#217 ‒ Exercise, VO2 max, and longevity | Mike Joyner, M.D.

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My guest this week is Mike Joiner. Now, Mike's someone I've wanted to have on this podcast for quite some time.

And I even, I think I mentioned it in the podcast. You know, Mike's someone whose research I've been reading personally for probably over 20 years. He's a physician researcher.

He is a professor and vice chair.

For research in the Department of Anesthesia.

And Perioperative Care at the Mayo Clinic.

He's co authored over 250 journal articles and he's written numerous pieces all over the place, including in magazines that maybe.

Some of you have read outside in Sports Illustrated. He also has his own website titled.

Human Limits, which as the name suggests, speaks to Mike's interest, which is really around the limits of human physiology. Now, his research background is in studying how the nervous system regulates vascular systems and blood flow, how age and sex disease states affect physiology, and understanding basically.

The limits of human physiology by studying elite athletes. In this episode, we talk mostly about exercise and within that we talk about.

How exercise helps us live longer, the.

Importance of exercise as we age, and.

How exercise compares to nutrition in terms of the impact it can have in health.

We talk about the impact of the.

Autonomic nervous system, blood pressure, heart rate, heart rate variability, heart rate recovery, and maximum heart rate.

From there, we talk about VO2 Max. We discuss how it's measured, we talk about what leads to the decline in VO2 max. As we age. We spend some time talking about the.

J curve as it pertains to over exercising. Is it possible? What are the dangers of too much exercise? We speak about how one should partition their time between training at high intensity and low intensity.

And we talk about a few other things like performance enhancing drugs in sports and if there's ever going to be a drug that mimics the benefits of exercise so without further delay, please enjoy my conversation with Mike Joyner. It is such a pleasure to be at least virtually sitting here with you today. As I was kind of alluding to a moment ago, if I were to sort of look at all the people I've had on this podcast so far and kind of ask the question, when was the first time I became familiar with their body of work? You would be pretty far up there in terms of duration. So growing up, endurance sports were always something that meant the world to me. And once I even made that decision to go to medical school, a big part of it at least, was understanding physiology better. And so it's been 25 or 30 years that I've been reading your studies. In some ways, it's a long time coming to finally be sitting down with you and hope to meet you in person one day.

Peter, thanks much, and it's great to be able to chance to visit with you today. Thank you for inviting me, and I'm glad somebody's been paying attention to what I've been doing for the last 25 or 30 years. So it's very validating. Thank you.

Let's talk a little bit about your background. You're a physician by training, I believe. You're an anesthesiologist, correct?

Correct.

You decided in medical school you wanted to do anesthesia. You've always had a lifelong interest in exercise and exercise physiology. Did you just view anesthesia as the most logical conduit to better understand human physiology?

Peter Before I went to medical school, I actually volunteered to be a subject in a study on the lactate threshold, or anaerobic threshold, when I was 19 at the university of Arizona. And luckily there were excellent physiologists there. But a couple of younger physicians came over from the med school, and it became clear to me when I was 19 or 20 that if I wanted to have a career as a research physiologist doing invasive studies, in other words, putting catheters in people in humans might be wise to go to medical school. So this was always sort of my vision, starting by age 20 or 21. And then what happened is I was thinking of going to cardiology or pulmonary medicine. And I was working at the Tucson VA at one time doing a surgery rotation. And I saw what they did in anesthesia, which is a lot like an exercise test. You're measuring people's breathing, you're measuring their blood pressure, their heart rate, and you're giving them drugs that affect their autonomic nervous system. And I've certainly done A lot of that. So I saw it as the flip side of the same coin. It is strange, though, to have pursued this vision for over 40 years now.

I remember having the same thoughts when I did my anesthesia rotation. I can't even remember if anesthesia was a required rotation in med school. I don't think it was. But it was positioned as sort of a very good thing to do, and I agree with that. And I had a field that, even though I think by that point I knew I was going to go into surgery, but I absolutely loved it as a sort of physiology geek. Anesthesia and critical care, for that matter, are both two remarkable specialties that are, you know, the tip of the spear of what physiology is.

When you think about exercise or people climbing mountains or adapting to some unusual environment, the brainstem back there has to do all sorts of incredible things to maintain what we call homeostasis, or the internal environment in a way that allows you to survive and thrive in anesthesia and critical care. You turn those mechanisms off, and the physicians and the nurses really become the patient's brainstem as they regulate the breathing of the patient, the blood pressure of the patient, the heart rate, and so forth. So, again, it's the flip side of the same coin. As soon as I saw what the anesthesiologist did at the Tucson V8, it just sort of clicked.

So where did you go on to do your residency in anesthesia?

So at the Mayo Clinic. And so what happened is I got out of medical school in spring or early summer of 87. Then I moved here. I've been here ever since. So 35 years in a couple of weeks.

Where did you grow up? Did you grow up in a warm climate?

Grew up in Tucson.

Obviously. The Mayo Clinic's a great program, but presumably there were other great anesthesia programs that weren't in the middle of a place like Rochester. No offense to those from Rochester. So what drew you to Mayo?

I'd read this paper, a review article about skeletal muscle blood flow, the regulation of skeletal muscle blood flow. And there were a lot of new ideas in the middle 80s about the regulation of skeletal muscle blood flow. And the world's leading expert was a man named John shepherd, who was a very senior member of the faculty here. And I wrote him a letter. You know, it was before email and stuff. So he was friends with the head of the department, a man named Alan Sesler. And John took it over to him. I wanted to be able to both do my residency and spend time in the lab. And I was able to work with Dr. Shepherd. And our department and our residency program were very research friendly. So that's really why I decided to come to Rochester. But I thought I'd stay three or four years and go back to Tucson, so that obviously didn't happen.

Let's talk about exercise. People who listen to this podcast know that I'm really passionate about this idea of longevity. We think about longevity through the lens of five sort of modifiable behaviors. Exercise, sleep, nutrition, emotional health, and all the tools around distress tolerance. And then exogenous molecules. Those are the five things that, as far as I can tell, mostly you can manipulate and they can both impact your lifespan and your health span. Four of those are kind of behavioral. The medications aren't really behavioral in the sense that compliance is relatively straightforward. The other ones really require a shift in behavior and in mindset. Maybe we all have our biases in our blind spots, but I just think exercise is in a league of its own in terms of its potential both on the lifespan axis. You know, its ability to extend life and reduce all cause mortality is well documented. We'll talk about that. But also on the healthspan side, it really has no rival. So it's for that reason, I think, that we spend a lot of time inside our practice focusing on exercise. It is really the biggest pillar within what we do because it has the most impact. And unfortunately or fortunately, it's also the most challenging one, I think, to get people to change their existing behaviors around because the time commitment is significant. So let's start with some of the basics. Just for folks who maybe aren't completely up to speed. What would you say if you're at a party and somebody came up to you and said, mike, I understand you're really into this exercise thing. Can you explain to me why it is that exercise helps you live longer?

I think there's a couple of things, Peter, and it's multifactorial. The first thing is that the risk factors that contribute to cardiovascular disease all cause mortality are all influenced by exercise and, and physical activity. These would be blood pressure, diabetes to some extent, lipids and cholesterol, and also how you deal with stress. So I think you get the big three there. There are some other new age or second wave risk factors like endothelial function, the lining of the blood vessels in your body that improve with exercise the way what's called your autonomic nervous system. And people may have heard of vagal tone or heart rate variability that's also influenced positively by exercise. So I think there's five or six things, but what's interesting is when you add up each one, you know, a modest increase in cholesterol, a modest reduction in blood pressure, those sorts of things, when you add them up, you get X percent improvement in health span, life expectancy, any metric you want to use. But when you look at the epidemiology, people who do the sorts of things you just mentioned have a much bigger benefit than just the simple sum of the other risk factors. So there does seem to be some sort of synergy here or some sort of X factor that we don't really understand yet. But again, this collection of lifestyle related factors, and again, the autonomic nervous system, blood pressure lipids, the lining of the blood vessels and diabetes would be the big five.

