So people that had a high Omega-3 index but smoked had the same life expectancy as people that didn't smoke but had a low Omega-3 Index. So essentially, if you just look at this data alone, smoking was like having a low Omega-3 Index. If you could pill up what you could do with vigorous exercise, then I think that is like, right now, what the best longevity drug we have for delaying the aging process and improving health span and improving lifespan.

Good morning. Nice to be here today. I was just mentioning that my son eats about two cups of pomegranate a day, so his urolithin A levels must be off the charts and maybe he'll live to be 100, but probably gene therapy is going to be involved in that. Today we're going to be talking about some of what I think are powerful lifestyle habits that can affect the way you age. So there's some what I call "low hanging fruit.". So these are things that I think are really easy. It can be as simple as a dietary modification or a supplement you take. And then there's some things that are a little more effortful, which require effort. And so that would, of course, be exercise. And so we're going to get into that as well. So the first part of the talk, we're going to just talk about optimizing micronutrient deficiencies. And in the second part, we're going to be talking about what kind of exercise and how it affects the way we age on a molecular level as well. So first up, I think there's really three main micronutrient deficiencies that I want to talk about for a couple of reasons. One, because they're widespread prevalence in terms of either deficiency or inadequacy, and two, because I think they played a very important role in a lot of physiological processes in our body that affect the way we age. So first we're going to talk about vitamin D. And most of you guys probably have already heard enough about vitamin D, but it's important to talk about because it's more than a vitamin. So vitamin D gets converted into a steroid hormone, and it goes into the nucleus of cells and interacts with DNA. So it recognizes a very specific sequence of DNA called a vitamin D response element. And this is encoded in our DNA. And that interaction then either turns genes on and activates them or it does the opposite. It sort of turns them down and represses them. So it's very important for orchestrating –. I mean, we're talking about over 5% of the protein encoding human genome is regulated by vitamin D, which is quite a lot. And so you can imagine if you're running a car and your pistons are firing out of sync with each other. I mean, that's kind of what's happening when you don't have adequate levels of vitamin D. Your genes aren't being regulated in the way they're supposed to be. So things aren't being activated when they're supposed to be or repressed when they're supposed to be. So things are kind of going awry. And as I mentioned, it's widespread prevalency in terms of inadequacy. So about 70% of the population has inadequate levels of vitamin D, which we'll talk about in a minute. It's about 30 nanograms per milliliter or less. And it's a very simple solution. And that's also why I like to talk about it, because it's almost just as simple as taking basically a supplement that costs a penny a pill. Vitamin D supplements are one of the most affordable supplements out there. And there's really just no reason, other than lack of education about vitamin D for people to be so deficient and insufficient. A lot of reasons for the widespread deficiency. We make vitamin D-3 in our skin. So UVB radiation is essential to make vitamin D-3. Anything that blocks out UVB radiation is going to stop that production of vitamin D. So we're talking sunscreen. Melanin, which is the dark skin pigmentation that protects us from the burning rays of the sun, also is a natural sunscreen. So that is also a form of sunscreen also, depending on where you live. So a northern latitude, UVB radiation can't even reach the atmosphere several months out of the year. So when you combine some of these factors, let's say you take someone with darker pigmentation from, let's say, East Asia, and they move somewhere like Chicago, or they move to Sweden, you know, six months out of the year, you're not even getting that UVB radiation you're talking about, just know. Compounding effect on vitamin D deficiency, because there have been studies out of the University of Chicago that have shown that, for example, African Americans have to stay in the sun anywhere between six to ten times longer than Caucasians with fair skin to make the same amount of vitamin D-3 in their skin. So you're talking, I mean, it's a compounding effect with respect to the melanin production as well. And then age plays a role. So as we age, everything is less efficient. So a 70-year-old makes about, I think it's four times less vitamin D three in their skin than their former 20-year-old self. And then, of course, modern day society. So we're inside, indoors, we're at our computers, we're in our cubicles, we're technology, it's not an agricultural society. We're not outside as much as we used to be. And so vitamin D is just not being made in our skins like it was 100 years ago. So there's a lot of reasons why it's widespread. I like to show this slide. It was a study published several years ago, it was 2009. And it's showing when you knock out the vitamin D receptor in mice that it affects the way they age. So at the top of the panel, you can see that both mice, that wild type and then the vitamin D receptor knockout, sort of aging the same. And then four months later, the vitamin D receptor mouse, it's an accelerated aging model. And yeah, it looks terrible, but like the organs on every level, things were sort of accelerated in the way they were aging. So it's just kind of a nice visual to see. But of course, we're not mice. And I've always, often wondered why mice even need vitamin