Rhonda Patrick: I'm sitting here with Dr. Benjamin Levine, who is an exceptionally accomplished sports cardiologist. He is the founder and president of arguably one of the most prestigious institutes for understanding cardiovascular adaptations to intermittent challenges, The Institute for Exercise and Environmental Medicine at UT Southwestern and Texas Health, Dallas. His expertise is sought after by major sports leagues, NASA, and really, he's just an expert on understanding the cardiovascular adaptations to a wide variety of challenges, whether we're talking about exercise, sports, microgravity, bed rest, and just, it goes on and on. So I'm so excited to have you here, Dr. Levine, and there's many, many things that I really can't wait to talk about with you today, but maybe we can start with bed rest and the effects of bed rest on cardiovascular health. So you were part of one of a very, I would say, famous and informative studies, the Dallas Bed Rest Study.

Ben Levine: Yeah. So, actually, I was only ten years old when that study was first done, so my part arrived much later. Thank you for that very generous introduction. But the cardiovascular community used to put people to bed after heart attacks or things like that. That was the standard of care. And in the mid-1960s, my mentors in Dallas, Jerry Mitchell, Gunnar Blundquist, and Bengt Saltin, some of the most famous cardiovascular physiologists ever, took five young men and put them to bed for three weeks and then trained them for two months. And frankly, almost everything we've learned about the cardiovascular adaptation to changes in physical activity began with that study. Only five guys. And so, like I said, I was only ten years old, so I didn't participate in that study. But 30 years later, we found those same five guys and brought them back to Dallas to study them and to compare the effects of 30 years of aging with what happened to them during bed rest. And quite remarkably, not a single person, not one, was in worse shape after 30 years of aging than they were after three weeks of bed rest when they were in their twenties. So three weeks of bed rest was worse for the body's ability to do physical work than 30 years of aging. That observation really started us on a whole series of studies trying to understand what's the difference between sedentary behavior, or lying in bed or being physically inactive, and aging.

Rhonda Patrick: So when you say that the 30 years of aging was no worse than three weeks of bed rest in terms of so what sort of physiological parameters are you talking about?

Ben Levine: I mean, these were the five most studied humans in the history of the world in terms of all the studies that were done to them. But the sort of simplest is the maximal oxygen uptake. That's the maximum amount of oxygen that can be taken in from the environment, brought into the body by the lungs, transported by the heart to the skeletal muscle, and used to do physical work. It's the exercise physiologist's marker of fitness. And so when we hear the term cardiorespiratory fitness, that's what we really mean. And there are ways to estimate it, there are ways to measure it directly. Many of your audience will have seen or even participated, had a mouthpiece in their mouth, run on a treadmill till they can't go anymore. And that's how you measure the maximal oxygen uptake. Back in the 1960s, they did a lot of other things. You should see the pictures of these guys. There are catheters in the arms, catheters in the bladder, catheters everywhere. They measured heart size. There wasn't echocardiography then, so they measured heart size by x-ray. Now, that takes into account both the mass, the muscle mass of the heart, and its volume, and the heart just shrunk in bed rest. So the heart shrinks, the muscles atrophy. And that's probably the single most important thing that happens, at least to the heart. The blood vessels adapt to meet the demand that's placed on them. So the blood vessels kind of get a little smaller. Also, everything kind of contracts. And that's probably, if I had to pick one thing that would be the archetype of the bed rest, is the shrinking and atrophy of the circulation, including the heart.

Rhonda Patrick: And you said that they were trained after bed rest, so, was this reversible?

Ben Levine: Well, that's really interesting, right? Because out of those five guys, three of them were just average joes. You know, they weren't athletic, they weren't sick, they were just healthy college students. Two of them were competitive athletes. One was a semi-pro football player player, and the other was a distance runner. They all decreased by about the same amount. They lost fitness. But what was really interesting is that the three guys who were relatively unfit quickly returned to baseline and even got fitter than they were beforehand. For the fitter people, it took them the full two months to get back, and even then they weren't quite back at where they were. So, people whose bodies are adapted and trained, they lose the same amount, but it may take them longer to get back. And part of that may have to do with the load that's placed on them. So you have to kind of build back up slowly after you've been in bed for a while and it just takes…people forget how much load they placed on themselves to get them back trained. And you can't just pop into that all of a sudden. You've got to build up slowly when you've been in bed. And we've learned a lot about this in the COVID pandemic where, where people went to bed and were placed in quarantine and lost a lot of fitness. I will tell you, to me, one of the most compelling observations is in sticking with the COVID pandemic for a minute, because it really is the same concept. So, you've heard about long COVID, for example, and people who have symptoms that last more than three months, twelve weeks after their COVID infection. Well, we were very worried when the COVID pandemic hit about what was going to happen to the athletes because we were worried that they were going to get infected. We know that COVID could infect the heart. We were worried it was going to cause sudden death. And so we were very intensely monitoring all the collegiate athletes. And out of hundreds, if not thousands, of collegiate athletes who had COVID and went through a brief quarantine, how many do you think had symptoms that lasted more than twelve weeks? Weeks? 1600, in Brad Petek'sPettic's study, what percentage do you think? Make a guess.

Rhonda Patrick: 8 percent.

Ben Levine: Yeah, 0.06 percent. Two people. Two out of 1600. Why is that? It's not that athletes are resistant to long COVID. No, it's because as soon as they got over their quarantine period, because they were in a competitive environment, they quickly returned to a trainer, a monitored and implemented return-to-play program. So it's really important as soon, for almost any condition, as soon as that forces you to bed, that you have to get up and start moving and progress your training to return to a, your baseline state. And in some cases, you can do even better.

Rhonda Patrick: So is the hypothesis that after being, let's say, in COVID's case, exercise may help protect against having this long COVID, whatever that is?

Ben Levine: Now, let me caveat that by saying some people get really sick with COVID and COVID can affect the heart and the lungs and the mitochondria and the muscles and the brain. There are all sorts of things, legions of things that can be injured by the body with COVID So we're not talking about those people, right? Cause that's a whole different story. We're talking about people who didn't get that sick and had to be placed in quarantine, which often resulted, if not in frank bed rest, at least dramatic reductions in their physical activity.

Rhonda Patrick: Well, the other thing that is that there was a lot of public health messages that were urging people not to exercise. I know, I know, because it was somehow. I don't even know exactly where that was coming from, but it was potentially dangerous.

Ben Levine: Well, that's what we were worried about with the athletes, right? That because we would check them for troponin, which is a marker of cardiovascular injury. We do echocardiograms. We check electrocardiograms. That was called the triad. I was part of the sports cardiology council that laid out those guidelines of the COVID triad testing. What we learned since is that that really wasn't that effective unless the individual, the athletes, had cardiopulmonary symptoms, if they had palpitations or exertional shortness of breath or chest pain. Those are the people who really needed more intensive evaluation to make sure that their bodies, their hearts and their lungs had not been injured by COVID. We then went on to do cardiac MRIs on a lot of people, a lot of athletes who had abnormalities in this triad. And if they didn't have cardiopulmonary symptoms, they didn't have anything wrong with their heart. We were deathly afraid of this, because, for example, in the military, the most common cause of certain cardiac death during basic training is myocarditis. That's an inflammatory infection of the heart muscle by a virus. And that remains and persists as a diagnosis as a cause of sudden cardiac arrest in young athletes. Once this COVID pandemic started and we realized that it affected the heart, we said, oh, my God, the streets and the playing fields are going to be littered with the dead bodies of young athletes. Fortunately, that was not the case, but we were worried about it. And I think it generated tons of publications and guidelines and things like that, and we learned a lot from it. You know, it gets us back to this bed rest model that you had started talking about, you know, and we, you know, in the original Dallas Bed Rest and Training studies, would we put people to bed for three weeks. And a lot of our high-resolution physiology experiments have used that kind of two to three-week model. And because at least in the early nineties, that was what we were doing in spaceflight. Bed rest is a model for spaceflight because you remove the head-to-foot gravitational gradient. So from head to feet, there is no gravity. So that's very expensive to do work in space. So we use bed rest as that model, but we put people to bed for a longer time than that. We've put people to bed for two weeks, six weeks, even twelve weeks of bed rest.

Rhonda Patrick: And this is like literally bed rest, like not getting up.

Ben Levine: You can't even get up to use the toilet. We're talking strict bed rest. And that takes a little practice for people, by the way.

Rhonda Patrick: So how much of, I mean, is this bed rest an almost accelerated aging model? And how much of cardiac aging… What is cardiac aging? How much of it is due to being sedentary?

Ben Levine: So that's a million-dollar question, isn't it? We found that the heart loses about 1 percent of its muscle mass a week in bed. So it just, when we moderate people for twelve weeks, the heart just got smaller and smaller and smaller. Now, obviously, it can't continue to atrophy forever. And we've sort of used spinal cord injury as a model for what that plateau is. How low can you go? And it's about 25 percent. So patients with spinal cord injuries have about a 25 percent reduction in the mass of the heart. We see the same things in young women with a disease called POTS or the postural orthostatic tachycardia syndrome. We can talk more about that later, if you want. I know that's not your prime focus. If we take people and look either cross sectionally, if we train them, we can see at least a 15 to 20 percent increase in the size of the heart. And if we look cross-sectionally, comparing elite runners to spinal cord injury, it's a 75 percent change in cardiac muscle mass. It's adaptable plastic, responsive to changes in physical activity. So we asked just the question that you asked, Rhonda, how much of what we see with normal, healthy aging is due to becoming sedentary? So one of the first studies we then did to follow up on the Dallas Bed Rest and Training follow-up study was we went out and recruited a group of extremely healthy, but sedentary older people. It's not so easy to do, by the way. You know, these are people who had no chronic medical problems, were taking no medications except for perhaps cholesterol-lowering medication, but just didn't do any regular physical activity. And we compared them to a group of elite masters athletes. These were individuals who trained virtually every day for much of their adult lives and were competitive at the regional and national level. And we used a technique that we developed in my laboratory to estimate and to quantify the, let's call it the flexibility or stretchiness of the heart's muscle. The medical term is compliance, but it's really how much will the heart stretch? And we all think about aging. You know, you think about aging of the skin, for example, right? That it becomes less stretchy. You know, it can stiffer. And the analogy I like to give people is with a nice, brand-new rubber band, right? Take it out of the box, stretch it. It stretches. Great, right? Stick it in your junk drawer. Right. And come back 20 years later and take it out of the drawer and try to stretch it again. It doesn't really stretch. It loses that stretchiness. And there are a number of specific biological reasons why that might be, and we can talk about that, but that becomes a really good marker for the cardiovascular system. The compliance or the ability of the heart to stretch and accommodate blood, not just the heart, but the blood vessels, also, is a marker of youthful cardiovascular structure. So we stick a catheter in the heart, we put it in through a vein in the arm. We then unload the heart. We reduce its volume by using a procedure called lower body negative pressure. Basically, you put someone in a box, sealed at the level of the hips, hook it up to a vacuum cleaner, and suck, and we can literally pull all the blood out of the heart. So we can make the heart smaller and measure the pressure and its volume using echocardiology cardiography. Then we give them a volume load. We put an IV in, and we blast salt water into the heart, and we make it bigger, as big as we can get it. And then we look at the slope, the stretchiness of the heart. And what we found is that when we compared the seniors to the healthy young individuals, we noticed that not only did the heart shrink, but it stiffened. Right? And then when we said, we looked at the elite athletes, their hearts were indistinguishable from healthy 30-year-olds. So a lifetime of endurance training at a level commensurate with being a competitive athlete was sufficient to prevent that aspect of cardiovascular aging. Now, that's really interesting from a physiological perspective, but it's not a very good public health measure. We can't really expect everybody to be a competitive master's athlete. So the next question we asked was, okay, where or how much exercise does someone need to do over a lifetime to preserve their youthful cardiovascular structure? So we turn to our colleagues at the Cooper Clinic, and we partner with them. Cooper Clinic is a center in Dallas developed by Ken Cooper, where they have tracked physical activity and physical fitness for 40 years. I mean, Ken was very prescient in starting that database, and we've learned a lot from that. And looking at people and tracking their fitness and their physical activity over a very long time. And we said, okay, we want you to help us find people who, over 25 years and multiple visits to the Cooper Clinic have said on their questionnaire, yeah, I do no regular exercise. And we call those people sedentary. And we would allow…so two, up to less than two days a week of regular physical activity sedentary. Then we took people, okay, who did two to three days a week consistently over their lifetime. We call that casual exercise training. Then we looked at people who did four to five days a week. We call that committed training. And then a whole 'nother group of masters athletes who are called competitive training. And when we did the same techniques, we measured their heart compliance and their vascular compliance. And lo and behold, two to three days of exercise over a lifetime had no effect at all. It did not protect against that aging effect. Four to five days a week got us most of the way there. Close to the competitive athletes. Not exactly the same, not all the way there, but pretty close. So that gave us the sense that the optimal dose, if you will, of physical activity is four to five days a week over a lifetime, making–it's got to be part of your personal hygiene. We can talk about that a little bit later, because then the next question we had to ask was, all right, we studied our masters athletes and our healthy sedentary people at age 70, and our youthful people were at age 30. So when in the aging process does this begin? Right. So we partnered with the Dallas Heart Study, a large, community-based, very highly intensive epidemiologic study. And we looked at people who were in their thirties, in their forties, in their fifties, in their sixties, in their seventies, and we did the same studies on them. And what we found is that the heart starts to shrink in that late middle-age period. You know, if you think about aging at so late middle age is kind of that 50 to 65 period, early middle age is at 35 to 50 range. So the heart will get a little bit stiffer, but it's in that late middle range that starts to atrophy and get really, you see the most dramatic effects of aging. So we said, okay, well, is this all reversible? That was sort of the question you asked me earlier. And so we took our healthy seniors and we trained them for a year. We used the same training program that we used in a group of young people trying to make them endurance athletes. Well, I know you want to chat about that a little bit also. But we put them… We trained them hard, and they got fitter for sure. But we didn't change the heart structure at all, not even a little bit. So once you got to be age 70, it was virtually impossible to change the heart structure. That was very disappointing because we really thought we were going to be able to reverse it. And when we trained our young people, we saw very marked and very impressive increases in cardiac size and compliance and things like that. But we said, okay, what if we made a mistake? What if we started too late? And what if we didn't train them long enough? And what if we didn't train them hard enough? So we then said, okay, let's take a group of those late middle-agers in the sweet spot, let's train them hard, train them increasingly fit over a year, and then sustain that at our perfect dose, that four to five days a week, and we'll do that for two years. And lo and behold, we were able to reverse the effects of sedentary aging by sustained training at the right dose at the right time period in the aging process. So that paper, which was published in Circulation, got a lot of press. It still is among the top ten papers for something called outmetrics, which is the interest within the media and the public and the, the professional community, the top ten in the history of Circulation, which is the American Heart Association journal.