I want to dive into a couple of these in depth. You know, you've thought a lot and you've looked a lot at this literature and one can say, look, the epidemiology is so overwhelming, the hazard ratios are sort of absurd. When we're used to looking at a field like nutrition and looking at the hazard ratios in nutrition, they're very small. In fact, they're so small and also so inconsistent that it becomes almost impossible to assign a mortality benefit or addition to almost anything you can eat. I mean, literally jelly beans to bacon to kale, the hazard ratios are trivial and they flip flop from month to month.

Yeah. Let me tell you something that's really interesting. It's good you brought this up. So I'm working on a review article on related topics. And one of the things I'm looking at is all of what you might describe as natural experiments where you have two groups of people that are otherwise similar exposed to different things. And that's a long, long used tool in epidemiology. And people are now using it in economics and behavioral sciences. And in fact, these natural experiments, the economist just got a Nobel Prize for them a couple of years ago. But the classic one is the London Bus Driver bus conduct led by Jeremy Morris after World War II, where they showed the physically active conductors who were walking up and down the buses all day had much lower rates of cardiovascular disease. And the sedentary bus drivers, and it was about 50%. And they had similar things with telephone operators versus people who were out walking around doing things. And you look at that 50%, it's incredibly consistent. Studies of longshoremen, studies of Harvard alumni. There's one in the last 10 or 15 years of 50,000 male and 25,000 female finishers of the Vasa Lopet 90 kilometer cross country ski race in Sweden and they compared them to match controls from the Swedish record system and they showed again about a 50% reduction in cardiovascular and all cause mortality. There's data from the National Cancer Institute showing the same sorts of things and showing four or five or six. Your increase in life expectancy among the people who got a substantial amount of physical activity or structured exercise, either one.

The sort of take home point for the listener is unlike nutritional epidemiology, where the risk increases and risk reductions are very, very small and they're never consistent. I mean, there's some things that are consistent and consistently small. For example, vegetarians consistently have a small reduction in mortality, which of course then gets to the next point, which is what are the confounders? And this is where I want to kind of talk about it with exercise. And this is where the natural experiments are much better on the exercise front than they are on the nutrition front. You see, going back to the example you gave, which is a very famous one, guys running up and down the buses, the sort of conductor guys versus the drivers, that's a great natural experiment because it's really not amenable to a choice. You would be less likely to believe that the bus driver who sits there is also making poor choices relative to the other guy when he's not at work. In other words, we wouldn't really have a reason to believe that he's more likely to be a smoker, he's more likely to, you know, make poor food choices, et cetera. Whereas when you look at sort of the vegetarian to non vegetarian dietary pattern in nutrition, it's pretty clear that a vegetarian diet is very restrictive diet. And therefore the person who's making that choice is likely very health conscious in a number of other ways. Some of which are easy to.

Yeah, they have a suite of behaviors.

Yeah, exactly. Some of which are easy to measure and correct for, like smoking, but many of which are not. That's what sort of makes the nutritional thing harder. The exercise thing is pretty profound. So let's explain to people what it means when you have a hazard ratio of 0.5, which means a 50% reduction in all cause mortality. What's the timeframe that that's usually looking at and how does that translate to a five year increase in life expectancy?

The way you would say it is the relative risk of dying of heart disease in any given period of time, whether it's year, five years, 10 years, whatever the study's doing is 50% lower. But obviously not everybody dies of cardiovascular disease. People die of other things. And, and so then you have to translate that into sort of years of life gained. And typically the years of life gained are somewhere on the order if you account for smoking of three to five years, something like that. And then if you look at the concept of health span, you know, you may get six or eight years of improved health span. So health span is, you know, Peter, how disability free you are. And so you have, you know, four or five year increase in life expectancy and a four or five year additional increase in health. Spanish and the idea is to live a long time and then die quickly with minimal disability.

That's right. And I've always found that the current medical definition of healthspan, I understand why it exists because you have to be able to quantify things, but I've also found it to be not entirely helpful. You know, freedom from disease and disability, which is the current definition, I think that's a pretty low bar. One of the ways we try to get around this idea of the vagueness of freedom from disease and disability is to make it very, very granular. And we do this by creating this model we have called the Centenarian Decathlon, which says if you go out to your marginal decade, and we define the marginal decade as the last decade of your life. So again, we don't know when that is, but let's just make the math easy and say, oh, that's going to be 79 to 89 or 81 to 91. You're in your marginal decade. What are the athletic events and the activities of daily living that you want to be able to do? But we do it by making people cross off things they do not want to do. So we make this a. You have to opt out of things. And they're very specific. So it's like walking three miles in one hour, being able to climb X number of stairs, you know, 60 stairs that are 8 inches in one minute, being able to carry 20 pounds of groceries a certain distance, being able to get up off the floor with at most one hand of support. So it's very specific stuff. And I think for most people the initial reaction is, well, that's really easy. Like I can do most of these things today, but when you're a 45 year old reading that, I hope that's easy. I don't think they appreciate the precipitous decline that will occur without deliberate training. And it's for that reason that I think exercise has more potential to offset all of those things. Than anything else. Sleep, nutrition, certainly any medication. To me, that's really what health span comes down to. It's not just, I'm not disabled, but it's, I'm really thriving.

Yeah, I'm engaged. I can engage in what I want to engage in. I think, Peter, you've hit the nail on the head. What we see in those decades, what's really instructive is if you look at the decline in performance in age group swimming, running, cycling, rowing, any sport where there's pretty good record keeping is people can start to decline at age 30 without training. You can push that back to age 40 with training. In other words, if you work out every day and relatively hard, but then something happens to people in their middle 70s where there seems to be a steeper rise. And what's interesting about that steeper rise is it seems to shift from sort of a cardiopulmonary limitation to sort of a skeletal muscle strength frailty situation. And what you described in terms of getting up off the floor, 70% of 70 year olds can't get off the floor. Not one hand, two hands, just can't get off the floor. And we both know from being doctors, if you look at what happens when a person in that age group falls, it's just no fun. So. So if you look at what really takes people out, it's things like falls, it's inability to do things. And so what happens is walking three miles in an hour takes some cardiopulmonary capability, but not a ton, just some. Whereas being able to go up the stairs takes more. Being able to get off the floor takes more. One of the things that people have to think about, especially as they get into their 40s and 50s, is adding strength or some sort of circuit training and agility training to their program. And one of the things I do is I'm 63, almost 64, is I have the jump rope my mother gave to me when I was 14. She gave me a beautiful boxer's jump rope, leather with ball bearings in the works. I carry it with me when I travel because you can always jump rope, even if it's out in the parking lot of a hotel. People think you're nuts, but it's a terrific exercise.

It actually is for a number of reasons, including foot reactivity. You know, the lack of foot reactivity is something that can contribute to the fall. So you're getting the cardio benefit, the coordination benefit, and also this gentle foot reactivity without. And it depends if you know how to skip like a boxer, you don't have to really pound your knees as well.

And the other thing is you do that with some body weight things as simple as pushups or planks. And if there's a place to do some pull ups, you're good to go.

There's so many things you said there, Mike, that I want to go back on and just make sure people really capture because it's so important. We'll probably find this study and I'll link to it, but there's an amazing study that demonstrates like muscle mass changes, strength changes and activity changes in men and women as they age. And it's one of those things where you don't actually need to understand the statistics to be able to see the figure. And it's exactly as you describe it. At the age of 75, there is a cliff that is so violent you can't believe what you're watching. It's at that cliff where physical activity level declines like this. It just goes boom. Muscle mass goes doom. Strength doom. Same thing. Of course, it begs the age old question, is the patient losing strength because they are no longer active or are they no longer active because they have lost strength? My view is it's both. I think these things feed off each other. Which one's the first insult? I suspect it's probably the loss of strength that contributes to the loss of activity. But then I think those feedback and accelerates this thing.

