and how How important or not important it is. So magnesium— I actually talk about this in some other videos you may have watched— but magnesium is an essential mineral, and about half the country does not get enough magnesium. Magnesium is found at the center of a chlorophyll molecule, which means it's found— chlorophyll gives plants their green color, so it means it's found in green plants like spinach and kale. Magnesium is very important because it is a cofactor for DNA repair enzymes.

So those same DNA repair genes I was talking about that are activated by FOXO3, that are activated when you have intermittent fasting, when you're EGCG, when you get exercise, or when you're heat stressed, all that stuff, those DNA repair enzymes require magnesium to function. So you need to make sure you have adequate levels of magnesium because magnesium is a cofactor for those DNA repair enzymes. And so magnesium is very important to repair damage that's been done to your DNA. And it's very important to prevent cancer incidence. So having enough magnesium, eating your greens is important for that reason among others. So in the back there with the striped sweater. Thank you. How can a person with type 2 diabetes Does that go in line with the intermittent fasting or can you not do that?

Normally you're told with diabetes to eat every so often, so what happens to the glucose levels? Yes, so you should always obviously talk to your physician before doing anything experimental and everything I'm saying here is completely informational. But they have shown that intermittent fasting It does improve glucose sensitivity— insulin sensitivity, sorry. And so, because it improves glucose metabolism, and they've shown this in like mouse models for type 2 diabetes, that it can help reverse some of the insulin-resistant effects. So, yeah, but of course, you know, it's not medical advice, so it's just something. Hey, so I know they recommend women of reproductive age take folate and all that.

I was curious if you thought men of reproductive age should also take folate or if there were any other supplements that you recommend for men and women of that age. That's a— yeah, that question could go on and I mean the answer for that could go on and on. Yeah, I think that folate is important for men and for women. Men's sperm DNA, they're making new sperm and so you actually need folate to make new DNA. And it's been shown that if you restrict folate, this can cause damage in your DNA that's similar to being irradiated with X-rays. So it— and it can— so the sim— like, it's like being irradiated. In fact, my mentor Bruce Ames showed that in a publication some years ago. So you obviously, if you're not getting enough folate and you're a male, then you could be damaging your sperm DNA.

So, obviously, I think that folate would be important. Making sure you have all the essential vitamins and minerals, essential fatty acids are important for men and women. So, let's go to the back again. The green sweater. Oh, that's me. Yes. I was just wondering, somewhere along the way, I think I read something about taking chlorophyll, and I was just wondering what form is the best suited for you to take. Is it powder, the liquid? I actually don't know. I don't take chlorophyll. Oh, okay. But it's very interesting. Maybe the magnesium's attached to it. Sorry, I can't answer that question. Okay, thank you. The pink. How do we know that the supplements that we take are being absorbed and used correctly? Yeah, I mean, that's a great question.

You know, there's a variety of supplements that are absorbed differently depending on whether you take them on an empty stomach or whether you take them with a meal, whether they're complex to other proteins. I mean, there's a lot of factors that regulate, you know, supplement— different supplement absorption. For example, fat-soluble vitamins, it's better to take with fat. You actually absorb more of them when they're taken with a fat meal. Like beta-carotene, for example, it's a carotenoid that's found in carrots and other orange-yellow plants. And we can convert beta-carotene into vitamin A, but we can also use beta-carotene as an antioxidant. So it does multiple things.

And it's fat soluble, so taking carotenoids or getting beta-carotene is actually dramatically increased when you eat it with fat. So yeah, it's— to answer that question, because each micronutrient is kind of different in terms of its absorption. And there's levels at the gut where depending on what's going on in the gut and how things are, that can affect absorption as well. So it's kind of a difficult answer. I can't just give you a one solution. Sorry. I have a question. We have time for one more question. One more question. Okay, who's really, really enthusiastic? Okay, I think she's been raising her hand a couple of times. I find it interesting that the male contribution to diabetes, like typically it's mitochondrial type disease that's generated and carried over by the mother.

Is it like a co-linked or a co-expressed type gene? So if— there's multiple things that are possibly going on. We're still trying to figure out the exact mechanisms. So for example, there's also imprinting that occurs, and that's— I can't even pretend to begin to explain it or understand all of it because I haven't researched it, but it also has to do with whether— so every gene you have, you get one copy from mom, you get one copy from dad. And so those are called alleles. So we have 2 copies of every gene. And certain genes, they seem to be regulated by if we got them from our mom or from our dad. And so they'll be— you'll make more of that certain copy of a gene whether it was from the father or the mother. Okay.

And so there's certain ones that have been identified, there's ones that haven't been identified. You know, I think that that's certainly one possibility with, you know, with that in terms of, you know, the other— yeah, the other things, it's very possible. I think that there's lots of mechanisms going on here, and a lot of these mechanisms interact with each other. On that note, let's thank our speaker.