Rhonda Patrick: Incredible. How much would you say the heart aging was reversed in these mid-late? Was it late middle age? 50-year-olds?

Ben Levine: Yeah, 50-year-olds. So the answer to that is, from the standpoint of the youthfulness, the compliance of the heart, most of it. So we didn't get quite back to being a healthy 30-year-old, but we got pretty close. So there are a lot of other things that happen with aging that are not just related to the sedentariness of the circulation. Of course, one of the things that happens is you get accumulation of advanced glycation end products. You know what those are?

Rhonda Patrick: Yeah. Tell the audience, please.

Ben Levine: Yeah, yeah. So those are the things that. Not you, Rhonda, but other people stiffen your skin and cause wrinkles. We measure it in diabetics with hemoglobin A1c. It's a natural biologic chemical reaction called the Maillard reaction. Your audience is probably more familiar with it from basting a turkey. What do you think causes that crinkling and stiffening of a skin when you baste a turkey, it's this reaction, this complexing of glucose, sugars with carbohydrate, with collagen. And it happens in the skin, it happens in the blood vessels. It happens in the heart. So we actually gave a drug, which doesn't exist anymore. I have the last of it in my laboratory that breaks advanced glycation end products. And we gave it to another group of healthy sedentary seniors. We gave it to another group of healthy sedentary seniors. And one group just got the advanced glycation end-product inhibitor. One group got a placebo, another group did a year of training, just training. And another group did the advanced glycation end product and training. So four groups just taking the advanced glycation end product inhibitor didn't do anything. It worked in animals. We saw a marked improvement in rats. Nobody really cares that much about that because we're not rats. But it didn't help the sedentary humans. And once again, we saw that a year of training didn't do anything. But when we added the training and the advanced glycation end product inhibitor, we had about the equivalent of a 15-year reduction in the apparent vascular age of the circulation.

Rhonda Patrick: In 70-year-olds.

Ben Levine: Yeah, in 70-year-olds. That's right.

Rhonda Patrick: So the advanced glycation end products, it's interesting because it's very, as you mentioned, tied to blood glucose regulation. And of course, people with type 2 diabetes are the extreme case where. Or type 1 as well, like, they're not able to regulate their blood glucose and have probably the most risk of having higher levels of advanced glycation end products and vascular damage. So you mentioned the heart aging, and you talked about, I don't know if you started with when this starts, but the stiffening, you said is stiffening until about middle age, and then it starts to shrink. Is that correct?

Ben Levine: That's right.

Rhonda Patrick: So the question is, it's interesting that you were able to reverse this cardiac aging in these late middle-aged folks.

Ben Levine: Late middle age, yeah, 50 to 65. That's our late middle-aged target.

Rhonda Patrick: So you're already stiffening the blood vessels at that point.

Ben Levine: Yeah, you're probably having some stiffening. That's exactly right. It's not fully ensconced. It's still reversible by then.

Rhonda Patrick: Okay. So the question is, it'd be interesting to see if there were a subset of people, too, that, let's say, had very low HbA1c or something that did respond.

Ben Levine: It's a good question, Rhonda. And if you think about it, hemoglobin, which is what we're talking about when we measure hemoglobin A1c that lasts for 120 days, those red cells don't last forever. That's why hemoglobin A1c is such a good marker of diabetic control. Blood glucose is measuring your glucose instantaneously. Hemoglobin A1c is measuring the average over the last few months because that's how long hemoglobin lasts. But collagen lasts forever, so once you've glycated it, it's done. And that's why measuring glycated hemoglobin products in the skin or in the vasculature is a marker of something over an even longer time scale. We hoped to be able to break all those. To be honest with you, I'm not sure that we did. The animal data is very compelling. We did not actually take cardiac biopsies to prove that we had broken the advanced glycation end products. We just used the physiological consequence. And so one could argue that we didn't even do what we thought we did. But I think I was impressed enough by the combination of exercise training and breaking the AGEs. I'll use the acronym for simplicity's sake, that I do think it plays some role. It's obviously not the entire issue, because just breaking them by themselves didn't do anything. But the combination of the stretching of the blood vessels and the heart during exercise is perhaps enhanced, or was perhaps enhanced by breaking the advanced glycation end products.

Rhonda Patrick: So what would you say to someone who's in their seventies, that's been sedentary and wants to train four to five days a week? And so you're talking about this two-year study. I mean, I've read the methods section, too, and it's quite impressive. I mean, these people are, you know, they're doing a lot of physical activity and including vigorous intensity exercise, you know, where they're doing very intense exercise at least once, maybe twice a week. So what would you say to someone who's in their seventies? I mean, how can they improve their cardiovascular health?

Ben Levine: So I'm not saying that we should throw our hands up and saying, oh, it's too late. Cause that's clearly not true. Right. I will say, if you hope to overcome 70 years of bad behavior, of bad diet and sedentariness and smoking, you can't make that up with a couple of years of exercise training when you turn 70. That being said, there are a lot of other benefits to exercise training that are not related to cardiac structure. Right. You improve endothelial function. What I mean by that is the arteries have a lining inside them. That is, it's not like a lead pipe. It's actually alive. It's biological, and it allows for that smooth flow of blood. And then as you need more blood, like during exercise, those blood vessels start to expand. So the endothelium relaxes and opens up the blood vessels, and it's damaged the endothelium with cholesterol and hypertension and smoking over years that causes atherosclerotic disease. So it's a very important biologic phenomenon that is clearly improved by exercise training at any point in life. So I think that's really helpful. I think we know that exercise training alters the autonomic control of the circulation. The autonomic nervous system is that part of the brain and the nervous system that regulates those things that we don't have to think about. Like, you're not sitting here saying, what's my heart rate? Is it 60? Is it 50? How do I make it 62? That just happens in the background, right? And the autonomic nervous system has a brake, which is the parasympathetic nervous system. You've heard the term "vagal responses." And an accelerator, that's the sympathetic nervous system. And you're constantly balancing the brake and accelerator throughout your life. During exercise, you take your foot off the brake, you withdraw the vagus nerve, and you increase the sympathetic nerve. That's what speeds the heart rate during exercise. And that comes from signals in skeletal muscle. That's how your brain knows what to do during exercise. So we know that if you… This is going to be a little bit… I'm going to take a step back for 1 second. We know that if you have an acute heart attack and if I, in a dog, if I tie off a coronary artery with a little snare while they're running on the treadmill, some dogs will develop ventricular fibrillation and have a cardiac arrest, and they'll do it every single time. And if we resuscitate them, and then we put them on the treadmill and stimulate the vagus nerve to the heart and tie off the coronary, none of them have ventricular fibrillation. They don't die. And if you train them before you tie off the coronary artery without even stimulating the vagus nerve, you have the same effect. So the ability to increase vagus tone or neural activity in that parasympathetic nerve may be very protective against sudden cardiac death. And those things will happen even if you start training in your seventies. Lastly, of course, is people get fitter. We know I can make them fitter. I told you that. And that's good. That's important because unfortunately, with aging, you get less fit. Even if you're a master's athlete, you get less fit. I would be a fool if I sat here in front of you and told you that exercise training can completely prevent the aging process. I wish that it could, but it doesn't. But one of the most important things is that it preserves your aerobic power. This VO2 max. And so think about a cliff, right? And you're heading towards that cliff with aging. And that cliff is where the maximal effort that you have in your body that you can do is what you need to do–activities of daily living, that's in that three to four metabolic equivalents –METs–the amount of oxygen you need to just sit here quietly, three and a half milliliters of oxygen per minute, per kilogram of body mass. And once you get to that, you're really kind of in trouble, right? Because then everything you do in life is a maximal effort. Well, if that point is here and you're a masters athlete and you're up here, when you're young and you train all your life, you stay above that really well. If now you're unfit and you don't exercise your life and you're heading towards that cliff, what you want to do is change that trajectory and either push it up or flatten the curve a bit so that you prolong that period before you become disabled. And that comes down to both endurance training and strength training because you need both of those to be able to maintain functional capacity.

Rhonda Patrick: This is great. I do want to get a little bit more into both of those. The cardiorespiratory fitness and what it means for longevity. But just before, a couple more questions on your intervention study, exercise dose, intensity. So what about people that, let's say they're exercising, they're doing the committed exerciser, right? They're four to five days a week, but they think, well, I don't, you know, I'm exercising frequently. I don't need to get my heart rate up to a high intensity, like vigorous, where you're like 80, 85 percent max heart rate. What do you think about that is important because in your study, at least in the two-year intervention, people were definitely doing vigorous intensity exercise in addition, right?