You really get into a death spiral. That's why it becomes important to keep exercising relatively hard as you get older, at least a few days a week to slow this decline, you know, and there are remarkable examples. There are some Swedish cross country skiers, men who were, you know, world and Olympic champions in the 40s and 50s. Many of them were woodsmen and lived in the countryside, remained very active, skiing and so forth. And they were studied in their 80s. Now you could argue that there was something special about these guys to begin with or they would not have become champion athletes. But their rates of decline were quite modest. And more importantly, their fitness levels were similar to what you would see in people in very early middle age. The other interesting thing about that is the classic studies from the 1960s, these fighter pilots, Navy and Marine and air force fighter pilots, were sent into outer space. These were incredibly fit guys. They'd go for a week and come back completely atrophied, couldn't stand up and really in bad shape. And in 66, NASA commissioned folks at the University of Texas Southwestern Medical center in Dallas to put five college age males, two athletes at bed rest. And they had tremendous reductions in their fitness over just three weeks of bed rest. And interestingly, Ben Levine and his group in Dallas, along with the late Jerry Mitchell, brought these same men back from 30 years later. So now they were, you know, early 50s, and it's incredible. But three weeks of bed rest, you know, caused losses of physiological function associated with 30 years of aging.

Wow.

So it's an incredible study. And that's one of the things that is instructive, those sorts of small studies. And that's why it's so important to just avoid inactivity of any type. And whether it's low grade physical activity, whether it's walking the dog, whether it's gardening, whether it's taking a flight of stairs once in a while, or intentional working out, it's really the way to go. And as you point out, really in those lifestyle factors you mentioned, really sort of overwhelms things. Overwhelms almost everything else you mentioned and.

Alluded to the danger of a fall in later life. And this is something we've been doing a lot of research on internally, given our concern around bone mineral density in the aging population, the mortality. When you look at 65 year olds and up who suffer a fall that results in the fracture of any part of the hip or femur at one year, depending on the study, it can be as low as 25%, as high as 60%.

Yeah. The magic number is usually around 40, 50. Yeah.

I want people to understand what we just said. You take all the 65 year olds and you look at those who fall and the fall results in a broken hip or femur and you ask the question, how many of those people will be alive in 12 months? The answer is half of them.

And the other half, it's not like the other half are.

They're not back to themselves necessarily.

No, exactly. You want to avoid a major health like that, for sure. You know, and the other thing, Peter, there's a couple other things that have really hit me as we've talked. One is this man named Lester Breslow, who was this very famous epidemiologist who died in his late 90s, was at UCLA for many years, and he studied people in Oakland in the late 50s and early 60s who made it to 90 and the sorts of four or five things you talked about. He identified the people in Oakland who made it to 90. And they were non smokers, they weren't obese, they remained physically active, they ate modestly, they stayed engaged in life. And there was just five or six things that they did. And the same is true in the Honolulu Heart Project when they've looked at a huge number of Japanese American males. Same exact stuff that you mentioned. They weren't as focused on the small molecules, but exactly what you've described. And then I think about natural experiments at the Cooper Clinic, they've looked at people's fitness levels. Now that's not exactly the same as physical activity, but in general the fittest people are also the most active. And they divided people into three or four groups of fitness and then had them look at a so called healthy eating index. Were you a junk food junkie? Did you eat okay or were you really conscious of your diet? The healthy eating index in people that weren't particularly fit did have something to do with all cause mortality. But among the fittest people there was very little impact of diet on the outcomes. Which is sort of interesting and always brings me back to the famous quote in a book about distance running called Once a Runner where somebody said if the furnace is hot enough, you can burn anything, even Big Macs. Now you have to take that with a grain of salt, but it does kind of give you the take home message. But just about what a powerful thing exercise is.

There's a very common mantra that says, oh, you can't outrun a bad diet. And I would argue that's probably not true. I think you can outrun a bad diet, but it's pretty hard to do. And most people don't understand the amount of running that's needed to do it.

There's this incredible study from the 50s, people who worked at a jute plant and in India and they categorized people on incredibly physically active, you know, doing manual labor, hacking away on jute to make I think linen or rope. They were going to make rope with this stuff all the way to office workers. As you got more and more physically active, people got lighter. As you got more inactive, they got heavier. But what was interesting is people that were in the middle rung of occupational physical activity also had slightly lower caloric consumption, remained very trim if people are physically active enough. If you read the old papers about what lumberjacks were eating when they were chopping wood all day long, I mean it's 5,6000 calories a day. The old order Amish who walk around and do manual labor all day long and don't have tractors and stuff like that, they eat an awfully lot and very few of them are obese. You can't outrun a bad diet or can out exercise a Bad diet in a modern high calorie, low physical activity world, I think is the caveat that has to go to that one.

And yet when you look at athletes that are doing insane amounts of exercise, most of them have a hard time keeping on weight.

Yeah, there's a terrific study about the Tour de Franche, where they get done every day and they're just handing them food and you know, these people are eating ad lib, except when they're on the bike. And even when they are on the bike and they have a hard time and they're eating 6,000 calories a day, they weigh about 150 pounds and they have a hard time keeping their weight.

They are catabolic throughout the Tour. I mean, they finish in pretty bad shape.

Correct. They look like not death camp survivors, but people who certainly haven't had a lot to eat for a few weeks.

So let's go back to something you said at the outset, which was the impact of exercise on the autonomic nervous system. Explain to folks what the autonomic nervous system is, how it differs from the sympathetic nervous system, and why it plays such an important role in our health, and of course, how exercise impacts it.

When we think about the nervous system, normally we think about our brain, our eyes, our ears and our senses, and also our ability to grab things, move our muscles, that sort of thing, feel pain or feel heat or cold, or sense the environment. But your autonomic nervous system is what controls your internal environment, and it's called homeostasis. So, you know, we can increase our metabolism 10 or 20 fold with exercise. Our body temperature only rises a degree or two. And so this happens due to the actions of the autonomic nervous system. Now, there are two branches of the autonomic nervous system. There's the sympathetic nerves and the parasympathetic nerves. And these used to be kind of categorized as fight or flight. You would either activate especially the sympathetic nerves if you needed to fight, or fly, run away. And whereas the parasympathetic nerves were seen as what happened when you were asleep, when you're digesting your food, so on and so forth. But it turns out there's kind of more of a balance and a yin and a yang between the two that happen all the time. But the parasympathetic nerves, and the most notable one is the vagus, they control part of your heart rate, make your heart rate slower. They also tend to lower blood pressure, and they're critical to digest your food. That's one side. The other side is the autonomic nervous system. Nerves that increase your heart rate, stimulate your blood vessels to constrict, help your muscles contract harder, and also do things like make you sweat. And the key thing to remember is that they help you regulate the internal environment. And that exercise really keeps these things tuned up. And by having your autonomic nervous system a bit better tuned up, it can do a better job regulating your internal environment. The classic example being your blood pressure.

Now, of course, what everybody knows, and we're going to talk in a moment about VO2 max testing and how that's done, because I want to get into the weeds on that. But when we have our patients tested, you know, we have a protocol, we look at their blood pressure before and then we look at their blood pressure throughout, and then we want to look where they are percentile wise, at the max exertion, what's their blood pressure? And without exception, a person's blood pressure goes up when we do a VO2 max test. So you take somebody whose blood pressure is 1, 115 over 75 at the outset, they'll easily be 160 over 95 or 100. And that's completely normal and healthy at.

A max, even higher if you measured it while they're weightlifting.

So explain to folks why it is that during exercise nothing looks good, right? Blood pressure's high, heart rate's high, heart rate variability is low. What is it about the recovery phase from exercise that produces a net positive effect? Even though in the moment, exercise presumably is doing things that are not necessarily in our body's best interest, in that.

Moment, I would say they are in their best interest, because what happens is the system shifts a little bit to kind of meet the demands of the skeletal muscle. You got to be able to contract the muscles to exercise. And again, that's sort of consistent with the fight or flight thing. If you're going to run away or be in a fight, you want to be able to contractor muscles. And so to do that, you need to send more blood flow to those muscles. And one of the ways you do that is by increasing your blood pressure. More blood pressure equals more flow. And the other thing you got to do is increase the pumping function of your heart at rest. People's heart is beating about 5 liters or a little over a gallon a minute. During moderate exercise, it can be 10 liters a minute. During heavy exercise, 15 or 20. And elite athletes who are very trained and have very large hearts, it can be 30 or 40 liters a minute. So what happens is you're pumping all that blood out against these blood vessels, and so your blood pressure rises. So it's a completely normal thing to generate that large cardiac output. Cardiac output is heart rate times stroke volume. That's the amount with each squeeze of the heart. And so naturally, you're going to want to increase your heart rate. So that's what happens. But then when you stop, stop, as you mentioned, heart rate falls, blood pressure falls, and things look probably better than they did. In somebody who is untrained and hasn't exercised.