D, because they're nocturnal. And it's just one of those things where it's like, I don't know how much of that actually translates to humans. So let's talk about some human studies. We know that there's a lot of data out there, observational data, that's correlated vitamin D levels to low, vitamin D levels to higher, all cause mortality risk, higher cancer mortality. But there's always that question of healthy user bias. Maybe people with higher vitamin D are outside and more physically active. And of course, you try to correct for as many confounding factors as possible, but you never really can establish causation. That's where Mendelian randomization comes into play. So we have a variety of genes that are responsible for converting vitamin D-3 into 25-hydroxy vitamin D, which is the most active, circulating form of vitamin D, and then subsequently into the steroid hormone, which is 1-25-hydroxy vitamin D. Some of these genes that make enzymes, we all are different. And so some people have ones that don't do it as efficiently. And so Mendelian randomization takes these genes, these single nucleotide polymorphisms in these genes, and says, okay, we're going to randomize them. People that have these genes that we know make them basically have lower levels of 25-hydroxy vitamin D and see what they're correlate that to health outcomes. Like all-cause mortality. So it's kind of, in a way, a way of randomizing people and people that have genetically low vitamin D levels independent of what their lifestyle is. They have a much higher all-cause mortality. They have a higher cancer related mortality, and they have a higher respiratory disease mortality with very little or no effect on cardiovascular mortality. And there's also been – with randomized control trials, obviously you're not going to have a lifelong randomized control trial looking at mortality, but there's other biomarkers that can be looked at. One is epigenetic aging, which I'm sure you've guys heard about yesterday. So one study that took people that were vitamin D deficient. And it's important to start out with a cohort of participants that are deficient, right? Because if you already have someone that's sufficient, giving them a vitamin D supplement really shouldn't do much because they're already at a sufficient level. So these were African American individuals that were also overweight and so they were very vitamin D deficient. They were given a vitamin D supplement with 4000 IUs of vitamin D a day and it decreased their epigenetic age by almost two years. So the question is, what is deficiency, insufficiency, adequacy? So technically I would say depending on what institute you're looking at. But the Endocrinology Institute defines deficiency as 25-hydroxy vitamin D levels, less than 20 nanograms per mill. Sufficiency is about 30, getting... So if you're insufficient, you're less than 30, but if you're sufficient, you're more than 30. And it seems as though the sweet spot for vitamin D is between 40 to 60 nanograms per milliliter. And there's all-cause mortality studies also looking at vitamin D levels, there's meta-analyses of these ranging from 1960s all the way to the mid, like 2015. And it seems like 40 to 60 is a really good sweet spot for the lowest all-cause mortality with vitamin D. As I mentioned, 4000. I mentioned 4000 IUs of vitamin D a day because that's the tolerable upper intake for vitamin D. So it's quite safe. And in general, 1000 IUs of vitamin D generally raises people's blood levels by about five nanograms per mil. So the key is to just get a vitamin D blood test. Do it after you're supplementing, make sure your levels are adequate. Because again, a lot of these single nucleotide polymorphisms in genes that affect our enzymes that are metabolizing vitamin D also affect how we respond to supplemental vitamin D. And some people can require a much higher dose than other people. So really the key here is blood test and measuring. You don't know what you don't measure, right? So the next micronutrient I want to kind of shift gears and talk about is magnesium. And this again, it's widespread inadequacy here. About half the US population has inadequate levels of magnesium. So magnesium is found at the center of a chlorophyll molecule. So, chlorophyll gives plants their green color. So dark leafy greens are a really good source of magnesium. And essentially people aren't eating enough greens, which is why half the country doesn't have adequate levels of magnesium. Magnesium is a cofactor for over 300 different enzymes in the body, a lot of metabolic processes. So it's important for the production of energy in the form of ATP, it's important for the utilization of energy in the form of ATP, but it's also important for repairing DNA damage. So DNA repair enzymes require magnesium to function. And this is where I think its role in aging comes into play, because DNA damage is something that's happening every day, it's happening right now. And all of us, as we're metabolizing food, as we're breathing in oxygen, immune system slightly activated, whatever, it's constantly happening and our bodies are repairing that damage. But it's an insidious type of damage, right? It's not something that you can just wake up and look in the mirror and see, right, scurvy is like, okay, my gums are bleeding and think something's wrong. You can see that, right? DNA damage isn't something that you really think about on a daily basis, but it's happening and it accumulates with age. So you want to be able to repair that damage effectively, right? For many reasons. So DNA damage can lead eventually, over the course of several decades, to oncogenic mutations that could lead to cancer. And so there have been actually a variety of studies that have looked and correlated magnesium levels, magnesium intake, with cancer mortality. So there was one study that found for every 100 milligrams of