Ben Levine: So that's, I think, one of the more challenging questions to sort out, right? Because if you were, I know you were listening carefully and reading carefully, I'm very, quite impressed by how prepared you've been to come to this interview. But we only stratify people by frequency. That's two to three, four to five, or six to seven. We didn't stratify them based on how many interval sessions they did or how long was their long run. Those are factors. The other components of dose include not just frequency, but intensity and duration. And you can imagine trying to quantify that over 25 years is kind of tough. People can tell you, yeah, I trained Tuesdays and Thursdays. I went out for a walk. I did my Zumba class. But if you ask them, well, how hard did you work and what was your heart rate and how long, that's a little harder to manage. I think that there clearly are advantages to higher-intensity exercise. There are also greater risks. So we know that exercise by itself does transiently increase risk for anybody at any time, and that's greater risk with higher intensity. Now, that risk is relatively small, and it depends on how fit you were to begin with. What do I mean by that? Well, the classic scenario is Detroit, Michigan, big snowstorm, the dad goes out, hasn't done any exercise, and needs to shovel the walk, and he has his cardiac arrest. Barry Franklin published those data many years ago. And what we know from a number of studies is that that risk of exercise is dramatically higher if you're unfit. So it may go up a hundredfold above. Background a burst of exercise if you don't do anything, if you're very fit, it may only go up. It still goes up, but it doesn't go up by that much. So maintaining fitness reduces the consequences of intense activity. But I think that we all have bursts of exercise during our lives, whether that be running up the stairs, trying to catch a bus or a train, running after a kid, whatever. And I think that we also know that high-intensity training relatively has relative advantages over lower-intensity training for improving maximal aerobic power. If you're going to ask me, what does high-intensity training mean? That's a whole 'nother discussion. I know you met with my friend Marty Gibala and had a discussion with him a few months ago. When I think about aerobic power, I like to think about Jan Hoff's 4 x 4, which is the old Norwegian ski team workout. Four minutes at 95 percent to max, followed by three minutes of recovery repeated four times. Even if you don't have a heart rate monitor on, it's basically as hard as you can go for four minutes. And at the end of that four minutes, you need to be ready to stop. And then at the end of the three minutes of recovery, you need to be ready to go again. And that's how you judge that intensity, completely independent of heart rate. And I think that if I compare a 30-minute moderate intensity session versus a 30-minute 4 x 4, clearly the 4 x 4 will have a greater benefit on improving aerobic power session per session. That being said, over time, I think there are great benefits to doing more moderate-intensity exercise. Also, it's lower risk, it's easier to do. It's emotionally easier for many people. Others love doing short-duration burst activity. They say, oh, my God, I can get… I mean, I can get the same benefit by only exercising for four minutes as opposed to 40 minutes. I'll do it. So it's very individual. And at the end of the day, certainly when you look at a competitive athlete, no athlete does just one thing. That's why a lot of the studies… That's why a lot of the studies in this field are a little bit artificial because they say, I'm going to do only moderate intensity training. There's a whole new burst of enthusiasm for zone two training. I mean, gosh, I've had about ten interviews about what is zone two training for your audience? Typically that means exercising hard enough that you get a little sweat on your brow, you can still talk, but you're a little short of breath. And I like to tell people, you can talk, but you can't sing. That's a good indicator of that higher level of zone two training. So the ideal strategy then is to incorporate all kinds of training. That's what the human body is best at adapting to. It doesn't really adapt very well to doing the same thing over and over and over again. You will not get fitter if you do that. And in fact, in our two-year training study, if you read below the lines a little bit, we markedly upscaled people. These were completely sedentary and we worked them very hard for a year, including multiple high-intensity sessions, prolonged sessions. But then we said, all right, I want you to sustain that for a year. So we dropped them to only one interval session a week and one long session a week. And we didn't increase the dose. We didn't increase the frequency or duration or intensity over that last year. And you know what? They didn't get any fitter and their hearts didn't get any bigger. The only thing that got bigger was the atria. And we can chat about that when we get to talking about toxicity of exercise training. So the human, to come back to our point, the human body doesn't adapt very well to doing the same thing over and over again. And so my prescription for life, if you will, is one that mixes things up. So I suggest to people that you spend, do at least one day of a long session that lasts at least an hour, and it should be fun. I don't care what it is. It could be, you know, going square dancing. It could be a long walk with your spouse or a long bike ride. It could be some other class that you take, but it needs to last over an hour and it needs to be fun. Second thing you need to do is do one high-intensity session a week. I like the 4 x 4. I think it's very effective. There's great data about it from the Norwegians, but I don't care if you did 2 by 6 or if you're a Marty Gibala fan, if you did 30 seconds times eight, it doesn't really matter. Just do one thing at high intensity, and then do two or three sessions of that moderate intensity, at least 30 minutes getting the talk test, and then supplement that with one or two days of strength training. And what I mean by strength training, it doesn't mean you have to go to the gym and pump iron. It could be Pilates, it could be strength yoga, anything that requires training of strength and skeletal muscle. And if you do that over your whole life, I think that's the best strategy for preserving cardiovascular health. Now, if you tell me you want to run an Ironman, you got to train different than that, okay? And that's a really important thing for your audience to understand. Training for health versus training for performance, right? Every coach knows how to train for performance. And so if that's your objective, if your goal is to have a competitive performance objective, then you have to train differently. If you tell me your goal is, I just want to preserve my health and stay fit and have a good life, then you don't need to train 30 hours a week. But if you want to compete in Kona, you need to train 20 to 30 hours a week or you're not going to be successful. So I think you've got to just clearly identify what your goal of your fitness is and your goal of your overall health, and that's what will guide your training program over your life. Let me just add one more thing. I can see the questions circling around in your head. I forgot what I was going to say. We'll come back to it later.

Rhonda Patrick: So definitely a lot of questions, and I'm trying to figure out where to go first. So I think the cardiorespiratory fitness and the VO2 max, and lots of questions with that, starting with you talking about what your goal is. Right. So do you want to be a master's athlete? Do you want to train for health and longevity? I loved the way you explained the cardiorespiratory fitness and function, how it keeps going down with age and how you kind of want to stay above this level. And if you start way up here, you know, it's easier to kind of go down. It's going back to that same analogy, like contributing to your retirement fund. Dr. Brad Schoenfeld talked about this on the podcast with muscle mass, and it applies to so many different areas. And I think cardiorespiratory fitness is another one. Right. If you're starting way up here, then the decrease with age, you know, it's not going to be as big of a deal functionally. So why do you think cardiorespiratory fitness does correlate with longevity? Is this relationship with reduced… So the higher the VO2 max, which is a marker of cardiorespiratory fitness, the lower the mortality risk.

Ben Levine: So I'm going to remember your question. I remember what I wanted to say, so let me go back to that. Okay. So the one thing I want to say is that exercise needs to be part of your personal hygiene. It can't be something that you just add on at the end of the day when you're tired and you don't really want to do it. It has to be part of your life, like brushing your teeth, taking a shower, changing your underwear, having breakfast. These are things you do to stay healthy. And exercise is one of those. And the mindset of people who sustain exercise over a lifetime and who are able to do this over and over again and who are able to stay fit and healthy is that it's part of their lives. It's not something they just add on.

Rhonda Patrick: Right. So you brush your teeth twice a day because you don't want cavities. Well, you exercise because you don't want cardiovascular disease. Right. I mean, that's, there's other reasons you exercise, too. Dementia. But, yeah, I love that "part of your hygiene" where it's not just, oh, it's this thing I, I have time for you. Right? No, it's, no, it's, you do it. It's just like you brush your teeth. So the VO2 max and longevity correlation. Why do you think VO2 max correlates with longevity?

Ben Levine: So, first of all, I think it's important to realize that correlation is relatively weak when we're talking about the effect of aerobic power on longevity. There's a number of reasons why I think that relationship exists. First of all, if you're not sick, it's easier to exercise hard and preserve your good power. So there is a bias associated with looking at those factors, regardless of how well you try to control for them. Statistically, that bias exists. There's nothing you can do about that. So, it certainly helps to be well enough to continue to train and be fit. So if you get cardiovascular disease or cancer or neurologic disease, it's harder to sustain your fitness. And so just be a little bit careful about that. VO2 max is a function of two things. There's a very famous equation called the Fick equation, which relates VO2. That's the volume or the ventilatory oxygen uptake. I started this podcast by talking about what that means, but it's a function of two things. The cardiac output, that's how much blood the heart can pump, and the AVO2 difference, the arterial venous oxygen difference, which is how much oxygen is extracted in the skeletal muscle. And so the cardiac output is also a function of two things, heart rate and stroke volume. Stroke volume is the amount of blood that the heart can pump per beat. So the heart relaxes, and when it's done relaxing, that's the end diastolic volume, the time when the heart is completely relaxed that it's at its biggest, and then it contracts and pushes that blood out. That's the end systolic volume. And the difference between those two is the stroke volume. The stroke volume times the heart rate is the cardiac output. Now, let's look at an elite athlete versus a sedentary person. An elite athlete can extract more oxygen than a sedentary person, but not so much more. It's not a lot more than a sedentary person. And the heart rate, the max heart rate of an elite athlete, if anything, is lower than that of a sedentary person. So the biggest difference between being sedentary and have high levels of aerobic power is having a big stroke volume. So having a heart that is nice and stretchable and compliant, that can relax to a large amount, let your muscles pump blood back to it, and can contract strongly and vigorously and pump that blood out into the blood vessels, that is the biggest adaptation that allows you to be an elite athlete.

Rhonda Patrick: Well, that goes back to your, you know how exercise improves cardiac structure and function because the heart's not atrophying, it's getting bigger, and it's not stiffening. It's being more stretchable. So.

Ben Levine: Exactly. So I think that there are clear advantages into heart structure and vascular function by sending all this blood out and pumping large amounts of blood. In a healthy vascular system, the aorta and the large blood vessels accommodate that blood. It's called the Windkessel effect. When the heart pumps the blood into the aorta, it expands. That's why it needs to be nice and compliant. And then in between heartbeats, it releases that blood into the rest of the circulation. So, that sustained dilation is what requires a flexible arterial system as well as a flexible heart. The heart and the blood vessels are coupled together very tightly. That's called ventricular arterial coupling in the physiology world, but they need to be coupled. And I think having a nice, regular, flexible aorta becomes really essential. Of course, if you've got aortic diseases, Marfan syndrome, for example, genetic diseases of the blood vessels, then exercise can be quite dangerous for some of those people, and the aorta can tear. That's called an aortic dissection. So we know that exercise clearly does drive more blood out into the aorta. I think that the advantages and the reasons why high aerobic power improves mortality is it preserves vascular structure, improves endothelial function, optimizes autonomic tone, preserves the mitochondrial function. The mitochondria are those little energy-producing organelles, subcellular things within your skeletal muscle, within your cardiac muscle, even within your brain, which utilize all that oxygen. So it preserves the energy-producing architecture of many of your organs. And all those things are advantageous and leading to mortality or preserving of mortality. Now, you have to ask yourself, what kills people? Well, one thing that kills people is cardiovascular disease. And again, I wish I could tell you that exercise completely protects you from cardiovascular disease. It does not. Athletes get hypertension. They have high cholesterol. There are genetic effects that influence the development of cardiovascular disease. So exercise will not provide immortality, but it will help you manage those diseases of human life. There is some evidence that exercise can be protective against certain kinds of cancers. That evidence has been challenged recently, but I do think the overwhelming weight of the evidence is that it reduces the risk of breast cancer and colon cancer. And how it does that, I'm not 100 percent sure, but I think increasing blood flow on a regular basis is beneficial. And it, of course, by utilizing energy, it helps to prevent diabetes. And if you have diabetes, it helps to manage diabetes. It increases blood flow to the brain and has some modest effect about preventing dementia. It will not prevent you from getting Alzheimer's disease if you're genetically inclined. I wish we completely understood why people get it. We don't, but it certainly will reduce that risk. So I think it is a combination of the physiologic adaptations to exercise at every step of that oxygen cascade, the heart muscle, the blood vessels, the mitochondria, the sustained high rates of energy expenditure of multiple organs that help to protect and improve mortality with higher levels of fitness.