What do we know about the rate of recovery? There's something called heart rate recovery, hrr. That is a pretty interesting metric. Tell us what we know about hrr.

So people do a maximum exercise test and their heart rate's, you know, 150, 160, 180, whatever their age is. And 220 minus your age is an interesting number. But there's a lot of patient to patient or person to person variability. So what happens is how fast does your heart rate go back down to some number? How fast does it get till it's under 100, how fast till it goes back to baseline, whatever. So the faster it goes down, the faster it goes down, the better the action of your vagal nerve, the nerve that slows your heart rate, the vagus nerve is also responsible mostly for your heart rate variability. And this nerve also suppresses funny heartbeats and is protective when it's in good shape against arrhythmias and ventricular tachycardia, ventricular fibrillation, sudden death, all of those things. And so heart rate recovery, heart rate variability, all of those things are indirect markers of what we call vagal tone or vagal activity. And that's a good thing.

Now, heart rate variability can be quite genetic, right, Mike? The absolute number in milliseconds between any two individuals can be quite distinct. And it seems to be not nearly as modifiable as some other factors. Have you found that to be the case?

Again, it depends what sorts of training people have been doing, what they've been exposed to. But in general, you know, most people can get a nice training braided cardio, which again, is vagal tone. And most people, if they're trained, can go from, you know, slow heart recovery to faster heart rate recovery and also have more heart rate variability. So I think worrying about the differences in the initial baseline, Peter, while interesting and what they might be attributable to is probably less important than the fact that they're modifiable. As you mentioned, you Know, as they say at the top of the show.

So let's talk about this VO2 max test, because we're going to talk about what it means and how predictive it might be of an individual's mortality. So let's just start by explaining to people what you do when a person comes into the lab.

So what you do is you get them on a bike or a treadmill, you put some EKG electrodes on them, and they either run on the treadmill or ride a bike. And they have a nose clip on if you're going to measure it directly, and either a face mask or a mouthpiece that they breathe. And that allows us to measure how much air they breathe in, how much air they breathe out. We know that the air has 21% oxygen coming in. If we measure the amount of oxygen in the expired air, we can make an estimate of how much oxygen has been consumed. And so what happens is when people start to exercise, they go from using about 3 1/2 mls per kg per minute, or maybe 250 mls or 300 mls. So like 10 or 12 ounces of oxygen per minute. And an unfit person in their 30s or 40s can typically increase that about 88 or tenfold to say 30 or 35 or about 3 liters a minute. And with training, most people can increase things at least 10 or 20%. And if you have some ability and or you train very hard, some people can almost double it. So what happens is once your VO2 max goes up again, just like physical activity, it's a measure of physical fitness and it's also linked to all cause mortality. So the fitter you are, the lower your chance of dying in the next year. 2 years, 5 years, 10 years. For many years they thought that things sort of plateaued at what they call about 10 or 12 mets a met mean your resting metabolic rate. So you had to be able to get 10 Mets, and 10 Mets is being able to run one mile in about 10 minutes roughly for the average person. Henry Ford in Detroit has shown that that continues to rise even up to 15, 16 Mets. So people that are quite fit continue to gain benefit in terms of all cause mortality. I mentioned the cross country skiers earlier, and while they didn't do VO2 max tests in those people, the people who had completed the most races and done the races the fastest. So people who had both been active for the longest period of time and probably were the fittest also had lower all cause mortality, not compared to sedentary peers, but compared to people who'd done a few races a little bit slower. So, yeah, peak fitness matters.

There's a paper in JAMA that I think is by far the most compelling description of this phenomenon. A couple things are noteworthy about it. I've talked about this on a previous AMA. I would consider it one of the 10 most influential papers that I have read in terms of changing how I think about healthspan and lifespan. As you said, the relationship is monotonic and it does not plateau. That's an important thing to appreciate, which is this is a more is better phenomenon. And very few things in physiology are more is better. Usually physiology behaves in U's and upside down U's or maybe J's and things like that, or plateaus, sigmoid curves. But this is not the case here. This study that we're talking about put people into the bottom 25th percentile, 25th to 50th percentile, 50th to 75th, and then the last group, it basically divided into 75th to 97 and a half. And then they had that little sliver of people that they called elite that were at the top two and a half percentile. And all cause mortality just went lower and lower and lower and lower. And if you looked at the hazard ratio the other way, because we often think about hazard ratios and risk reduction. But if you look about it in risk increase, when you compared the people in the top 2 1/2% VO2 max to the bottom 25%, the hazard ratio moving in that direction was 5.04, if my memory serves me correctly, that means there's a five fold increase in all cause mortality between the fittest 2.5% and the least fit 25%. And even when you took something less extreme, I believe if you looked at the least fit, 25% to the third quartile, so the 50th to the 75th percentile, the hazard ratio was still about just below 3. I think it was 2.75 ish, which was kind of right on par with the increase in mortality that you would see from having end stage renal disease, which is, by the way, greater than the hazard ratio associated with smoking.

Being unfit is an incredible risk factor. And people like Frank Booth have argued that it should be, for lack of a better word, the risk factor. And Jill Barnes, one of my fellows at the time, she's now at the University of Wisconsin, a faculty member, she and I wrote a editorial for Mayo clinic proceedings maybe five, 10 years ago where we said, look, if people had, you know, 12, 13, 14 met peak exercise capacity. Other than doing cancer screening, you could probably just ignore everything else. I don't think anybody's ready to go there, the sorts of people who do health screening and that sort of thing. But if you screened people for physical fitness and again, just did the routine kind of cancer screening, and you could even argue that you could probably cut back on the routine cancer screening for most things except skin cancers, because fit people tend to be outside of it more. You can make that argument and you can make it with a straight face and the data is there to support it.

And I would belt and suspenders it and say, but look, I still do the cancer screening. I'd still consider aggressive lipid management and things like that. But you're absolutely right. I mean, there's really no intervention that we have that's going to rival it.

I think you mentioned limpids. I think there's a couple things you gotta remember. One, especially for people who pick it up late in life, you know, exercise is not a vaccine. And one of the most incredible studies ever done, again, we're talking about n of one experiment of nature sorts of things. There was a man named Clarence Demar. He won the Boston Marathon seven times. Born I think in 1888 or 1890. Also won a medal in the 24 Olympics, got a bronze medal in the marathon. And he really is almost like master athlete number one. So he kept training his whole life, ended up dying, I think of stomach cancer at about age 70. So he didn't live to be a gazillion. But remember he was born in 1888 or 1890. Paul Dudley White, a famous cardiologist. We know him from something called the wolf Parkinson White syndrome. A weird kind of funny heart people get did an autopsy on Demar and he'd run really till very late in life. And he had some plaque or fatty buildup and calcium buildup in his coronary arteries. But his coronary arteries were huge, were just massive. And subsequent to that, a man named Bill Haskell at Stanford in the middle 90s studied a bunch of people who've done ultramarathons. And they did the same thing, except this time they put catheters in and injected drugs to make the blood vessels expand. And they showed the blood vessels were bigger and they expanded more. So again, while you could still have some blockages even if you exercise. And there are people with horrible lipids who do in fact get heart disease in spite of exercise. So it's not a complete vaccine. Its overall protective effect is quite Large, both in terms of what it does to people's lipids, but the fact that the blood vessels get so much bigger and the linings of the blood vessels are healthier.

Mike, one of the things that we've looked at a lot internally is the literature that argues a different point. The literature that argues that, in fact, there's a J curve here. And we all agree that a person who doesn't do anything is at the highest risk. The literature is so unambiguous there, it doesn't warrant any further discussion. But let's now look at the addition of work. Now, I just want to make sure the listener understands the way we're going to talk about this. Let's talk about these in MET hours per week.

A weird metric, for sure.

I've actually had to convert my own training into a MET hour per week spreadsheet so that I can interpret what I do in the context of all the literature. Totally weird, but let's explain to people what it is. Right, so you told us what a MET is.1 MET is the metabolic expenditure of sitting at rest, which corresponds to about 3.5 milliliters per minute per kilogram of minute ventilation, or actually VO2. So oxygen ventilation, not pulled minute ventilation. Then let's talk about how that ramps up. How many mets is it, Mike, to walk three miles in an hour?