magnesium intake, there was a 24% decrease in pancreatic cancer risk. And also another study that found that people that had the highest levels of magnesium, they were in the top quintile, had a 40% lower all-cause mortality compared to people in the lowest. And then they had a 50% decrease in cancer mortality compared to people in the lowest. So magnesium is one of those. Again, I think it's best to try to get it from dietary sources. Dark leafy greens are a great source, but also supplemental forms of magnesium, I think is a great sort of insurance, so to speak. So magnesium glycinate, magnesium malate, magnesium citrate, these are all pretty bioavailable forms of magnesium. The requirements for magnesium depend on age, gender. So men require a little bit more than women. It's somewhere like 400 milligrams a day for men and somewhere like 300 to 350 or something like that for women. If you're athletic, if you're sweating, if you're physically active a lot, use the sauna. You actually can require anywhere between ten to 20% above the RDA because you do lose magnesium through sweat. So if half the US population isn't meeting even that RDA, then you can imagine the physically active people are probably faring even worse because their requirements are even higher. So it's a simple solution, simple dietary modification supplement you can take to help sort of get your magnesium levels higher. So omega-3 is sort of the last micronutrient that I want to cover before getting into the next part of my talk. And omega-3, there's three forms of it. So there's ALA, which is found in plant forms like flaxseed walnuts. There's EPA and DHA, which are marine sources, so they're found in seafood. And there's a study out of Harvard that was published. Gosh, it was like 2009. And this study identified the top six preventable causes of death. So these are things that are lifestyle related. So hypertension, for example, smoking, like not having... Avoiding hypertension, avoiding smoking, those were some of the top six preventable causes of death. Well, omega-3, not getting enough omega-3 from seafood. So this was a marine source of omega-3. EPA and DHA was in that top six. And researchers from Harvard had identified that not getting enough omega-3 from seafood was responsible for about 84,000 deaths a year. And that was compared to trans fats. So, trans fats were one of the top avoidable, preventable causes of death. Well, eating trans fats were responsible for 82,000 deaths per year. Pretty much the same as not getting enough omega-3 from seafood. And what's funny is that everybody knows about trans fats. You walk into any supermarket, any grocery store, everything's marketed, oh, zero trans fats, zero trans fats. But nobody's thinking about they're not getting enough omega-3,, they're not eating enough seafood or fish or taking microalgae or fish oil supplements to get omega-3. And so I just kind of like to highlight that, because, again, I think that the way – thinking about food in that, what do we need to feed our body, our metabolism? We need cofactors, magnesium, vitamin D, omega-3. These are things, if we focus on what we need to consume, we don't end up eating all the other stuff. And so people sort of get fixated on what to avoid and don't think about what they're actually supposed to be taking in what they're supposed to be eating. So the Omega-3 Index is one of the best measures of omega-3. So this was pioneered by Dr. Bill Harris and his colleague von Shackey many years ago, back in 2004. And it's measuring omega-3 levels in red blood cell membranes as opposed to plasma phospholipids. And the reason for that is because it is a long term biomarker of omega-3. So your red blood cells take about 120 days to turn over, whereas your plasma phospholipids, it's more like if you get your omega-3 levels measured and it's plasma phospholipids, it's more like, what did I eat the past week? Or something like that. So it's kind of a comparison… fasting blood glucose would be the immediate biomarker, and then the HbA1c is your long term blood glucose level. So it's sort of similar here. So Omega-3 Index is a really important way to measure omega three. And it's now being increasingly used in many scientific studies. Of course, many. I think a lot of conflicting data out there also has to do with the fact that plasma phospholipids were measured. And again, it goes down to this. Well, was it just that they didn't eat omega-3 in the last week, or they did? And so we're saying they have high omega-3 because of that. Just a recent dietary choice. Right. So the Omega-3 Index was. This is, again, from Bill Harris's group. He found. Him and his colleagues found that people with a high Omega-3 Index, which is defined as 8%, at least 8%, had a 90% reduced risk of sudden cardiac death, compared to people with a low Omega-3 Index of 4%. In the US, the Omega-3 Index, most people, it's less than 5%. So it's about 4%. So most people in the United States are at a very low Omega-3 Index. They don't eat enough seafood and fish. So sudden cardiac death is reduced by 90%. If you're in that high Omega-3 Index group. Cardiovascular disease is the number one killer in the United States. And actually, in most all developed countries, every 33 seconds, someone dies of a heart attack. So anything you can do to improve cardiovascular health is really, really on your side in terms of improving health span, improving your lifespan. The high Omega-3 Index, also from Bill Harris's group, found that people, again with an 8% Omega-3 Index, had a five year increased life expectancy, compared to people with a 4% Omega-3 Index. So that was the low end. And it's interesting because in Japan, their life expectancy, on average, is about five years longer than in the United States. Our average life expectancy is five years less here than in Japan. And they happen to have an Omega-3 Index, in