Rhonda Patrick: So you've, I'm sure, seen this JAMA study in 2018 that was published and looking at cardiorespiratory fitness and mortality. And the interesting thing to me about that study wasn't so much that, okay, well, if you're low cardiorespiratory fitness, you have a five-fold increased mortality rate over people that are more elite. So they're in the top 2.3 percent of cardiorespiratory fitness. But what was so interesting to me, and again, you mentioned reverse causation, so that's obviously, people that are more fit are able to exercise more. With that in mind, the fact that when all these other diseases or negative habits were looked at, for example, smoking, it was, at least by the data and the hazard ratio, it was clearly worse to be in the low fitness group. So the bottom 25 percent of the population that was looked at, they had a higher risk of mortality being in that low fitness group than smoking.

Ben Levine: So be a little bit careful about that for your audience. What often is reported in literature is relative risk, not absolute risk. So there is a protection of one compared to the other. But, for example, if being low fit were to be a low absolute risk, then a little bit of protection doesn't change if, let's say, your risk of dying in the next ten years is 1 percent, and I reduced that risk by 50 percent, 1.5 hazard ratio, I've only reduced your risk by 0.5 percent. So the absolute benefit is relatively small. So you sent me that paper, and, of course, I was aware of it. It's by my good friend Dermot Phelan when he was at the Cleveland Clinic and his team there. So I know the data well. We knew about that when we put together the scientific statement for the American Heart Association suggesting that cardiorespiratory fitness be included as a vital sign, the same thing as your blood pressure and your body weight. When you go to see your doctor, you're supposed to have them ask you, what's your fitness level? There are ways to do that within the electronic medical record now. Simple. Liz Joy and Bob Salus, when they were both presidents of the American College of Sports Medicine, have pushed the exercise vital sign, which is very simple. How many days a week do you exercise? Enough to get a little bit of sweat on your brow and make you a little short of breath. And how long do you do it? Multiply frequency times duration. Get your physical activity vital sign. So your doctor should be asking you that, or if he or she isn't, you should tell them. But. So when you come back down to that Cleveland Clinic study, remember there are two things. First of all, these were people who were referred for exercise testing. These were not healthy people. Okay? These are people, all who had some complaint. Some of them had valvular disease, some of them had heart disease. None of them were a fitness test on a competitive athlete. And if you look at the elite fitness level, they are nowhere near elite. The peak VO2 was in the young people was 50 mls per kilogram per minute. I mean, that's 50 percent less than a competitive athlete at that level. So calling them elite was a little bit disingenuous. In my mind, they were the top percentage of people referred for exercise testing, but they're nowhere near elite. These are not people doing 10, 12, 15 hours of exercise a week. This is 50 mls per minute per kilogram. That's an average fit. Good, good fit, but good fit young person. So by looking at percentages of predicted of healthy people, you can get a little bit of a different perspective. I don't think you should take the message home that there's no upper limit, and you can just keep on training and you'll keep getting better. I do think the message that fitness is as important as other cardiovascular risk factors is critical, and I think that's a very important take-home message. I don't put too much stock in comparing relative risk scores. I don't think that's helpful without knowing the absolute risk data. But my friend Steve Blair used to say, I'd rather be fit and fat than lean and sedentary.

Rhonda Patrick: Yeah. So it sounds like measuring your cardiorespiratory fitness is, at the very least, a good biomarker.

Ben Levine: Absolutely.

Rhonda Patrick: Of your health. And like you said, relative risk. Well, so you're talking about a 30-year-old. Yeah. Their risk of death is quite low, but when you start to get to 70, you got a 75-year-old male. Their VO2 max that relative, I mean, that absolute risk matters more. Right? Cause they do have a higher risk of dying from heart diseases or whatever. Right. Age-related diseases.

Ben Levine: We're not going to get rid of that. We're not going to extend the human lifespan forever. But you're right, and we made a strong case for that in our scientific statement. I do think that the risk is as important as smoking and as hypertension, and they have different treatments. I think the other thing to be careful about is there is some data from the Cooper Clinic mostly, but also from others. Jonathan Myers at the VA in California has shown that if you measure fitness at one particular point in time, people who gain fitness gain advantage equivalent to people who have sustained fitness, and people who lose fitness lose that advantage. There are much fewer studies of changes in fitness over time, as there are about a single-point measure. So you have to. The data are not as robust as what happens if you stop smoking, or what happens if you treat high blood pressure, or what happens if you treat high cholesterol. Those data are hundreds of thousands of people, really high-quality clinical trials treating these diseases. So we know what the outcome is. I know less about what happens if I take a 50-year-old and I train them and I increase their VO2 max by ten or 20 percent. What does that do to their subsequent mortality? I don't know that as well. There are data there. I think they're encouraging, but they're not as certain. For example, I know for sure that I need to lower your blood pressure if it's too high, and I think our targets are getting progressively lower. Same thing with cholesterol. I know for sure that treating it will lower your cholesterol or lower your risk of having a heart attack, for example, or having cardiovascular outcomes. So I do think that measuring your fitness gives you a leverage to say, okay, let's improve that fitness. And there are many reasons to do it beyond mortality. I view lifespan as only one objective of healthcare. Healthspan is at least, if not more important. Certainly, that's true for me.

Rhonda Patrick: Right. I also think that you said, you mentioned the changes in VO2 max, and so if you're not improving at a certain point, you mentioned earlier about people that are doing the same thing. For example, they're not really improving their cardiorespiratory fitness. And I'm wondering if that also goes back to this non-response. What is this non-response where people will…They'll meet the requirements for, you know, physical activity guidelines? They're doing two-and-a-half hours of exercise a week, and yet they can't improve their cardiorespiratory fitness.

Ben Levine: So I think there are a couple of things to think about there. Number one is if those people were doing nothing, they would be a lot less fit, okay? That's for sure. And I can make almost anybody fitter. And there's a little bit of disingenuous about the non-responders also, it's non-responders to the dose that they've been given. It's the same thing, like saying, you telling me, look, you know, when I take one Tylenol, it doesn't get rid of my headache, but if I take two, it gets rid of my headache. My husband, he does fine with just one Tylenol, right? So I think there is a dose response of exercise just like there is for any other medication. That's one of the rationales behind Bob Salus's "exercise is medicine." And so Carson Lundy and his group in Copenhagen have shown very clearly that if you take someone who's a non-responder, non responder in quotes, and increase their training dose, they all improve. So I don't think, I'm sure there must be some people who are non-responsive. But in our study in Erin Howden's. Erin now is a player and cardiovascular expert at the Baker Heart Institute in Melbourne, Australia. In her study about the two year training in the 50-year-olds, we had zero non-responders. Zero.

Rhonda Patrick: Right. But you were also adding in, I think some of those non-response, like you said, the dose changes or the intensity, they add in some high intensity, all of a sudden they're responding. So again, going back to your point where mixing it up, and you do want to continually to challenge yourself. Right. I mean, you don't want to just do the same thing every single day.

Ben Levine: Right. And I think that there's a number of benefits to that. We're talking now as a, how do you adjust your hygiene? Right. I'm not necessarily saying that you want to do things to steadily improve your fitness progressively over a lifetime. I think that's almost impossible to do. You want to achieve a level of fitness and sustain that over life. That's a difference. And we're coming back then to the performance versus the health benefits of exercise. So I think doing the same thing over and over again for some people, they love it. They find that very satisfying. And doing that and preserving their fitness, I think is important. For some people, it gets boring and they want to mix it up and they want to change what they're doing, and that gives them more, more joy, and it also helps them stay compliant with physical activity over a lifespan. So I think, though, and my own bias is that the different kinds of exercise have different roles in improving and preserving fitness over a lifetime. I mean, if you want to run your 5-K faster, you gotta train harder, you know what I mean? But if your goal is, look, I'm happy with my, you know, 30 minutes, 5-K, and I don't care about running that faster. I just want to stay, well, then increasing the dose has less benefit for you.

Rhonda Patrick: So you're mentioning the stroke volume being really important for cardiorespiratory fitness. I mean, is that the limiting factor? Like, is that how, what is the limiting factor for improving your VO2 max?

Ben Levine: Right. So I think that for an elite competitive athlete, the stroke volume and the cardiac output are the limiting factor. And I know this because if I blood dope them and I give them more blood, their muscles can accept that just fine and they get faster. It's just the ability to get that blood to the muscle that's important. The muscle has a lot of reserve, and obviously there comes a point where you can't make the heart any bigger. But I do think that that is the primary difference between the elite of the elite and the sub-elite. Now, that's different. If you told me I've got a 50-year-old guy who wants to start training, or a patient with hypertrophic cardiomyopathy, a genetic disease of the heart muscle. James McNamara at our institution has been studying how you make those people fitter. They've been told their whole lives don't train because earlier data suggested that patients with that kind of genetic disease were at risk for dying during exercise. Turns out that now the evidence in the last couple of years has become much more obvious that those types of individuals can safely train. And in fact, regular physical activity and fitness is critical to their survival. Some animal data suggesting that if they train when they're young, they may even prevent the full expression of the disease. We're working on that right now. But those kind of individuals, particularly some who may be limited by cardiac limitations, will improve their ability of the muscle to extract oxygen. And I think when you get to the elite level, everything ends up being optimized. Maximal lung function, maximal cardiac function, maximal muscle function, and they are all linked together in the entire oxygen cascade. For people who are sub-elite, who have not raised each particular part of that physiological process to their limits, can improve VO2 max by increasing oxygen extraction, they can increase the enzymes producing oxygen in their muscle. They can increase the number and size of mitochondria they will increase their AVO2 difference. They can't increase it forever, and so you increase that. And particularly if you've got a cardiac limitation, if you're sedentary and don't have one, you may increase both in parallel. But it's the cardiac limitation that gets differentiates the highest levels of aerobic power fitness from the less lower. Let me give you an example. We tried, we took a group of young people because I wondered how much of this extraordinary aerobic power is genetic and how much is trainable. We took a group of sedentary young people in their thirties, and I train them to be marathon runners. I train them to be successfully complete, either a marathon or a hundred-mile bike ride. And we made them a lot fitter. Some of the largest gains in heart size and fitness than anyone's ever seen, including long duration, two hour, up to two hour runs on the weekend, multiple workouts, high-intensity sessions over the weekend. I threw everything I could at them, and frankly, I couldn't make their hearts as big as our competitive athletes, the lifelong competitive athletes. No, no, these are young people. These are 30. So, well, lifelong. Up until then, so high level competitive athletes, I just couldn't get the heart size the same. They got a lot bigger, but not the same. And I've wondered why that is. One thing to remember is that the heart is constrained by a stiff fibrous sac called the pericardium. The pericardium is really important. It allows the right and the left ventricles to function together. Remember, the right ventricle pumps blood to the lungs. The left ventricle pumps it to the body. They work in concert. The pericardium preserves that ventricular interaction in a positive way. And it may be that training for one year, or maybe even two years, isn't enough to stretch that pericardium. The myocardium, the skeletal muscle is very adaptive, the pericardium less so. It's also possible that you have to train when you're growing to get the biggest bang for your buck that you know. Obviously, the pericardium constrains the heart of a baby as much as it does the heart of a elite athlete. And as the heart grows and adds myofibers, the muscle fibers within the heart, the pericardium adapts and remodels to accommodate that. It may be that those things have to rise together in order to get the truly biggest hearts of the most elite athletes. I don't know that. There are some studies ongoing in Europe and in the US to try to address that. Guido Klassen and Andre Laguerre have the Pro at Heart Study that are looking at young athletes. I don't know that anyone's looking at kids that are starting when they're 12, though. Justin Lawley and Innsbruck is trying to do that. A group in Norway is trying to do that. So I think that we are, as a community, trying to get that. It's hard to study kids, but I guess I suspect that you've got to train when you're growing to get the maximal ability. Antonio Pulisia from the Italian Olympic Committee, really, one could argue, the father of the whole concept of sports cardiology in the world, has studied athletes who have participated in multiple Olympics, up to four, even five Olympics. That's a lot of Olympics. And what he shows is that if he looks at their heart size over 12 or 16 years of sustained, high-intensity Olympic competition, it doesn't get a lot bigger. And so these are people who have acquired that fitness to get to the Olympic level and then to sustain that over time. It's not that they're progressively getting bigger, they're sustaining and preserving their fitness and their heart size, but there may well be a limit to how big that can be. Of course, you're limited by the size of your body, right. The heart can't just go continue to get big forever. So obviously there's an upper limit to that.