Probably four, five, six, something like that. I don't know.

Oh, is it that high? Okay, I would have guessed lower.

It may be because remember, a 10 minute mile is 10 Mets.

10 minute mile is 6 miles in an hour. And that's pretty nonlinear. Yeah, you're right. It's probably about three to four METs, I would guess. And then of course, as you noted, to run six miles in an hour would be 10 METs. So let's say you did that. You ran six miles in an hour for an energy expenditure of 10 METs. So that would be 10 MET hours. You did 10 METs times one hour. And if you did that four times a week and that was the only thing you did, you'd be at 40 met hours per week of activity. So I do this for my training. I spend how much time am I on the bike at this many watts, at this many watts, and in the weight room and, you know, carrying my rucksack and, you know, I'm sort of in the hundred met hours per week category. So if you look at the literature, the epidemiology on this, it would say my mortality risk might be higher. That would be the headline. Than someone who's doing 40 met hours per week. In other words, it's a J curve. So it sort of starts up here. Highest mortality at nothing. Mortality comes down sort of Naders, depending on the study, between 50 and 75 MET hours per week. And then the mortality tends to climb. Now, I won't go into this in great detail other than we've looked at every one of these papers and we find significant fault in each of them. What do you see?

Not all of them say that in the sense that some.

That's right, some of them don't.

The big NCI study with 650,000 patients or subjects didn't say that. And again, what I really like is that cross country ski paper that I mentioned from Scandinavia. If somebody's going to ski 90km and if they're going to do it year after year and they're going to do.

It fast, they have to be training a lot.

You're going to have to be training a lot. You're going to be training year round. You almost are certainly getting all sorts of med hours and training pretty hard. Now, the one caveat in all this, and I agree with you completely, I don't think the evidence for a J curve is particularly good. The other thing is in many of these studies, the number of people that are way out there is very small. So even one death, somebody gets hit by a car or something, it can make a difference. That's certainly one of the problems with a study from Copenhagen, as I recall, or Norway, but one of the Scandinavian capitals. So I really think that the dispositive study here is the real world data from the Vasa Lopez story. Now, the one thing that does happen is people do have an apparent increase in risk of atrial fibrillation. A couple of caveats to that. The first thing is they do not have any increased risk of fatal arrhythmias. Atrial fib is no fun, but it certainly can lead to medical problems, but not typically. Didn't kill you the sorts of things that kill you. You have ventricular arrhythmias. These are not seen to any greater extent in these people that are really heavy exercises for their entire life. So then the question becomes, do these people actually have more atrial fibrillation or is it just that they're exercising and notice it? And that's the controversy. I think you would probably have to say that people who train what you're talking about for their entire life have certain some increased risk of atrial fib compared to people that are just super healthy otherwise physically active at that 50 to 70 met hour per week thing you're talking about or level you're talking about. But your risk of atrial fibrillation is still probably lower than people who are sedentary, hypertensive, obese, diabetic, and so forth. And there are good treatments for atrial fibrillation, and you continue to be protected against fatal arrhythmias.

And what do you think about sort of myocardial fibrosis? There's been some talk about that. Do we see compelling evidence to suggest.

Again, the data from Ben Levine's group down in Dallas, where they've done a bunch of echoes and loaded the heart and done all kinds of things, and they show that fit young people have very flexible, compliant heart muscles. And they show that that declines with age, but doesn't decline nearly so fast in people that are either habitual exercises or people who remain master athletes, remain highly competitive. So, again, I think that you can talk yourself into these sorts of things through a case report here, a case report there. But when you look at the sort of data that came from Ben's lab and other things, you see that this sort of training keeps the ventricles compliant, flexible, and able to handle the increased demands and pumping demands of exercise. So I think the fibrosis argument's a little spurious. I think we've talked a little bit earlier about large coronary arteries in people that are habitually physically active. We've talked about that those arteries vasodilate better. They probably are less likely to generate a clot. And then we've just simply said you're protected against fatal arrhythmias. We've just simply said there may be a subtle increased risk in atrial fibrillation, but again, good treatments for atrial fib. So I think you're in good shape, I think in that regard, doing as much as you do, Peter. And the other thing to remember is that it's not an absolute vaccine or an absolute you work out an hour a day, you're never going to get have heart disease. But I think your risk can be dramatically reduced.

The other thing I think that argues against a J curve is the VO2 max data that we just discussed, which is an enormous cohort, probably the largest cohort after the Copenhagen cohort, and far more balanced in terms of the number of people in each group and has.

Been repeated in other populations.

So there you have to ask the question, how is it that people in the top 2.3% of the population for VO2 max have the lowest mortality by a long shot if they're not training significantly. I know those numbers very well. I mean, we put all of our patients up against that template and we show them where they are and where we want them to be and we actually hold them to an even higher standard. Mike. We kind of want our patients to be at the elite level for a decade below where they are actually are, age wise. And I'll tell you in a moment why we do that. I want to see if you agree with my logic. Logic. I don't see how you're going to get there doing 40 mat hours per week. You can't achieve a VO2 max of that level. Just doing a little bit of maintenance stuff here and there. You have to be training.

Yeah, you have to be training. You have to be doing some high intensity training. So I agree with you. The other thing is, if you look at some classic studies by people like Bob Hickson and more recently Wysloff's group up in Norway, people who do some longer intervals three or four times a week can get a lot of bang for their buck in terms of VO2 max.

I want to come back to that, Mike, because I want to talk very specifically about the different modalities for training. Before I do, I want to see if you can check my logic on this. A big part of where we come up with the reason you want to have a high VO2 max when you're young is we want to be able to prepare for the inevitability of decline. So I want to start by just asking you what is the most up to date understanding of how much peak VO2 declines? And let's do it in a non training individual and a training individual.

So in General, people think VO2 max declines about 10% per decade starting in the fourth decade. So sometime in your 30s, you know, some people say 9, some people say 12, some people say, but roughly 10%. A lot of that is driven by age related decline in heart rate. But in people that are not training, it's driven because their heart can't pump as much blood and their muscles can't use it. So among people who are training, you start at a higher level and then if people continue to train, you probably don't see a big decline until your late 30s or early 40s. And we see that among athletes because there are world class endurance athletes in their early 40s. And then you can reduce the rate of decline by about half up to certainly up to your 70s, probably now. Not everybody keeps training hard. If People stop training, their VO2 Max falls precipitously. Dr. Dave Costell, really one of the founders of exercise physiology in the United States, studied a lot of elite athletes in the 60s and 70s. He brought them back to his lab when these guys in the 90s, 1990s, when they were in their late 40s and 50s, and about a third of them had continued to train very hard and had minimal reductions in their VO2 max. A third had become sort of joggers, had some reduction, and there was a third that had just stopped doing anything. And they look like regular sedentary people. So you do have to stay at it. A group of master athletes out in the LA area who were studied, same sorts of things, people declined and their VO2 Max declined. But among the people who continued to train intensely, in the case of the men do some strength training, their VO2 max declined at a much lower rate. So you have a situation where it's 10% if you do nothing, and if you really work at it and stay with it at a really high level, it's, you know, maybe 5 or 6% per decade. But most people who've been super competitive can't quite keep doing that their entire life. So they drop off a little bit. But even if they drop off 10% per decade, they start at a much higher baseline. If your baseline is 60 versus 35 and you lose 10% per decade, you're still gonna be way, way, way ahead. And at age 60 or 70, you're gonna have a VO2 max value higher than, you know, 30 year old.

The reason we push so hard, Mike, for our patients to have as high a VO2 max as possible when they're in their 40s and 50s, is based on this inevitability of decline. And with the hopes that we're extending life by a decade so that, hey, even though actuarially you might only be expected to live to 81, we're kind of hoping you, you're going to get to 91. And if you say you want to be active, then we have to reverse engineer what that means. So what do you think is the VO2 max above which you have absolutely no limitation on any normal person's activities? In other words, if you said to me, hey, look, when I'm in my 80s, I want to be able to do pretty much anything reasonable. I don't have to run a five minute mile. But what I do want to be able to do is I want to go on a hard hike. And if that means I got to climb 100ft in half a mile, so be it.