general, above 8%, whereas, again, I mentioned we're below 5%. So sort of an interesting sort of observation that also correlates with the increased average life expectancy in a country that eats a lot of seafood. But this is what really, I think, is almost. It is eye opening. It's part of the same study from Bill Harris's group where they stratified these participants and looked at their Omega-3 Index and then also looked at their smoking. So the very, very top curve, the green curve, people lived the longest if they had the 8% Omega-3 Index and they were non-smokers. And the very, very bottom curve, the red one, was people that were smokers and had a low Omega-3 Index, 4%. So they had the lowest life expectancy. But this is what blows my mind. If you look at the orange and blue curves, they're completely overlaid on top of each other. So people that had a high Omega-3 Index but smoked had the same life expectancy as people that didn't smoke but had a low Omega-3 Index. So essentially, if you just look at this data alone, smoking was like having a low Omega-3 Index. And again, it's one of those things where, of course, it's observational data and you can never really establish causation. But I just feel like that's really eye-opening, because, again, everyone knows smoking is bad for you, but nobody's thinking about how we're not getting enough omega-3 and how easy is it to take a fish oil supplement, for example, or increase your salmon intake? So, to summarize this part of my talk with respect to micronutrients, we talked about vitamin D, low hanging fruit, as simple as a supplement. 4000 IUs a day is a pretty good start to get most people who are deficient to a sufficient level. That's been shown in several studies getting people from a deficient level up to a sufficient level can be done with 4000 IUs of vitamin D a day. Omega-3 fatty acids, Omega-3 Index. Getting the Omega-3 Index test. You want your levels to be in the 8%, you want to be high. And then there's been studies showing that it takes around 2 grams of supplemental omega-3 to get from a 4% Omega-3 Index to an 8%. It's really not that hard. And then again, omega-3 is found in prescription form. I didn't go into all the randomized controlled trials today because that would take the remainder of my time here. But you can get omega-3 in purified ethyl ester form, either in the form of EPA only Vesepa or DHA, plus EPA Lovaza. And those are prescribed at 4 grams a day per dose. And so what I said was sort of conservative. It takes about 2 grams a day just to get from a 4%, on average, 4% Omega-3 Index to 8%. And again, it's as simple as getting the test done and supplementing and then testing again and seeing if you're getting your Index up to 8%. And then magnesium. We talked about getting that RDA, hitting it with either increasing or a combination, ideally increasing leafy greens and also taking a supplement. Magnesium glycinate, citrate, malate are all pretty bioavailable sources of magnesium. Okay, so we're going to shift gears and we're going to get into the effortful part of this presentation, this talk. This requires putting in the work, right? This isn't as simple as taking a pill, but at the very least, I think that taking a pill is easier for a lot of people. But then there's, of course, the people that want to go the step further and they're willing to put in the effort. So let's talk about that. We're going to talk about why I'm convinced that vigorous exercise is the most powerful longevity drug that you're going to get. More than metformin, more than rapamycin, more than any of those things. If you could pill up what you could do with vigorous exercise, then I think that is like right now, the best longevity drug we have for delaying the aging process and improving health span and improving lifespan. So when I say vigorous exercise, what do I mean? Generally speaking, of course, there's a sliding scale here because you can take someone who's completely sedentary and never really done any aerobic exercise. Vigorous exercise for them is going to be probably more what light to moderate exercise is for people that are physically active. But generally speaking, once you kind of adapt and get used to being physically active, vigorous exercise is about getting to 80% your max heart rate, or estimated max heart rate. That's really what I'm talking about, 75% to 80% of your maximum heart rate. So cardiorespiratory fitness, this is one of the best biomarkers for longevity, in my opinion. So cardiorespiratory fitness is measured empirically by VO2max. So that's the maximal amount of oxygen that you can take up during maximal exercise. So when I use VO2 max, sometimes these are like, interchangeable, cardiorespiratory fitness – VO2 max – I kind of use them interchangeably in this talk. But VO2 max is just directly measuring cardiorespiratory fitness. So cardiorespiratory fitness is associated with improved longevity. It does improve longevity. And the biggest improvements you're going to get is if you're going from low normal. So for your age group, for your gender, if you're low normal and going anywhere above that is where you get the biggest bang for your buck. So people that have a low normal VO2max, if they just go up to a… If they're below normal and they go up to just low normal, they get about a 2.1 increased life expectancy. If they're below normal and they go up to high normal, they get almost a three year increased life expectancy. And then if they go from below normal to the upper amount of normal. So this is the top 5% of the population. This is more like you're getting into the elite athlete level that's associated with almost a five year increase in life expectancy. So just to give you some perspective here, about half of the US population is – they have a low normal cardiorespiratory fitness, and the other half has about a high normal cardiorespiratory