Rhonda Patrick: At some point, can you sort of differentiate between... So I've heard you talk about, I mean, you're talking about the adaptations to endurance type of aerobic exercise, versus, I mean, Olympic athletes that are more strength training. Right. So in terms of this adaptation of the heart getting bigger, how are the adaptations different?

Ben Levine: Well, so I'm going to give you the traditional thought, and then I'm going to tell you that that's not probably 100 percent right. So the traditional thought, what has been called the Morganroth hypothesis, is that strength training, which does not increase venous return, that is, the blood returning to the heart, it doesn't increase stroke volume very much because it imparts a huge afterload, a rise in pressure during a static strength contraction. Any idea how much the blood pressure goes up during exercise? Do you know this?

Rhonda Patrick: Which kind of exercise?

Ben Levine: Strength exercise.

Rhonda Patrick: Definitely [with] hypertension, I mean, 180 systolic.

Ben Levine: So if you're going to do. If I take a competitive athlete and I do a 90 percent, one repetition max squat, what do you think the systolic blood pressure gets to?

Rhonda Patrick: Oh, like a multi-joint squat, like 200.

Ben Levine: Keep going.

Rhonda Patrick: 250.

Ben Levine: Keep going.

Rhonda Patrick: 300.

Rhonda Patrick: 400.

Ben Levine: 400 millimeters mercury. Yeah. John Sutton and his colleagues put arterial lines and showed that many years ago. So you generate that kind of pressure by intense muscle contraction, which contracts the blood vessels. So now you're driving stroke volume into a very small, much smaller space than you did before. There's massive sympathetic activation from something called the exercise pressor reflex, which is a function of both the relative intensity and the total maximal muscle contraction. That raises arterial pressure very high during the contraction. To adapt to that, in order to reduce the load on the heart, the heart has to thicken because the wall stress, the stress on the heart muscle is increased, the bigger the heart is, but is decreased, the thicker the heart is. So traditionally, purely strength trained athletes tend to have thicker hearts, what we call concentric hypertrophy, as opposed to dilated hearts, which we call eccentric hypertrophy. And athletes who do almost exclusively endurance training, runners, swimmers, cross country skiers, in the days before skating technique, they have massive increases in blood flow. So the adaptation of the heart is to get bigger to accommodate and then sustain those big stroke volumes. So that's the sort of traditional view. The endurance athlete has a bigger heart, which is eccentrically remodeled. I mean, if I just stretched it without making the heart thicker, the walls would get smaller. That's not what happens, right? The heart adapts, gets bigger and more muscular, but the walls don't get thicker. A strength trained athlete, the heart doesn't dilate, the walls just get bigger.

Rhonda Patrick: And it's the eccentric hypertrophy that's important for stroke volume and thus cardiorespiratory fitness.

Ben Levine: Exactly. That's correct. It turns out that it's not, probably not so simple. And it's not so simple for a number of reasons, because even during dynamic exercise, when you contract your muscles and run, you're actually occluding blood flow during those too. And many sports, like rowing, for example, are an intense combination of both static and dynamic, or strength and endurance type activity. So, rowers, every time they pull on the oars, they use a massive amount of skeletal muscle that's contracting. But they're also doing that in a rhythmic basis like a runner or a swimmer. So they're doing both strength and endurance. And they have the biggest hearts of any athletes. The biggest hearts that you ever see are in the rowers and now in some skiers. So, you know, skating technique in skiing is a huge strength as well as an endurance component, you know, and in the, I guess, gosh, this is 1984. For 40 years, we've been classifying sports into their static versus dynamic exercise. And we created a little matrix, low, medium and high endurance, low, medium and high static. So a nine-box factor. In the Bethesda guidelines for managing of athletes with heart disease, we put sports in these different bins. We're revising those guidelines, those scientific statements right now, and we're going to change how we display this. We've eliminated the individual boxes and we say there are increasing amounts of endurance requirements in the sport and increasing amount of strength requirements in the sport. But it's not so simple. I can't just put them into little bins because, I mean, even golfers strength train, right? And even some strength trained athletes will do aerobic exercise. You know, most football, American football players don't do anything more than 10 seconds, never. You know, I tend to recommend to the trainers that even the strength trained of those athletes will be better off if we incorporate some higher intensity. They're the perfect people to do not just a ten-second effort, which is all they ever do, but do a one minute or a two minute. I mean, how long do multiple, multiple plays series take last in a football game, for example, American football game, I think they need to do 4 by 4 or 2 by 2, and that's what's going to allow them to sustain their fitness and not get tired when they're playing fast on the sport. So I think we realize that sport is not so simple even within a sport. You know, the goalies are different than the fullbacks. In American football, the defensive backs are different than the linemen. It's just really different. And so we can't just bin sports. And all of sport, people will train with strength, and even runners are training with doing weight training and doing strength training. Even runners are doing strength training these days.

Rhonda Patrick: You know, to not, I'm trying not to bin them, but I'm going to bin them. So let's say purely strength trainers. There does seem to be an argument then that they should definitely incorporate some endurance training, if not for the stroke volume increase and eccentric hypertrophy and the effects on cardiorespiratory fitness.

Ben Levine: So I think that for, I think for strength trained athletes, it's a mistake not to do any endurance. We can argue about what endurance means, whether that two minutes or four minutes or 40 minutes is endurance. And I think that there are different ways to skin the cat, so to speak. Certainly for long term health, that becomes critically important. Jonathan Kim and Atlantis worked very closely with the National Football League to help retired NFL players figure out how to change their training and their eating and their habits to preserve their health over their lifetimes. So the football careers just aren't that long. So I think you're right that for performance, maybe not for Olympic weightlifting, you know, but for other strength sports, I think there's no question that endurance is important. And for sports that require repetitive bursts of strength activities, I think some type of endurance training of some degree, whether that be high intensity 4 x 4s or something, is critical for performance and will enhance performance. When we talk about cardiovascular health, that's a little bit of a different story. And I think that it is important for overall cardiovascular health, in fact, essential to include that over time. Again, I'll come back to the point that no good athlete does just one thing. I think that's where our studies are a little bit too isolated, because in order to do the research, you've got to focus on and ask one simple question. But training is not that simple in real life.

Rhonda Patrick: There are people that are much more focused on resistance training and strength training that are not athletes. They're just interested in health. And some people wonder, well, I'm getting my heart rate up to sub-, almost maximal heart rate when I'm doing my compound lifts, my deadlifts or my squats. And how much of that counts towards, am I getting this improvement in eccentric hypertrophy and stroke volume? Or do I need to then incorporate some other types of training as well?

Ben Levine: You're articulating the CrossFit concept, basically. I think that. I'll tell you that it kind of depends. I think that if you ask what happens to the heart rate and cardiac output during a purely strength activity, there are things that drive the heart rate that are controlled differently in a strength activity and an endurance activity. Let me dig into that, if that's okay. There's a little bit of science.

Rhonda Patrick: Please do.

Ben Levine: All right, so let's first talk about something called the exercise pressor reflex. So simply, the easiest to study by doing just a hand grip exercise. Okay. But it would be true for any. If I squeeze my hand, okay, that's the same as, you know, doing a short static exercise, do a hand grip, and I do it at, let's say, 30 percent of a maximal contraction and I hold it. Okay. Heart rate will steadily rise. Blood pressure will steadily rise. If I put a little needle in an efferent sympathetic nerve as it passes by the fibular head, that's called microneurography. I can actually record signals from the brain to the blood vessels which cause vasoconstriction throughout the body. Okay? It's a brain-driven process which comes from feedback from skeletal muscle. How do I know that? Let's say I do that, and until I can't do it anymore, and I take a blood pressure cuff and I blow it up on the arm, and I trap all the muscle, all the metabolites, the things that are happening in the muscle that are causing fatigue, that are utilizing that energy, and I trap them there, and then I stop exercise. I let go. Heart rate comes all the way back to baseline immediately, but blood pressure stays up and the sympathetic nervous system stays up, and that is the essence of the exercise pressor reflex. The heart rate is… Now, you can ask me, is the heart rate controlled by the brain then, because I've stopped exercising. So the brain's no longer trying to make something happen. That's called central command. Or is it happening because muscle tension, nothing to do with metabolites, because I stopped exercising? Well, to address that, one of my mentors, Jere Mitchell, went to Copenhagen, and Neils Secker injected some curare into the nerves, which paralyzes them. And they had them look at a screen, and they said, I want you to try to squeeze as hard as you did before. But because the hand was paralyzed, they couldn't contract the muscle, but they could try really hard. And heart rate went up even higher, even though the muscle was not contracting. So we know that this vagal withdrawal and sympathetic activation comes to some.. The heart rate in particular comes from the central command. The sympathetic activity also is stimulated by what's called group three and group four, large and smaller, unmyelinated fibers, fibers that are not insulated, that carry signals from the muscle to the brain and say, something's wrong. Let's alert. Let's get that blood pressure up. Increased nerve activity, constricting the blood vessels. So that's called the exercise pressor reflex. The harder you squeeze, the longer you do it for. Okay. The more amount of muscle mass, the bigger the blood pressure response. So that's one component. Okay. How is the heart rate regulated during dynamic exercise? During running, for example? Well, it turns out that it is almost certainly coming from an energetic signal in your skeletal muscle. How do I know that? Well, some patients have diseases of the mitochondria. They're called metabolic or mitochondrial myopathies. And one of my colleagues at the Institute for Exercise and Environmental Medicine, Ron Haller, studied… He was a neurologist that studied those patients. He's since retired. He's not dead, just retired. And what he found is when those patients started to exercise, their cardiac output went through the roof. Their venous blood looked red because they couldn't extract the oxygen. They had a problem in the muscle, but they would… You and I might increase the cardiac output by about five liters for every liter of oxygen uptake, these people were increasing up by ten or 20 liters. So even just walking down the hall is maximal exercise to them. And what that tells us, it is a signal that we need energy, we need oxygen delivered and fuel that drives the heart rate response and the cardiac output response during endurance exercise. So those are two fundamentally different things. One increases the heart rate during a muscle contraction from central command. The other drives cardiac output to match venous return. The more the compliant the heart, the more blood could come back, the more it can pump out. And those two things are happening to a greater or lesser degree with any combination of movements. That's why, I mean, it's no longer so simple to talk about just strength or just endurance. And then that gets me back to the question we started with. Why are you training? What's the purpose? Some people tell me they want to look good. They want their muscles to be big. They want to have, you know, relatively little muscle fat. They want to be strong. I say, well, then you got to do a lot of strength exercise. You know, if what you want is to perform during a CrossFit competition, you gotta do CrossFit work. I think CrossFit is very interesting to me because it's a combination of repetitive strength type maneuvers, but they also include repetitive muscle contraction. So I think that kind of exercise does have both an endurance and a strength component. Mike Emery from Cleveland Clinic now is a huge fan of the CrossFit type training and believes that it will get you a combination of eccentric and concentric type hypertrophy. And again, it's where this Morgenroth hypothesis kind of falls apart, because it's not one thing or the other. It's kind of a combination of both. I don't think you can lift free weights and expect that… Yeah, I slammed down the weights on the floor, walked around in between my sets, that you're going to get an endurance type trained heart that requires a more sustained repetitive contraction and more dynamic type exercise to engage. I know that's a little complicated. Does that help?