That's a great question. It goes back to one of your earlier comments about your scale versus the traditional kind of anti frailty scale. And what do you want to not be able to do when you're 85 or whatever. The magic number is VO2 of 14mls per kilogram per minute, or 4 Mets. 4 Mets is required from an oxygen consumption perspective for people to do their activities of daily living, which means an occasional somewhat brisk walk for a few minutes and be able to kind of get around the house, go to the supermarket and be quote, independent, whatever that means. If you want to be able to run a mile in 10 minutes, that.

Would be 35 VO2 max.

Yeah, yeah, 35 or 10 METs. So somewhere between those two are the magic number. So I would say that, you know, if somebody in their 80s had a max in their 20s or lower 30s, that'd be terrific.

We have arrived at 30 to 31 as the Magic number.

That would be a rough guess. And what's interesting that you mentioned that is those Scandinavian elite skiers I mentioned had values in the very high 30s.

Or low 40s in their 80s.

Any sort of biological gifts or genetic gifts that those men had and or fact that they started to train, you know, probably be very physically active as youngsters and were maximally physically active from age, you know, 13, 14 to probably 30 would account for that. I think 30 be a terrific goal. But I think the other thing too is how many pushups do you want to be able to do? And how many sorts of body weight type of things do you want to be able to do? What sort of agility maneuvers do you want to be able to do? And I think, you know, you have to factor in orthopedic problems and that sort of thing. But again, we have good treatment for those now, and our orthopedic surgeons can fix a lot of things that otherwise would have made people difficult for them to walk and move around.

Yeah, we think a lot about those things, and we think that strength and stability need to be trained in parallel and as hard as we're training from a cardio standpoint. But I do think this idea that if you're trying to reverse engineer ending your life with a VO2 max in the mid-20s to high-30s, the good news is you are never going to not be able to do something that you want to do. If you're in the airport and the escalator isn't working, you don't care.

Yeah, right. And I Think the thing you have to ask people, and this really resonates, is, do you want to be able to play with your grandchildren? That's one question for people, the escalator question. That's a terrific question.

I was just in the airport last week, escalator down, and it's a long. It was one of those really long ones. You got your carry on, bag, plus your backpack, and you got to get up the escalator. Now, I'm sure somewhere out there there was an elevator. But the point is, do you want to be able to do this stuff? And if you do, then you have to do the math.

You have to work that. Agreed. In what's interesting, you see a few people around here in rural Minnesota who, you know, grew up on less than fully mechanized farms and remained, you know, active, milking cows and doing these sorts of things, doing a whole lot of chores. It's remarkable, the muscle mass that some of these men and women have. Well, and if you look at in Japan, for example, and the hilliest parts of Japan and some of the hilliest parts of Italy and Greece are where the longevity is the highest. And people have argued it's because people have to walk up and down the hills, and also they keep their balance, they keep their glute strength, they don't fall, that sort of thing.

Peter.

And also that they're, you know, living a more rustic lifestyle is probably getting them some de facto strength training on a daily basis.

Let's talk a little bit about VO2 max, again, in terms of, like, what is actually driving it? So let's go through all the variables. You've got gas exchange in the lungs, in the lung.

Correct.

Then you have pump efficiency.

Correct.

We went through the mechanics of that again, but just so people understand what we talk about, you've got stroke, volume, contractility, of course, afterload and preload, and all these things that determine basically the efficacy of the pump to move the medium to the capillary bed, and then you have capillary exchange in the muscle bed. So broadly speaking, let's just say those are three variables, right? You've got the gas exchange at the source, you've got the pump, and then you've got the gas exchange at the destination. I know that's overly simplistic, so let's just think.

You got air to lung, lung to blood, blood from the heart to the tissues, and oxygen from the blood to the tissues. There's four or five steps like that, and you enumerated three big ones. And so in general, oxygen Uptake is cardiac output, how much blood you're pumping per minute times arterial venous oxygen difference, how much blood you're extracting or oxygen you're extracting out of the blood. And it turns out that if you look at all the studies and all the people fit, unfit, trained, untrained, in general, the biggest issue is how much blood can you pump. So what is that heart rate times stroke volume equation? Where does that leave us now? When you train, you get so you can extract more. And if you're at high altitude or if you've got problems with your lungs, maybe the lungs don't work as well. But in general, I like to tell people you cannot extract what has not been delivered. So the key is delivery, and that's heart rate times stroke volume. And interestingly, Peter, as you, I'm sure you've seen is some of your fittest people actually have slightly lower peak heart rates. And one of the reasons is, is because their stroke volume is so high. One of the really interesting, again, experiment of nature, patients or subjects is a man called Eskild Ebison, who won gold medals in five Olympics and rowing for Denmark. They have serial VO2 max date on him from the time he was 18 or 19 till his early 40s. And his VO2 max stayed around, you know, 5.6 liters per minute, which is quite high. And he weighed about 70 kilos, I believe. He was a lightweight rower. But his peak heart rate dropped from about 190 to 150 over that period of time. Which all that means is that he was able to pump the same amount of blood, but he had to do more with each beat.

That's an insane example, actually. So in other words, in the individual, as they age, we think that the majority of the reduction in VO2 max is coming from cardiac output reduction.

Right. And the majority is probably coming from a reduction in peak heart rate, which can be buffered to some extent. If you have a nice compliant ventricle.

Like we talked about. I'll tell you, I'm not quite yet 50 and I am just saddened by the reduction in my peak heart rate. It is really breaking my heart. I mean, I.

Mine was never very high anyway. And I don't worry about it, but I'm 63 so I've stopped worrying about it. I worry about where my workload is.

I remember thinking like, there will never be a day when I can't get my heart rate above X. But actually, I'll tell you, for me, it fell quite precipitously in my 20s. So as a teenager when I was training obscenely hard, inappropriately hard, a heart rate of 200 was an everyday occurrence. There was never a day in high school that my heart rate didn't hit 200 to 205 beats per minute by the time I was in Medical School. So 24, 25 years old, all of a sudden it dropped immediately to about 180. It became very difficult to get over 180, which by the way, was far lower than the 220 minus your age prediction.

I was in two famous studies as a subject. One is this lactate threshold study when I was 19. And then a few years later, I went and worked one summer at Washington University in St. Louis and I stopped training. I just finished my last year of track and field at the University of Arizona. I'd run 10,000 meters in 3048 and didn't done well on the Pac Tens, which was fast. Well, I was good enough to get lapped by the world record holders is what I like to tell people. But anyways, what happened is my peak heart rate was like 185 or 188, I can't remember. And over the period of 12 weeks of detraining, it went up to about 10 beats a minute, which would have been, you know, in the high 190s, which would have been, quote 220 minus my age at the time. There are all sorts of examples. There's a bunch of data on elite athletes showing that some of them have peak heart rates similar to 220 minus their age, but many are lower than that. And they're like Eskel Debison. There are some people that have been world record holders, Olympic champions, that had peak heart rates in the 150s.

If I hit 170 today, that's a good day, which is about 220 minus my age.

That doesn't surprise me. My guess is I'd be very impressed to get to 140.

I was talking with Lance Armstrong on a, had him on the podcast maybe about less than a year ago actually. And we were talking about back in the heyday of his tours. They weren't really looking at their power meeting when they were competing. So they trained with the power meter. When it was race day for the time trial, you just went off heart rate and I was just blown away. I mean, you gotta think Lance was winning the tours between 28 and 35, he was still holding 200 beats per minute for the entire time trial. So imagine 45 minutes at 200 beats per minute when you're 30 plus years old is kind of insane.

The other example though would be a man named Bob Schewell, who is an American who won the 5,000 in 1964, who did interval training all day and all night. It was incredible how he trained. And I have the data someplace was like 154, 156. Jim Ryan's the great miler was not particularly high in his 20s.

Yeah. So just incredible stroke volume.

Correct, Correct. Correct. Big heart, big pumps.