fitness. So again, just mostly having to do with being physically active or not being physically active. And on average, for every unit increase in VO2 max, it's associated with a 45 day increase in life expectancy. And there was a really important study published in JAMA back in 2018 that I just like to mention, because it kind of established that there was no upper limit to the mortality reduction of having a high cardiorespiratory fitness. I mean, obviously, within normal human life expectancy ranges, right? So people that were in the bottom 25% of cardiorespiratory fitness, or their VO2 max, and also, I like these studies because they're measuring something empirically. I'm talking about VO2 max, right? This is a fitness test that's done. It's measured, it's empirical versus a lot of studies and conflicting data out there where you have these questionnaires, how physically active are you? And you think about your last week or month, and then that's, like, extrapolated out and they go, okay, well, based on this last week, this is how physically active we think this person is over their lifetime or whatever, and it's all we have in some respects. But if you can measure something empirically, it's going to really help clear up a lot of the confounding and a lot of the conflicting data that you see out there. So I really like studies that measure VO2 max because it's something that's actually empirical rather than going off a questionnaire. Right. Those have all sorts of problems. So going from the low bottom 25% of VO2 max up to the elite level, so you're talking about the top 2.3%. I mean, these are the elite athletes. That's associated with an 80% reduction in all-cause mortality. So comparing those two groups, people in the low 25% group versus the elite level, but even going from the high cardiorespiratory fitness, so this is the top 25% of the population. They're good. I mean, these are people that are – they're committed exercisers. They're physically active. If they go up to the elite level, they get even 20% more reduction in all-cause mortality. So if you compare the elite to the high cardiorespiratory fitness, you're still getting a 20% lower all-cause mortality by just moving up to that elite level. And what was really interesting about this study was that being in that low 25% group, that they're in the bottom 25% for VO2 max, that was comparable to either same risk or greater risk than for mortality, early mortality, as type 2 diabetes, as smoking, and as having heart disease. So, again, putting that into perspective, we all think about these diseases and how they're increasing our early mortality risk, but just not having a good cardiorespiratory fitness can do the same thing. So how do you improve your VO2 max? How do you improve your cardiorespiratory fitness? Well, any exercise, any aerobic exercise is obviously going to be good for small changes in cardiorespiratory fitness. But in particular, there have been meta analyses that have found that vigorous intensity exercise, as I mentioned, and particularly high intensity interval training, which we're going to talk about. So this is where you're doing sort of short bursts of very vigorous exercise. You're at least at 80% max heart rate, sometimes going even above that and then having rest periods, and you're doing those intervals. And why that's important is because there have been some studies that have found that even people that are meeting the guidelines for moderate aerobic exercise, so they're doing two and a half hours of moderate intensity aerobic exercise per week. About 40% of those people do not respond. In other words, they do not get VO2 max improvements. They are not improving their cardiorespiratory fitness by doing two and a half hours of moderate intensity exercise every week. And it's not really known why exactly there's these non responder effects, but that's a large percent of the population. However, when those people do more of a high intensity interval training workout, they do more vigorous exercise, they start to respond and improve their VO2 max. And it's thought because VO2 max cardiorespiratory fitness, to get those changes, to get those improvements, you really have to increase cardiac output. So the stronger the signal, the more intense the signal, the adaptations are greater, so your body responds by improving the delivery of oxygen to your tissues. Right. So that's essentially what you're wanting to improve your cardiorespiratory fitness. And so it's kind of thought why vigorous intensity and particularly high intensity interval training is so important for improving cardiorespiratory fitness. There's been several studies looking at this, and, for example, Dr. Martin Gibala out of McMaster University, over in Ontario, Canada, has done a lot of studies looking at different high intensity interval training protocols. And it really seems if you're really wanting to improve that cardiorespiratory fitness, that you have to do longer intervals. So three to five minute intervals of just the maximum intensity that you can maintain for that three to five minutes. And so a really good and well studied, a lot of evidence on the Norwegian 4 x 4 protocol. So this is four minutes of the highest intensity that you can do, and then it's three minutes recovery. So you're really going down to light, light exercise. You want your heart rate to go down, you want to sort of really give yourself some rest so that you can do it again. So you repeat this four times. That's why it's called 4 x 4. And this is one of the best protocols for improving VO2 Max. If you don't want to go into a lab to get your VO2 max measured, or you don't have access to it for whatever reason, one of the best evidence-based ways of measuring VO2 max at home, so to speak, not necessarily home is what's called a 12-minute run test or walk test, depending on your fitness level. Essentially, you