Rhonda Patrick: Wonderful. Wonderful. I mean, I also love that you did bring up the CrossFit. I have been doing in CrossFit for the last few months. And also there is an incorporation of a lot of high intensity. There's rowing, there's jumping rope, there's getting on the bike. So it is like you said, it's not, you can't just put strength training and resistance training in one bin and endurance in another. Particularly with a lot of these programs now that are available, like CrossFit. Orange Theory's another one. They do, they have something very similar. But you're right, just like if you're just raising the dumbbells and doing, there's not as much of the endurance kind of training there. So it's good to talk about the science there on that. I kind of want to go back to the blood pressure thing as well, because there was an interesting study that was recently published that made a lot of headlines on these isometric types of exercises. Right. The static hold and being better at improving blood pressure. What is the best exercise to improve blood pressure? Right? I mean..

Ben Levine: So, you know, when we take care of patients with hypertension, the first thing the community tells us to do is lifestyle modification. Reduce intake of salt, reduce intake of alcohol, make sure you're getting plenty of sleep, and increased exercise. I will say that traditionally, my approach has been that dynamic exercise is best because that causes relaxation of blood vessels. That's how you get the blood to the exercising muscle. And we'll do one more little science thing, because the body has both a general alerting response as a function of the exercise pressor reflex and a local response. So when I'm exercising hard, the muscles that are contracting are relaxed. Blood vessels everywhere else are contracted. It's really interesting. So if I'm running, the blood vessels in my arms are contracting as they are in my kidney and my gut. And that's why you sometimes will get catastrophic gut ischemia during extraordinary endurance exercise, because you just don't have enough blood in your circulation to maintain your blood pressure if you've got a lot of skeletal muscle that's requiring blood. It's one thing that the, let's call it the Saltin hypothesis about the cardiovascular limitation to exercise. Because if you add arm exercise while you're doing intense leg exercise, you start to constrict the blood vessels, even in the legs, because you simply cannot sustain your blood pressure with all the blood vessels relaxed, even with a maximal cardiac output. So the blood vessels have to constrict, but they constrict from this general alerting, increased sympathetic activity. But in the muscles, you get something called functional sympatholysis. What that means is the muscles are releasing metabolites, not just from the muscle, but from the blood vessels and from the red blood cells themselves. ATP and ADP are dramatically potent vasodilators. So you get constriction in one place and dilation in another place. And it is the regular contraction, the need, the release of those metabolites, the driving of the cardiac output response that causes relaxation of the blood vessels. And that's what I want in hypertension. I want the blood vessels to be relaxed. Remember we started this by saying blood pressure. I didn't. Maybe I didn't. We talk about the Fick equation. Blood pressure is also a function of two things. Two things only, cardiac output and vascular resistance. We talked that cardiac output is heart rate and stroke volume. So blood pressure is the triple product of heart rate, stroke volume and vascular resistance, with probably resistance being a very major component. What I typically think is that people need to do sustained endurance activity to dilate those blood vessels, cause that relaxation, and let those blood vessels start to relax as the best way to reduce blood pressure. I don't know what to make about the static training study. It's just one study. It really contradicts a lot of other data in the literature. I don't think that people say, oh, let me quickly switch to doing planks in leg sits against the wall just because this one study showed a low blood pressure. No, for the most part, unfortunately, if you have hypertension and have already done your lifestyle modification, you're probably going to need medication to drop your blood pressure. Hypertension is a cardiovascular disorder, and we've learned that a lot of people are going to develop it. And so I think the lifestyle stuff is the foundation. I don't think it's going to make a huge difference whether you do, whether it changes my prescription for life, that remains the same. And I think having a strong component of endurance exercise, but incorporating strength because that's important for life and function as you get older, I think all of that is really important, and it's not going to change my prescription. I do have specific approaches to hypertension in physically active people, but I will remind your audience that many people are salt sensitive, and reducing salt intake in the diet is important. If you have hypertension, maintaining a high potassium intake is also important. And then watch your alcohol, because I think sometimes doctors don't tell you that, but that too much alcohol intake is a very strong contributor to hypertension and making sure you've got good sleep and don't have sleep apnea. So sleep apnea is another thing. If your spouse or partner snores, that may be one… and has hypertension, talk to a sleep doctor. That may be something that's a little easier to manage and can cause dramatic reductions in blood pressure.

Rhonda Patrick: So along with those, you think it's possible to, with lifestyle intervention, reverse hypertension.

Ben Levine: I think in some cases, in mild hypertension, I think that that's true. If you've got hypertension in a young person under the age of 40, I think you need to look for other causes. I don't think we look hard enough often enough. Probably the single most important is to measure a renin and an aldosterone to look for hyperaldosteronism production of one of the hormones that raises the blood pressure by the adrenal gland and the kidneys. That ends up being really much easier and more directed to treat. And it's grossly under diagnosed in our country. So you should have a renin and an aldosterone level measured. There are other rare causes of hypertension. Severe hypertension in young people should get a plasma metanephrines to look for unusual tumors of the adrenal gland. But I think that garden variety essential hypertension, at least at its earlier stages, can well be modified by behavioral modification that we've been talking about.

Rhonda Patrick: Great. Including someone maybe in their late sixties, if they perhaps do the training, the sleep, looking at the sleep, the alcohol, salt intake. All the things…

Ben Levine: Yes. That can have a huge effect.

Rhonda Patrick: Okay, what about, I've heard you talk about recovery, and recovery days being as important as how much load you're putting on your heart, and so how much training, essentially. I'm curious what you mean by that.

Ben Levine: Right. So recovery is a essential part of training, and I think most athletes and coaches understand that. But it's a way that many athletes get into trouble, because if they're not performing as well as they want, they think, oh, I just need to train harder. And that ends up just getting them into a vicious cycle of increasing overtraining. You know, the athletic community has thought a lot about this overtraining syndrome for years. There's a guy from the Netherlands named Harm Kuipers who did a really interesting study with horses. You know, horses are some of the great endurance athletes of our time, of our world, right? Biologic world. And he tried to overtrain them, and the first thing he did was he increased their base training load, and they all got faster. And then he said, okay, well, let me increase the intensity of their training. And they all got faster, and they said, let me increase the number of intensity training sessions. And they all got faster. And finally, he said, well, I don't know what else to do. Maybe I'll just change their recovery. And what I mean by recovery is, you know, they do a high intensity session in the morning and then the next session after a high intensity session is something easy. So a simple canter, just a walk around to get the blood moving. And as soon, within a week of increasing the intensity of the recovery sessions, they were all overtrained with marked reduction in performance, increasing resting heart rate, fatigue, every sign of overtraining. In order to reap the benefits of a training stimulus, the body has to do something. The muscles have to produce protein, the blood vessels…there's a release of a variety of downstream metabolites from the oxygen sensing cascade, from hypoxia inducible factor through VEGF, the vascular endothelial growth factor, the things that make the blood vessels that improve the lining, the endothelium, that add muscle fibers, that make them bigger. All these things have to happen. That's what, beneath the skin, those are the things that are happening after you do a training stimulus and if you don't allow those, their full expression, then you won't get the benefit of the workout that you do. And so most good coaches and trainers will always incorporate an easy session after a high intensity session. And always, I think, should always have a day off. Whether that day off is some, you know, strength training or technical training or things like that, that's okay by me. Watching film, doing some basic technical things, shooting free throws, if you're a basketball player, whatever, but it has to be something easy that's unstressed and that's what allows you to, to get the most benefit. And I think that people who are not coached or who have a coach that's perhaps a bit more inexperienced, they get driven to do more and more and more and they find that they're not getting better and that's probably because they're not having adequate recovery. One of the things we did in all our altitude training studies, we spent more than a decade studying the best way to do altitude training for, for USA track and field and the US Olympic Committee is to monitor early morning heart rate. That was our best indicator. So we'd have the athletes put their heart rate monitor on, you know, set an alarm, put their heart rate monitor on. If you've got a watch at rest, it's pretty accurate. During exercise, the watches that just use the PPG, the plethysmogram are not accurate. That's a whole 'nother discussion that we should talk about, but put it on at rest and track it for go back to sleep and see what it was for those five minutes before you woke up again. And as you start to get overtrained, that resting heart rate starts to climb. And that's a signal that, okay, I need to reduce the frequency of my intensity sessions. I need to make them a little shorter, or I need to make sure that I'm adding adequate recovery and take a day off.

Rhonda Patrick: Inadequate recovery. If I'm just… I want to make sure I understand this. It includes, on a day you're training, doing something a little more light in terms of aerobic exercise.

Ben Levine: If you're used to doing stuff in zone three, in zone four or zone five, you might do in a zone one. Okay, so do you know what I mean by those five zones?

Rhonda Patrick: Go ahead. And it'd be great because it seems like definitions vary depending on what journal you're reading.

Ben Levine: And I think that that's true. And there are different coaches who use different zones for us, you know, and I learned, you know, my basic practical exercise science from Jim Stray-Gunderson, my partner in crime, for. So from Jim Stray-Gunderson, who passed last year, my good friend and partner. I'll get there. Just give me a second. Okay. So I learned most of my exercise science from my good friend and partner, Jim Stray-Gunderson, who unfortunately passed from pancreatic cancer last year. And we, in all our studies, we used a five training zone model. And typically what that means is we would pick the, generally the second ventilatory threshold where ventilation starts to really increase out of proportion to oxygen uptake, where VE/VCO2 has gone down to its nadir, where lactate is between that two to four millimolar range. They all reflect what we call the maximal steady state. That's the highest level that you can sustain for a prolonged period of time. Most good marathon runners are running at the maximal steady state. And let's just say for argument's sake, that was at a heart rate of 155, because there's no magic to heart rate, and it changes on a day to day basis. We're not machines. We would bracket that and call it say, the maximal steady state or threshold, or zone three training would be 150 to 160. Okay. Then zone two training is about 20 beats below that. So 130 to 150. Okay. And then zone one or recovery is less than 130. So a recovery effort would be below the lower limits of zone two. Now, zone four is probably the hardest to quantify because in the physiology world, you need to bring people back and do multiple repeat testing to do that. Zone four is what we call critical power. That's the highest intensity you can sustain without failure, without a drift towards VO2 max. So when Kipchoge was trying to run the under two minute, two hour marathon, he worked with Andy Jones and Mike Joyner and trying to say what exactly is my critical power? And its amazing. If you look at Andy Jones from the UK's work, he does exercise in an MR magnet and looks at truly phosphocreatine ratios and hydrogen ions. One or two watt differences is the difference between sustainability and failure. Its extraordinary and its delicate and its hard to pick. It's my belief… I think Andy's also, is that the reason that some of these great runners from East Africa or some of the great swimmers spend so much time doing what they're doing is they want to feel what.. they got to figure out what the pace zone four is. They have to know what that is. And it's hard to prove that in a lab. Everybody, the good athletes know that. When can you push that pace and when do you have to back off? And so we know zone five because we're measuring maximum heart rate. And in the model that I gave you, let's say the max heart rate was 180. Okay, so the top of the zone three was 160. So often what I typically will do in the lab is I'll split the difference and we'll call zone four 160 to 170 and zone five 170 to 100. 180. And so that gives you a nice broad heart rate, five zone, which reflects different kinds of events. So zone three typically is a marathon. And I'll calculate running economy. And so I know the speed at any given oxygen uptake for a runner, for example. And if I take zone three, heart rate and running economy, I can tell you what your marathon time is going to be. And if I figure out what zone four is, that's about a 10K pace or so. So you can't run that pace at an entire marathon, right. But you can run it for 45 minutes or an hour. Right. And then 5K in short, or 5K is run at VO2 max. So 5K is run at in zone five. And anything shorter than that, we know for sure that you can't run 10 meters a second for a marathon. You can't even run it for 5000 meters, but that's still going to be zone five. So anything that's pretty much 5K and shorter will be run at those higher heart rates and those higher training zones for endurance activity.