All right, so let's talk a little bit about the training. So let's start with something that we haven't talked about, which, you know, when you look at the best high output endurance athletes today, it's one thing to talk about their peak engine performance, but it's easy to overlook what they're doing at the low end. You know, I've had Inigo San Milan on the podcast twice and we've talked at length about Tadip Pogachar. And it's amazing to talk about how high his FTP is, his functional threshold power. We could talk about his VO2 max, but. But equally amazing to that is how much power he can put out while keeping lactate below 2 millimole. He's over 4 watts per kilo while keeping lactate below 2 millimole. Why that's amazing for someone who doesn't ride a bike is if you took an average fit person off the street and said hold 4 watts per kilo, they could maybe do it for a minute. Most people couldn't do it for a minute and this guy can do it for four hours. That low end aerobic efficiency. I always try to explain to my patients if your VO2 max represents the height or peak of your pyramid, the wider your base, the higher your peak. Do you agree with that sentiment?

What I would simply say, as we think about performance and you think about these elites, we think obviously about their VO2 max. Then you start thinking about their lactate threshold, which would be sort of the FTP. And they're all sort of related anaerobic. There's a lot of terminology here you can get in arguments with people about the details, but what fraction of your VO2 max can you perform at for, you know, minutes to hours? And typically it's about 60% in untrained young to middle aged people. Lower in people that are really untrained, just sort of sedentary, and people that are very fit. It can be 75, 80, 85, even 90% of VO2 max. And in some older athletes, close to 100. So that's exactly what you described. Somebody like that probably has a peak work rate that they could sustain for 10 or 20 minutes of 6,7 watts per kilo. So the fact that they can do 4 watts per kilo forever shouldn't surprise anybody. You look at somebody like Mr. Kipchoge, you know, who's running 440 miles at a pace that doesn't really probably cause much of an increase in his blood lactic acid levels at all.

Did they ever reveal any of those metrics when he.

That data has been published.

Now tell me, what was his lactate level at the completion of the just under two hour marathon?

Remember, at the end of the race, you wouldn't have a lot of carbohydrate on board, but I would just simply say he can run 440 miles or over 12 miles an hour at levels that barely nudges lactic acid levels. When I first started thinking about this and making models of performance, I thought that the highest number was 85% of max and it's probably closer to 90 for somebody like him. And when you were talking about FTP for one minute, the other interesting thing about that, Peter, is, you know, the Kipchoge challenge, people have put treadmills at 12 and a half miles an hour.

Yep, I've seen it done.

Yeah. And see how long somebody can last on the treadmill, you know, and it's.

Like, yeah, they're getting spit off in 30 seconds.

Yeah, less than that.

It's insane.

So same sort of thing, that sort of training, you know, for. And these people are training two, three, four hours a day. If you look in terms of the runners running is limited to some extent because of.

Yeah, the impact just becomes a problem.

You know, orthopedic issues. Impact, right. And so it's really difficult for people to run more than about 120 or 130 miles a week and ever run, do hard training, prolonged periods of time. Now there are a few people who can do it. And if you look at what Kipchoge does, it's almost identical even day for day. What Bill Rogers and Frank Shorter did does it at altitude. But there's a lot of mean medium 8 and 10 and 12 miles of runs, a couple of hard interval sessions per week and, you know, long run, and that gets them to 120 miles a week, you know, week in and week out. Now the cyclists can do more.

They don't have the impact because you.

Don'T have that issue but remember that with cycling, you know, you're going up and you're going down, and you have always a chance to take a break here and there. The swimmers do a ton as well, you know, and again, because swimming is very forgiving in terms of not beating people up, provided your shoulders, you know, don't get a bunch of tendonitis. But what's amazing is, is that if you look at what the elite of the elite are doing, does not really change that much for 50 or 60 years. You have better equipment, you have better races, you got better this, better that. But in terms of if you look at the data on the elite of the elite from the late 60s and early 70s, it's not like Kipchoge's VO2 Max was 90. It was high 70s, just as what you would anticipate and so forth. I think a lot of what's happened in terms of at the very edge of things has been better races. People now have longer careers. They don't stop when they're 25 or 26. Sports medicine is better. So if they get injured, they can recover. We saw this last night with Klay Thompson. He had two injuries that 30, 40 years ago would have been basically career ending. And he's come back from a combination of an ACL issue and Achilles, especially, used to just destroy people. He's playing very well. So I think those sorts of things. The races are much better, you know, and they used to run the Boston Marathon at noon, when every so often you'd get, you know, a really hot day. So most of the improved performance can be equipment, these sort of social factors. Unfortunately, in the case of Mr. Armstrong, people, you know, bending the rules and so forth and so on.

So let's talk about kind of the intensity levels that one needs to be training at. I mean, we could pick the most extreme example and talk about Kipchoge. How many hours per week is Kipchoge running? Because I know he also does a ton of other strength training and bodyweight training.

My guess is that the total amount of time he's running is somewhere between 14 and 18 or 20 hours a week.

Yeah, he's covering a much greater ground.

Of course, you know, if you looked at it in terms of the lactate threshold or the equivalent of critical power on the bike, probably 60, 70% of that is fast, but not that fast. They typically start off, their group run, sort of jogging, and then they pick it up over time. Also remember that he's doing this at 7,8000ft, and then my Understanding in reading. His training program is a couple days a week he goes to a track and they run multiple 400 meters, let's say 200 meter jog, or multiple kilometers with a 200 or 400 meter jogger, like 10 times a kilometer, very fast. So the total amount of time he's running faster than race pace might just be 10 miles per week. So he's probably running about 60 or 70% of his stuff, some of it quite slow, but most of it, you know, medium fast. But certainly not where he can't talk to you, where he's short of breath, then he's probably spending about 20% of his time. He can still talk to you, but he's pushing it a little bit. And probably 10% of his time where he's pushing question it a lot.

I mean, that's exactly my impression and it's the same impression I have of elite cyclists and elite swimmers.

Those sorts of breakdowns, kind of the 60, 70, 20, 30, 10 are pretty typical. Now what's interesting is that's really emerged the last, say 20 years. If you look at people who've looked at the history of training and they have gotten training logs from people, and I told you, we have lab data on people that's quite good starting in the 19, some even in the 1930s, but certainly by the 50s and 60s we got plenty of good data. And if you look at what these individuals who have tremendous treadmill values, tremendous VO2 max values, ran very fast times on like dirt tracks and muddy conditions, that sort of thing. What we describe as a kind of a kludgy bike. Now, it's certainly no aero bars. Look at the swimsuits, people racing. So if you look at what those people were doing, they were doing all kinds of things. Runners. In the 60s there were people again like Bob Schewell, a fascinating man who's still alive. His morning workout would be 40 times 100 meters with a short jog in between. And his afternoon workout might be 20 times 400 meters. And he rarely ran continuously at all except in races. And it would be a fast interval, slow. And there are other people who ran up to 200 miles a week and hardly ever ran fast again except in races and some strides. There are already people doing the sort of mixed training I described a minute ago. So what is interesting is the extent to which things have sort of converged on this 60, 70, 20, 30, 10 sort of model.

It makes sense if you've ever done it yourself. And I can understand why there is a benefit to just the mitochondrial efficiency that comes from the continuous effort that you'd miss out on if you were just doing the short bursts and similarly.

Yeah, right. You make more mitochs.

Yeah, well, it depends what short is. I mean, again, if you're moving to four hundreds into eight hundreds, unless you.

Do a whole lot of them, and the recovery is a jog, because these guys aren't walking.

Do you think there is a training benefit? I know there's a health benefit, but a training benefit in the lowest. So we kind of think about zone two as where Kipchoge is probably spending 60 to 70% of his time. He can still talk, and then obviously he's in zone three, four kind of race pace, and then he's like 4, 5, 10% of his mileage, which is, you know, really stretching himself. Now, is Kipchoge or are other athletes deliberately putting time into zone one, which is truly a recovery pace, or.

Yeah, they do that when they're recovering between intervals. And you would be amazed at how, because I did it many, many years ago. So the first mile or two can be very slow. It can be just almost a walk, jog, and then they kind of drift into it. But thinking about the listeners who are just trying to improve their health, that's where you come back to physical activity, you know, versus intentional training. You start looking at the health benefits of just less than brisk walking, you know, purposeful, but not really brisk walking. They're substantial. You know, parking your car farther out in the parking lot and strolling in, I think, you know, walking the dog. And that can mean all sorts of things, depending on what kind of talk you have and who's in the neighborhood. The data on gardening, you could be out there hacking away weed with a machete or. But most of us think about gardening as relatively light exercise. The health benefits of light physical activity, light exercise, are substantial. And remember, you're correct in the sense that at least from our perspective, there is no J curve and things go up, but it's not completely linear. The biggest benefit people get, health wise, is the first 10 or 15 minutes a day.