need some sort of wearable device that can track your distance. So, Apple watch, your Fitbit, whatever. And you need to have a flat surface that you can run on. So like a track field. And you want to run for 12 minutes or walk, depending on your fitness level, the maximum intensity that you can maintain for that 12 minutes, basically your distance is going to be covered. And then you look up this equation and it converts your VO2 max based on that distance. And the reason you don't want hills and stuff is because that'll make you run… the distance will be less. So you want to make sure you're giving yourself a flat surface so that you actually are more accurate in terminating what your distance is during that twelve minute run test. This study out of UT southwest in Dallas by Dr. Ben Levine is really what has convinced me that vigorous exercise is extremely important for the heart and the way the heart ages. So I mentioned cardiovascular disease. I mean, that's the number one killer in developed countries, right? So as we age, our heart undergoes certain inevitable changes. It gets smaller, it shrinks, it gets stiffer, less flexible. And this affects a lot of things. It affects our cardiovascular disease risk, it affects our cardiorespiratory fitness, the ability for us to do aerobic exercise. And so what Ben did in this study, Dr. Levine did in the study, was really remarkable. He took a cohort of participants that were 50 years old on average, and these were sedentary individuals that were otherwise healthy. So they didn't have any type 2 diabetes, hypertension, et cetera. They were quote-unquote healthy, but they were sedentary. And he separated them into two groups. So the first group was the control group, who did sort of stretching and yoga for two years. And then the second group was the exercise intervention group. So these were the people that were going to be doing the exercise, and it ended up being a vigorous exercise protocol. But because they were sedentary, it started out sort of lower to moderate intensity. And by the time it was six months, these individuals were doing five to six hours a week of aerobic exercise, with a large percentage of that time being in what's called the maximal steady state. So that's what I'm talking about. When you're going as hard as you can and you maintain that for about 20 or 30 minutes. So it's usually around 75, 80% max heart rate, and you're doing that for about 20 to 30 minutes. They also did the Norwegian 4 x 4 protocol once a week. And after two years, they essentially reversed these structural changes in their aging heart by 20 years. So their hearts were essentially looking more like a 30 year old heart after that two years of vigorous intensity exercise. Now, like I mentioned, they were doing five to six hours a week of vigorous, a large portion of it in vigorous exercise. But it's simply astonishing, the structural changes that they found. So there was more than 25% improvement in the elasticity of the heart after those two years, particularly in the left ventricular muscle of the heart. Of course, they did increase their VO2 max by about 20% as well. So it's just quite astounding that you can take a 50 year old, put them on a pretty intense exercise program for two years, and essentially reverse a lot of the structural changes that happen with the heart, with the aging process. Blood pressure improvements are also, for people that are willing to put in the effort most of the time. I mean, there's always non responders, but they can have drug sized effects. In other words, they can be comparable to some drugs that are given to reduce hypertension. So there's been an analysis of 24 different randomized controlled trials found that six weeks of a pretty moderate to vigorous intensity exercise, 20 to 60 minutes of that, three to four days a week, had almost drug size effects in reducing blood pressure. So hypertension is not only a risk factor for cardiovascular disease, it's also a very, very important risk factor for dementia and Alzheimer's disease. So there's every reason to want to not have hypertension. And 20% of young people aged 18 to 39 have hypertension. And then about half the US population of older adults have hypertension. So it's a very common thing that, again, can be modified to quite a bit of an extent with aerobic exercise, particularly vigorous intensity exercise. Let's talk a little bit about, on the molecular level, why I'm talking about vigorous exercise, and really that 80% max heart rate. It has to do with the fact that when you push your muscles to work harder than the oxygen can get to them to make energy, they shift from using mitochondria and using oxygen for energy to using glucose through glycolysis. And it's a quick process that doesn't require oxygen. It makes lactate as a byproduct, only it's not a byproduct. We often thought about it as a metabolic byproduct, but it's so much more than that. So lactate, generated from muscles, it's an exokine, it's a myokine, and it's a signaling molecule. It gets into circulation, and it is consumed by the brain. It's consumed by the heart, by the liver, also by the muscle. It's consumed as a very easily utilizable source of energy, but also as a signaling molecule, as we'll talk about. And this is called the lactate shuttle. It was pioneered by Dr. George Brooks out of UC Berkeley. And when I say a signaling molecule, it's a way for your muscles to directly communicate with other parts of the body, like the brain. And so lactate itself has been shown to be responsible for increasing brain derived neurotrophic factor, both in the plasma – this in human studies, humans that exercise lactate correlates with the BDNF activation in plasma. BDNF can cross over the blood brain barrier, but also animal studies showing that it directly increases brain derived neurotrophic factor in the brain. So BDNF is a very important