Rhonda Patrick: So you mentioned the importance of looking at your resting heart rate early morning for recovery and sort of a good….

Ben Levine: As a guide.

Rhonda Patrick: As a guide for training. Right. What about, you hear a lot about heart rate variability?

Ben Levine: Yeah. So, you know, we spent decades and I published probably 100 papers about cardiovascular variability. So first let's ask what is heart rate variability? So heart rate variability looks at the change in heart rate over time. And there are two, this is grossly simplifying it, but there are two main stimuli to heart rate variability. Number one is respiration and breathing. When you breathe, there are two things that happen. Your brain is sending signals to your diaphragm to breathe. The nerve that carries those signals also goes to the heart, that's the vagus nerve. There are also changes in blood pressure and stroke volume that occur as you breathe, because when you breathe in, you're decreasing intrathoracic pressure. Blood flows into the heart. When you breathe out, the blood comes out of the heart. You're changing stroke volume, you're stimulating the arterial baroceptors, which are in the carotid arteries and in the arch of your aorta. There are a number of things that happen when you breathe that move blood in and out of the heart and also send neural activity from the brain to the pacemaker of the heart. That's the respiratory variability. That happens at the respiratory rate. Then there are other intrinsic rhythms within the circulation. They happen a little bit slower. If you think in terms of cycles per second, or Hertz, 0.1 hz or ten cycles a second, is the low frequency Mayer wave frequency. If I were to measure sympathetic nerves, the Mayer frequency is mostly sympathetically driven. Not entirely. It's sympathetic and vagally driven. So the problem is that all measures of heart rate variability when you use a heart rate monitor, do not take those into account. So if I told you to breathe at six breaths a minute, I would slam the high frequency on top of the low frequency rhythm and I would markedly increase your heart rate variability. If I had you breathe a little bit faster, I would separate those out. And most of the heart rate variability that's being measured by your heart rate devices, most of the heart rate variability that's being measured by your heart rate devices is mostly looking at the high frequency variability, but that is absolutely dependent on respiratory rate, and nobody controls that, right? You're not given a tone that tells you you breathe at this frequency and we'll measure your heart availability. No, it's not doing that. And then I'm going to add one more. That as you move around, very low frequency rhythms will alter heart rate. So when you stand up, heart rate goes up. When you lie down, heart rate goes down. When you pee, you have vagal withdrawal. It's the only way to pee. So your heart rate goes up when you pee. When you talk to somebody, your heart rate goes up. These are uncontrolled factors. In my laboratory, if I control every single factor, so, same time of day, same food in the body, same... I control how deep and how fast you breathe. I can't get better than a plus or minus 25 percent day to day variability. So I'm just telling you that even under the best of circumstances, these measurements are very technique dependent and very variable. So I don't think people should use them as an indicator of anything, because I think it's too. The science is not there. You can read lots of articles about heart rate variability. I was the thesis advisor and opponent for one of my good friend, Heikky Rusko from Finland, from Evasculus students who tried a lot to look at heart rate variability as an indicator of training and overtraining, and it's just too hard to standardize and get right. So I think you. If you try to use that, except under extraordinarily controlled conditions, I think you'll find. Yeah, I think that you'll find you'll make more mistakes than benefit.

Rhonda Patrick: Well, that goes with what my gut was telling me, because with my training, I can see improvements in resting heart rate. I can see it in my heart rate. My maximal heart rate going even lower, like getting lower. But my heart rate variability, according to my Apple watch, nothing. You talked a little bit about the performance, cardiorespiratory performance and limitations, and that got me to thinking of men versus women and these sex differences. So my husband and I go for a run together, and he smokes me every time. He's faster, and we're not doing a six hour run. Maybe that would change. Maybe I would outperform him. Who knows? But I'm curious, like, what are the cardiovascular performance differences between men and women?

Ben Levine: Okay. All right. So you're asking a really interesting question, and there are some fundamental differences between men and women, particularly younger men and women, which is virtually all due to the androgenic effects of testosterone. Testosterone builds muscle, reduces fat, builds blood volume, makes the heart bigger, makes the body bigger, changes the power outputs of skeletal muscle. So that's why we have women's sports, right? Is because men and women, given equivalent access to training and coaching, men are still faster. And if you're interested in reading more about this, we just published a definitive scientific statement about the biologic differences of sex from the American College of Sports medicine. Sandra Hunter from Marquette is the first author on it. It's been published. It's in the public domain. It just came out a number of months ago. So that has a lot of information about this. If you looked at. I'm not sure I'm going to get the exact numbers correct, but if you looked at in some of the great middle distance runners, female middle distance runners, Alison Felix, Sandra Richards-Ross, those are the great names that we hear about in, know about in women's middle distance sports. And if you looked at their world records that they set during the peak of their career, at the same time, 20,000 or 10,000 boys ran faster. Boys, these are high school kids. If they had to compete against the boys, we would not know their names. This is not. This is not benign. And if our society wants and views having women's sports and women to be able to be successful, which I think is a tremendously important goal, it's important that women compete against women and men compete against men. And let me say that differently. It's important that males compete against males and females compete against males, because there's a difference between sex and gender. I don't want to get into that. I don't think that's what we're here for. But biological sex makes a difference, particularly the sex that you are, your biological sex as you go through puberty. That's where the differences between boys and girls start to become most dramatic. Before puberty, there's not much of a difference, but it's at puberty, when the massive increases in testosterone come about, and your husband's going to beat you. Now, I wouldn't beat you because I'm an older man and I'm probably not as fit as you. So it's not that every man is going to beat every woman. That's moronic. Right. But given the same training and the same level, the males are going to run faster.

Rhonda Patrick: Yeah. The same age. What about this? There was a study this year that was published in the Journal of American College of Cardiology claiming that women can reap the benefits of aerobic exercise with doing less exercise as men. So it was like twice as less exercise than they had the same cardiovascular disease.

Ben Levine: So I'm underwhelmed. You know, I think that there's not a huge amount of benefit. The bottom line is that premenopausal women, they just don't have a lot of cardiovascular disease. There's extraordinary protection against cardiovascular disease by estrogen and progesterone. And what I tell many of my patients is there's one thing that will turn a woman into a man, and that's cigarette smoking. So cigarette smoking abolishes most of that difference, and we see that clinically all the time. But I think that women should not necessarily consider that their dose response relationship to exercise is fundamentally different. And that's why after menopause, all those differences basically change. And so what happens is you simply shift. Now, once you've got a woman who's well past menopause now, from an endocrinologic perspective, she's much more similar to a man. And now the risks start to accelerate at the same level, at the same rate. They're just pushed off by a decade.

Rhonda Patrick: What if she undergoes hormone replacement therapy?

Ben Levine: Yeah, that's an interesting question. And there are risks and benefits of that? I think that there are clearly benefits, cardiovascular benefits, particularly if the hormone replacement therapy is started early in the menopause transition. When it starts later, you lose the protective effect and you increase the risk of breast cancer and other bad things that counteract the male female mortality differences.

Rhonda Patrick: So the timing of the timing…

Ben Levine: Timing, I think, is this obviously been studied by dozens of people and hundreds of thousands of women. So that's a whole 'nother complex task. But I think the simple answer is, I wouldn't count on it. I would say that the dose response relationships are the same, and we've seen that we have always tried to incorporate women in our studies. We're the only studies that included women in all our altitude training studies, because women are competitive athletes and we need to know how they respond to altitude. We did the same thing in our year long training program. So to our community, everybody knows this, but we have to include women in all our studies. It is essential, but I don't think women should think they are special in terms of their adaptation to exercise. We mostly found them the same, except that in our year long training study, women increased the size of their heart in the first three months, similar to men, and then they stopped, they plateaued, and the men continued to increase. And I think that's a testosterone phenomenon, and it's another example of why testosterone enhances the building of cardiac as well as skeletal muscle. So that's one of the fundamental differences.

Rhonda Patrick: Well, I really want to get into some of these risks with outcomes with extreme exercise beause you're really also an expert in that area. And there's been a lot of interest and worry in, you know, extreme exercise. Like, I guess we should define what that is. But in some instances, you can find studies saying seven and a half hours of exercise a week can, in some cases, what they call double the risk of cardiovascular disease. And I think you'll clarify, maybe that depends on they're actually looking at other biomarkers, not necessarily someone dying of cardiovascular disease. But what is extreme exercise? How does it affect coronary plaque calcium? What is coronary plaque calcium? Why is that significant?

Ben Levine: All right, so first, I think extraordinary exercise can be defined by multiple different things from an epidemiological cardiovascular health perspective, I think what we're talking is about people who do more than [3,000] to 10,000 MET minutes a week. And I'll tell you why I chose that. In our studies in the Cooper Clinic, we used more than 3000 MET minutes a week, which is about 8 hours, and on about 6 hours. But on average, our high volume exercises did about 8 hours a week. So the nadir, where you reach the maximal cardiovascular benefit, is about 5 hours a week. Five, maybe up to 10 hours a week. For heart failure outcomes. Once you get more than about 10 hours a week, you're starting to get to what I think most would agree on, extreme exercise. The coronary calcium story is interesting. The original concern about coronary calcium came from the German study by Mullenkamp, where they looked at a group of runners who had done lots of, lots of marathons and found that they had more… initially when they compared them to a population based study, the Heinz Nixdorf recall study, they didn't have more coronary calcium. But the authors of that study kind of said, well, that's not fitting our hypothesis. Part of it is the athletes had better risk factors than the controls. So they said, let's only select athletes who had the same risk factors as the controls. And then the athletes had a little bit higher coronary calcium and a little more non-zero calcium. But 50 percent of those runners were smokers and they all started training later in life. And that's a consistent theme in much of this world. So a lot of the masters athletes tend to start later in life. They're not the young elite Olympic athletes, and many of them are doing it to try to combat bad behavior when they were younger. So just keep that in mind. When we look at.. then the next big study was the one out of the UK which did CT angiography, which looked at more than just coronary calcium. And now is a good point to step into that, right. Calcium is the footprint of atherosclerosis. As the atherosclerosis, the hardening of the arteries, that we think about as cholesterol mediated, as that progresses from accumulation of cholesterol there, import into macrophages, the cells that suck up the cholesterol, into the lining of the blood vessels and injure it and start to accumulate and obstruct the blood vessels. As that heals or progresses, there's always a little bit of…there's a little plaque rupture, a little bit of injury here, and the blood vessel calcifies. It's not the calcified blood vessel that I worry about, it's the company it keeps. Because calcified blood vessels don't crack, don't rupture, and don't cause heart attacks. Okay. It's the non-calcified, what's often called soft. It's not really soft. It's just non-calcified plaque that ruptures and causes a heart attack, occludes the blood vessel. That's what a heart attack is. So the more calcium you have, it's really just a sign that there's more non-calcified plaque. Does that make sense? So the atherosclerotic burden is higher.

And what the British study showed was that first of all, their female participants had almost no coronary calcium and no atherosclerosis. So let's talk out, toss out the women for a moment. But the males, the higher intensity, more volume athletes had more plaques and more calcified calcium. What was interesting though, is all the plaques were almost all calcified, and in the non-athletes, it was a mix of calcified are non-calcified plaque.