neurotrophic factor. It's responsible for neuroplasticity. So that's the ability of your brain, your neurons in your brain, to adapt to changing environment. It's very important during the aging process, as things are changing and stuff, you want your brain to adapt to those changes. It's also important for depression. People with depression don't often adapt to the changing environment, and it is partly responsible for some of the depressive symptoms. But brain derived neurotrophic factor also is important for neurogenesis. The increase of new neurons, particularly in some brain regions, like the hippocampus, which is involved in learning and memory, it helps existing neurons survive. There have been animal studies that have shown that when you induce them to do exercise and they get those learning and memory improvements that have also been found in human studies, that if you give them a drug and block brain derived neurotrophic factor, they don't get those learning and memory benefits. So it really seems as though brain drive neurotrophic factor is important to get those learning and memory benefits from exercise. And again, lactate is a key signaling molecule that increases brain drive neurotrophic factor. Lactate is generated from your exercising muscles when you're forcing them to work hard, this isn't just going on a brisk walk. This is really getting your heart rate up, sweating, getting flush in the face. Lactate is also a signaling molecule to increase neurotransmitters in the brain. This has been shown in both human studies and animal studies. So it's important for the production of serotonin so studies have found that people that exercise produce a lot of lactate. This correlates with an increase in serotonin, which also correlated with improved impulse control. Serotonin plays an important role in many neurological processes, including impulse control. So they're being able to have this inhibitory effect, which also plays a role in focus and attention. Norepinephrine is another one that's been shown. So as we're exercising really hard, our muscles are working harder, our heart is working harder, but our brain is also working harder. And there have been human studies out of, I believe it's Norway, that have found that the lactate produced during vigorous intensity exercise crosses the blood brain barrier. It's consumed by the brain, and this correlates with a burst of norepinephrine production, which fuels the brain to work harder during exercise. It's also important for focus and attention and some of those effects that you get after you do a vigorous intensity workout. So there's some protocols that have been shown to maximize brain derived neurotrophic factor in humans, and some of these have also correlated with lactate levels. It seems as though the best is getting the best of both worlds. So you want vigorous intensity, about 80% max heart rate, but you also want duration. So you want to get like 30 to 40 minutes, that is the most robust at increasing brain drive neurotrophic factor, as measured in plasma and people. But 20 minutes will also increase it as well. Just 30 to 40 minutes does it even more. There's also some protocols that are more high intensity interval training. So doing six rounds of 40-second intervals, where you're going as hard as you can for 40 seconds, followed by a recovery period, also really increases brain derived neurotrophic factor. In fact, it increases it four to five times more in people, compared to individuals that are doing about an hour and a half of more lower intensity cycling at about 25% their VO2 max peak. I want to just shift gears for a minute and talk about some of the anticancer effects of vigorous intensity exercise independent of the immune system. So the immune system exercise activates the immune system. There's a robust effect on a variety of antimetastatic effects there, but just the mechanical force of blood flow. Blood flow actually affects what are called circulating tumor cells. So circulating tumor cells escape from the primary site of the tumor, get into circulation, eventually travel to distant sites, and then they take residence and establish a new tumor elsewhere. So this is metastasis. So circulating tumor cells, you obviously do not want to have them in circulation because they can play a role in metastasis. Well, the shearing forces of blood flow itself can kill these circulating tumor cells, because on every cell surface we have these mechanoreceptors that respond to movement, and cancer cells are all wonky and disrupted and messed up, and so they just can't handle that movement and they die. So the more intense the exercise, the more, the greater the blood flow, the higher proportion of circulating tumor cells that actually undergo apoptosis and die. There have been some studies looking at people that undergo about six months of aerobic exercise, anywhere between 50% to 70% max heart rate, for 150 minutes a week. That significantly reduces the circulating tumor cells in people with anywhere between stage I to stage III colon cancer. Other studies have found and correlated that circulating tumor cells are linked to a three times higher risk of cancer recurrence and a four times higher risk of cancer mortality in people with cancer. Also, stage III colon cancer patients that engage in aerobic exercise have a 40% reduction in cancer recurrence and a 63% reduction in cancer mortality. So exercise is also a very important, plays a very important role in cancer metastasis and also in helping as an adjunct therapy to treating cancer as well. But you don't have to do the 40 minutes of vigorous intensity exercise every day to get benefits. So there's something called exercise snacks. These are very short. Anywhere between one to three minute bursts of intense exercise, you're getting your heart rate up 75, 80, 90% max heart rate. You can be doing anything from