And they're the ones who first raised this issue is maybe exercise training stabilizes plaque and makes it more calcified. And that's why the athletes tend to have a lower mortality and a lower risk of a heart attack. But none of those studies looked at events. They just looked at the anatomy of the arteries. That's where our Cooper Clinic study came in. Laura DeFina's paper in JAMA from 2019, we looked at 25,000 people with multiple different ranges of physical activity. From the middle group, which is sort of that guideline, directed 3 to 5 hours a week, a low group who did less than 3 hours a week, and then a high volume exercisers who did about 8 hours a week. It turned out that about 75 percent of both groups, all three groups, about 75 percent of them, had relatively little coronary calcium. We worry about a score of 100, because that's where the higher the calcium level above 100, the greater the risk. So that's our clinical cut point, where it becomes really clinically meaningful. And among those individuals who have the majority, so 75 percent of our group had coronary calcium scores less than 100, there was no difference in coronary calcium among the three different activity groups and a 50 percent reduction in events. Quite dramatic. Now, there was a small about 11 percent increase in the risk of having a calcium score over 100. I'm parsing my words carefully. There was a little bit of a greater risk of having a higher score. But if I look in all the individuals who had scores over 100, there was no difference in the absolute score between those who did no activity and those who did 8 hours a week. And there was a 25 percent reduction in events. Didn't quite reach statistical significance. But it wasn't a greater increase, for sure. No greater increase. It was a lowering. The bottom line, if you look at now, absolute versus relative risk, which we're coming back to, we talked about at the beginning, you're better off having no calcium than having a lot of calcium. Absolutely right. Because calcium is a sign of atherosclerosis. If you've got calcium, you're better off being fit than unfit. In Nina Radford's paper, also from the Cooper Clinic, we showed that there's an interaction between calcium and fitness. So the higher your fitness, the closer the high calcium group comes to those with no calcium. So if you're unfit with a high calcium score, that's a disaster. If you're very fit with a high calcium score, you're worse than if you had no calcium, but not that much worse because the fitness ends up being protective. What causes calcification and atherosclerosis? I mean, if I knew that, I'd have the Nobel Prize, right? We have lots, I mean, billions of studies about the nature of atherosclerosis and what causes it, but it's due to many of the risk factors we know, high cholesterol, how that cholesterol interacts with the vascular wall, hypertension, smoking, diabetes, and your parents–genetics.

Rhonda Patrick: So the question, if you're measuring, let's say, by CT angiogram, looking at the quote unquote soft plaque, which isn't so soft, but it's not calcified, non-calcified plaque, then does physical activity reduce plaque formation?

Ben Levine: So I have to say that just a few months ago or last year, the Pro at Heart Study that I mentioned before kind of threw a big wrench into this because they looked at elite, low, young, and older athletes and they did show more plaque related to high intensity endurance activity. I don't know exactly what that's going to mean. I don't think that exercise removes plaque. I don't think you can count on that. It may, it certainly provides protection and it may… against cardiovascular bad outcomes, and it may cause the non-calcified plaque to be more calcified and more rupture resistant. But I don't think it makes it go away. There are idiosyncratic studies looking at this training and this reduction, but there's also idiosyncratic studies showing… Aaron Baggish showed in Run Across America that when they did that, they had an increase in plaque. I will tell you, because I just got a notification yesterday that we have a new paper from the Cooper Clinic showing that if you look at, try to parse out the exercise dose into intensity versus duration, as you increase the intensity, calcium is less. And as you increase duration, calcium goes up. So I think the higher intensity efforts are probably more protective and the very longer duration ones are probably more calcium inducing. Why that is, I don't know. You can look at some of Wendy Kohrt's data from Colorado. She's the one who's shown that when you start to exercise, calcium in the blood goes down. That causes an increase in parathyroid hormone, and parathyroid hormone causes a leaching of calcium out of the bones. And where that calcium is going, when it goes out of the bloodstream, I don't know, maybe some of it gets deposited in the blood vessels. We don't know exactly what the path of that calcium is. I think there's an area of active investigation, but it's one of the reasons why endurance athletes always thought, this is going to protect my bones. But it doesn't, it doesn't protect your bones. It actually may worsen it. Some of that is nutritional, but also it's because of sustained increases in parathyroid hormone and sustained leaching of calcium from the bones to preserve blood calcium levels, which are essential to everything that is necessary for life.

Rhonda Patrick: The other, I would say the other outcome, well, not necessarily outcome, but risk factor for a negative outcome that people are worried about with extreme, particularly extreme endurance activity is atrial fibrillation–Afib. So what's interesting though is that you look at numerous studies, there's a decreased risk in Afib with increasing physical activity. But it seems as though there might be a certain point when that changes.

Ben Levine: It's absolutely true. And that's the one thing I tell all my masters athletes. This is one of the consequences of the duration and the intensity of activity that you do, is you'll increase your risk of atrial fibrillation. We know why. There's a very elegant study by, again, Guido Klassen and Andre Laguersch, which talks about the damming effect of the valves. Remember that the heart has upper chambers called the atria, that collect the blood, and pumping chambers called the ventricles, which eject the blood out of the heart. In between them are valves, A-V, atrial ventricular valves. On the left side it's the mitral valve. And let's talk about that one for a moment, because most of the atrial fibrillation is probably generated within the left atrium. When the heart contracts, that mitral valve snaps closed and the blood gets ejected out. But the blood continues to flow into the atrium because the cardiac output is increased. It's got to keep flowing in. The blood doesn't just stop, it accumulates in the atrium. That's called the reservoir effect of the atria. Then when that valve opens, the pressure that has built up in the atria drives the blood into the ventricles to help fill it. And then so there's blood to pump in during the next cardiac cycle. Does that make sense? Okay, so now let's take exercise, which increases the cardiac output, so increases the speed and volume of blood that's being pumped. And now the other thing it does is it increases the heart rate. And when you increase the heart rate, now you have more asystoles. So instead of having the valve open now it's [snapping]. And you spend more time with those valves closed. And so it creates a dam in between the atria and the ventricles. And the atria just dilate. And as you dilate the atria, you increase the risk of atrial fibrillation.

Rhonda Patrick: At what point? Like, is there like an amount of exercise?

Ben Levine: Yeah, yeah. So that's a good question, because the Tromso Heart Study is probably the one also from Norway, which shows the point that you made. And we all know that being unfit is also a risk for atrial fibrillation. And probably that targeted middle dose, if you will, 3 to 5 hours, moderate intensity physical activity gets you to the nadir. In their population based study, as you got past that, you started to increase the risk. There was a lot of noise around the point estimate and nowhere near that, you know, increase it by, I can't remember exactly, by one and a half times, something like that. Nowhere near the fivefold increase that you see in the competitive athletes. So I don't think anyone who is doing recreational or even occupational exercise needs to worry about Afib. I think, you know, particularly as we've talked about, the optimal dose for health and joy and wellness, you know, is up 3 hours is what's recommended. Up to 3 to 5 hours probably gets you most of the bang for your buck. And as you start to get beyond that for performance, then you have to accept the risk of atrial fibrillation.

Rhonda Patrick: Now, the risk of Afib, the reason people worry about it is it increases stroke. Do athletes have an increased risk of strokes?

Ben Levine: Athletes in general don't have an increased risk of stroke. Anybody with atrial fibrillation has an increased risk of stroke. Do athletes have less of an increased risk? Maybe, but we don't really know that for sure. So I think that it's easy to protect yourself from stroke by taking anticoagulation. Of course, we base that… there's obviously risk to taking blood thinners because you may bleed. And for some athletes, like cyclists who get into crashes, that's a bad thing. Depending on the nature of the athletic event. Someone who's a runner or a swimmer, I don't think you have to worry about it. But cyclists, when you are at risk for a crash or, you know, other kind of athletic events that involve collision, then that becomes an increased risk if you're on a blood thinner. So we don't know the best way to manage that. Some of it depends on how often you're in Afib. Afib can be paroxysmal, meaning it only occurs intermittently, or it can be persistent or permanent. If it ends up being persistent or frequent, then ablation is the way to go. Just keep it from happening. There's a new study out called React. It's actually recruiting right now, and we're asking the question, if someone develops Afib, can I just take anticoagulation for a couple of weeks right then, and then take a medicine to get rid of it, and then when I'm back in sinus rhythm, stop taking the medication? So only take it when you're in Afib? That requires you to be able to detect it either symptomatically or with your watch. And we just don't know. Most right now are saying, if you have other risk factors, older age, hypertension, diabetes, heart failure, other heart diseases that increase your risk of a stroke, probably better off taking the anticoagulation, depending on what your risk of bleeding is, and that depends on your sport.

Rhonda Patrick: And do most endurance athletes have lower risk factors? Probably. I mean, generally speaking?

Ben Levine: Most of them do, you know, and if we… There's a scoring system that we use called CHA2DS2-VASc, don't worry about the details of that, that help you define that risk. Unfortunately, there weren't a lot of elite athletes in the populations that developed that scoring system. So I don't know how perfect it is for a competitive athlete, but for a middle-aged athlete under the age of 65 with no other risk factors, no hypertension, no diabetes, no other heart diseases, the risk of anticoagulation is probably greater than the risk of stroke. You have to say, well, look, I'd rather take anticoagulation than have a stroke. I'm willing to accept a little bit of a risk. That's a discussion to have with your doctor.

Rhonda Patrick: I want to be mindful of your time. I know you have to leave, but one quick question. Life expectancy of what we would call this extreme type of endurance training, what data is there to support or refute?

Ben Levine: Yeah, I think that as you get out to the extremes of age, most things start to fall apart. I think that what enables somebody to sustain extraordinary exercise at the edges of lifespan, so after, let's say, 85, for example, the extreme old, is really joints and muscles. It's nothing to do with the cardiovascular system, so you need to be able to run those durations or without injury requires some unique genetic predisposition. So I don't think that anyone should be an extreme athlete because they hope that it will make them live longer. I think that would be presumptuous. Regardless of whether there's a small study here or a small study there, I don't think it increases the risk. There was the Danish Copenhagen Heart Study, which frankly, should never have been published, is ridiculous, which looked at runners who did a lot of running. This one, that generated a lot of press, but people who did a lot of running had an increased risk of death. How do they know that? There were two deaths. What did they die of? I have no idea. Maybe they got hit by a car while they were running. The confidence limits on that point estimate were so big as to be useless. I think that was a terrible study. And in fact, we presented at the American Heart Association a few years ago. We looked at, again, the Cooper Clinic database. We looked at more than 10,000 minutes a week. This was stimulated by Amby Burfoot, by the way, who asked us this question. What about, you say only 8 hours a week? That's nothing for many of my runners. He said, okay, these guys average 30 hours a week, and there was no increase in mortality, there was no increase in events, the number of cardio, it wasn't a lot of people. It was twice the number in the Copenhagen Heart Study, by the way, you know how many cardiovascular deaths? Zero. So I would not say I'm worried that my extreme athletes are going to take my life. I don't think that the evidence is strong in that regard. I don't think there's evidence that it will prolong your life. And you have to, as you start to get to older and older, really, it's healthspan, not lifespan, that matters the most.

Rhonda Patrick: Thank you so much, Dr. Levine. I mean, this has been incredibly informative. I have so many more questions that I would like to ask you. Maybe we can do a round two sometime. And thank you again for all your research, all your contributions moving the field forward and our understanding of how physical activity affects cardiovascular adaptations and how that does improve our healthspan and to some degree, our lifespan.

Ben Levine: Well, it's absolutely my pleasure. Thank you, Rhonda, for your wonderful, your homework that you do prior to these interviews. It's really quite impressive. And your podcast is high quality and reaches a lot of people. So thank you for inviting me.

Rhonda Patrick: Thank you.