jumping jacks to sprinting stairs to high knees, to air squats. There's a lot of ways to do it, and you do it just in a short burst. So it's a really great way to break up the workday. It's also a really great way to improve metabolic health, particularly when you time it around meals, which we'll talk about in a minute. And the way it does that partly, well, there's a lot of mechanisms at play, but one of them again comes back to lactate being generated very acutely from exercising muscle, which then causes glucose transporters on the muscle surface to translocate to the muscle surface. So these are GLUT4 transporters. These then allow glucose circulating in circulation to then be taken up into muscle, therefore improving your blood glucose levels. And it also improves insulin sensitivity as well. When they're timed around mealtime, anywhere between 30 minutes to an hour dramatically has an effect on blood glucose levels and insulin sensitivity, particularly in people with metabolic syndrome, type 2 diabetes. So it's a great way. Also, you just get up, do some high knees for a minute, or jumping jacks, or do something that you can do quickly to get that exercise snack in. And another way it's improving metabolic health, I'll just mention briefly, because we're running out of time, is through improving mitochondrial biogenesis, the generation of new, healthy, young mitochondria. It's been shown to do this in muscle cells, and this is also happening through lactate. Lactate is a signaling molecule, yet again increasing the expression of a very important protein involved in mitochondrial biogenesis, called PGC1-alpha. And so it plays an important role in increasing new mitochondria and muscle. This has been shown in human studies, but also animal studies have found that exercise increases lactate, which crosses the blood brain barrier, gets into the brain, and increases mitochondrial biogenesis in the hippocampus, in neurons in the hippocampus. So mitochondria in neurons in the hippocampus are being increased. I don't know why that mechanism wouldn't be conserved in humans. So the fact that it's happening in animals is also encouraging. But exercise snacks are also associated with improved longevity. So I was talking about this sort of deliberate form of exercise snacks, where you're doing high knees or jumping jacks. Well, there's large studies that have been underway and have been published, and there's ongoing studies looking at vigorous, intermittent lifestyle activity. So it's a type of exercise snack where you use everyday life situations to get your heart rate up high for a minute or two minutes or three minutes. For example, you have to take the stairs every day to get to work. Well, instead of walking up the stairs, you sprint. So people are wearing these accelerometers, so their heart rate is being measured. And scientists have been able to gather all this data, and they found that people that have engaged in one to two minutes of vigorous, intermittent activity three times a day have a 40% reduction in all-cause and in cancer mortality and a 50% reduction in cardiovascular related mortality. This is compared to non-exercisers. Now, also, people that even identify themselves as non-exercisers, so they're doing this vigorous stair climbing and stuff, but they don't actually go to the gym or do any leisure time activity. They still get these improvements. So it's a really great way to break up sedentary time. Being sedentary itself is an independent risk factor for all-cause mortality, cancer mortality. So, in other words, just periods of when we're sitting, like now, is a risk factor, even if you're going to go to the gym later today. So breaking up sedentary time is really important. There's a lot of ways to break up your sedentary time, and I think that these exercise snacks are a great way to do it. You just get up and you do high knees for one minute, two minutes, three minutes. And I really kind of wanted to just have everyone do it for 30 seconds. If we could do that real quick. And then I'm ending my talk. So if you guys could just get up and we're going to do high knees right now. So that is where you try to get your leg as high as you can and you do the opposite hand up. And then we're going to just do it. Or just do it for 30 seconds, but really try to do it as hard as you can. If you're wearing heels, take them off. You. Ready, set, go. All right, get your heart rate up. You really want to get your heart rate up to go fast. Now, remember, we're doing 30 seconds. And I said one, two minutes. You do this, you're actually going to be tired. You're probably like, oh, my gosh, is it not up yet? All right, we're only going to do 30 seconds because of time. All right, time. But as you can see, it works, right? So maybe we get a little more brain derived neurotrophic factor, a little more attentive for the next talk. And I just want to close by saying, yeah, we've talked a lot about vigorous intensity exercise, but the reality is that any exercise you can do to form a habit that you can do on a daily basis. If it's not vigorous intensity, any kind of exercise is beneficial. So keep that in mind. I was kind of going for the top here. Like you want to reach for the stars, but really what you want to do is form of habit. So that's the most important thing. With that said, we talked about a lot today. I think I've covered a lot of the summaries, avoiding micronutrient insufficiencies, addressing the lack of vigorous intensity exercise, but again, forming that habit. Do what you can do. I think I've given you guys a lot of tools here to measure things. Try to implement some Norwegian 4 x 4, which is brutal or just do exercise. Next, you guys tell the next speaker in a couple of hours, we got to get up and get our blood flow higher, heart rate up. And with that, thank you so much for listening today. Hope you guys learned something.