And why do you think that is?

If you look at what 10 or 15 minutes does, I mean, I think it begins to do things in your skeletal muscle that improve your insulin sensitivity and help you fight against diabetes. I think just a tiny bit of additional physical activity is at least some buffer against weight gain. I think that there's some improvement in your alignment, in your blood vessels, and probably some improvement in your autonomic function. Is your heart going to get bigger, you're going to get more efficient cardiac pump? Probably not. But are you going to begin to do some of the things. And the answer is yes.

So, Mike, should those of us who really kind of care about this and care about using as many metrics as we can to understand this, should we be looking at heart rate recovery and adding that to our kind of repertoire of something we track in ourselves as we train?

I think that there are people that are really into tech and monitoring, then they're sort of tech nudies. I'm a tech nudie. And part of the reason is there wasn't as much around it when I started. I mean, we just were getting digital watches and they weren't even stopwatches. And the other reason is at the time, one of the big innovations was rating of perceived exertion, you know, the 6 to 20 scale, or some people use a 1 to 10 scale about how hard you're working. And I think that what's been shown is because, you know, you can have a good day and a bad day in terms of the metrics, that they're all sort of parallel. And if you learn to read your own body, body via, you know, the rating of perceived exertion and or metrics, you know, find one you like and then just focus on sort of big picture things. So I would not get too hung up on heart rate recovery and too hung up on heart rate variability. I would just more say, are you. How much are you doing? 30, 40, 60, 180 minutes a week? Are you also doing other forms of. Not a week a day. Are you also doing other forms of activity, you know, like taking the stairs, as you mentioned? And what sort of combination are you doing? How much time are you spending where you're really short of breath? How much time are you spending where you're a little bit short of breath and how much time is it? Kind of a pleasant sort of pace. I think that that sort of information can get you as much as you need. And I think the main thing then, Peter, is to make sure that you have some accountability, whether it's a training partner, maybe with a device or a diary, maybe, you know, with just how far did I run today? That sort of thing.

So what is your current exercise regimen? I mean, you sort of downplayed it a minute, but 30 minutes and 40 seconds for a 10K? I don't think people understand how fast that is.

I once ran a 225 marathon, but, you know, the older I get, the Better. I was right. I'm a big believer in what's called hard, easy, hard day, easy day. What I'll do, like tomorrow will be a hard day. So I'll get on, you know, a stationary bike in my workout room, on the bike and the rowing machine, do some sort of warm up for 10 to 15 minutes. Then I will do a circuit that starts with 25 squat thrusts, a minute of jumping rope, static wall set to failure, and then some drop sets where you go down the weight stack. Then drop sets with inclined flies, then drop sets with leg extensions and drop sets with a combination of pull ups and lat pull downs and military press. Then some additional stuff for my legs, push ups, bar dips and upright rows, followed by something else for my legs. So I alternate arms and legs and I work my way through this with no rest. Drop sets on each thing for all large major muscle masses. And that takes about 22 minutes.

22 minutes for one circuit.

One circuit. Then I get on the bike and I'll do like eight times three minutes of a ladder where you start unloaded, go up a notch, go up a notch, go up a notch. And I get to maybe about 350 watts for the last 30 seconds. Come back down to about 100 watts. 350 watts, do that times eight and.

Sorry, how long do you take to ladder? Three minutes.

Three minutes. Something like 100 watts for 30 seconds, 150 for 30, 200 for 30, 250 for 30, 300 for 30, 350 for 30. Come back down times eight. And that takes about an hour.

And how long in between your three minute sets?

No, you just go up and come right back down.

Your rest from the.

So the recovery is exactly. That takes about an hour. And that'll fix your wagon for a while.

That'll be your hard day tomorrow. And then what?

That'll be my hard day. And I'll do that basically every other day or every third day. My easy days will be something like this morning, I want to go do 20 more minutes. Not because I need to do 20 minutes, because I wanted to watch the first bit of Obi Wan Kenobi. So my easy days are built around what documentary or, you know, how many times can you watch the Mandalorian? How many Clint Eastwood movies can you watch? And this started during lockdown, right? So my easy days are 30 to 40 minutes of light cycling, transitioning to rowing back and forth of around 30 to 40 minutes. Sometimes I do one, sometimes if I come home from work, I do another one. But the goal there is an old concept called active rest. So I'm not trying to get a real training effect. I'm trying to loosen up from the day before. It's workout because I'm sore. You do what I described you warm up for 10 or 15 minutes, do 20 minutes of drop set and that type of intervals at the end, you will be sore. Right. So you have to recover the next day. Now, I'll do this for about six months, and then probably when it gets starts getting dark again, I'll do what I did like last year, where I start just doing kind of maintenance circuits in terms of the strength and maybe only twice a week and I'll start doing longer rides. We have a peloton. I don't do any of the classes, but I started doing this hour of truth to see how many watts I could average for an hour.

Okay, what are you at?

I think my best during lockdown last year was360. Average 316 watts for an hour.

Wow, that's obscenely.

Yeah, that's pretty good for it. And the things are calibrated pretty well. I got a lot of equipment. I got a Watt bike, and I think they're pretty close. If you look online, they claim they're close. Right. It's consistent with what I think. I haven't measured my VO2 max in a while, so I want to see if I can get like 320 watts next year.

What do you think your VO2 max is right now?

Well, I'll tell you, back when I was quite young, it was 5.4 liters a minute.

At what weight?

My weight then was probably between 75, but close to 80 kilos. So I was right at under 70. I think my weight now is probably about 95 kilos because I've actually made an effort to gain some weight. And I think my max is probably 4.5 liters a minute would be my guess.

That's still an amazing wattage under any.

Circumstance, assuming the machine is okay. But I think it is because remember when I'm doing those ladders that I was telling you about or those pyramids, that's after I've done a heavy leg workout, you know, so my legs are pretty fatigued when I've done that. That. But remember, I have some ability too, because.

Well, clearly, given what you ran.

Yeah, I didn't really start running until my senior year in high school, so I started late. And I'm six four and I tell people if I come back at the next life, I'll be a swimmer or rower because I used to show up with these tidy people. I'm the world's largest relatively good distance runner. Formerly relatively good.

On your easy recovery day, Mike, are you just paying attention to rpe or are you looking at a spot split time on the rowing machine or a low wattage bar on the bike?

No, no, it's just all rpe. It's really just active rest, which is a lost concept.

Do you have a sense of what your heart rate is as a percentage of your max heart rate?

No, I don't even measure it. It's probably about 140 is my peak heart rate. That would be my guess. Again, I go with rpe. I go till I suffer. It's unusual to be able to do intervals on your own and really push it. Not everybody can do it. And that's why you need a class or you need a coach, or you need a group and so forth. But I'm lucky enough to be able to do it. So my training's really polarized. I mean, like, really polarized.

So let's talk about folks who are listening to this who want to boost their VO2 max. Let's talk about the different protocols that exist. I'll tell you what we typically tell patients to do, which is, in my experience, one of the most efficient ways that you can do it. But I'm curious as to what other ways. So we typically talk about a four by four or four on, four off protocol. So we'll tell people. And again, the easiest way that I personally can do this is on a bike on an incline. And it can't be a very steep incline. It's gotta be like 6% grade. I want to stay in the saddle, but I never want the resistance to go away. And I basically want to be in the saddle climbing against resistance for four minutes. And I use a power meter and a heart rate, so I just want to keep the power as steel steady as I can. Invariably, it dips in about the third minute, and then I can recover it in the fourth minute psychologically. And then the recovery is four minutes of literally doing nothing but rolling back to the starting line. And then it's basically just repeat that.

No, no, I'm with you. What I tell people, for example, that have come and say, I want to run a faster marathon. I want to do this, I want to do that. And they're running a lot of miles. They need to get their VO2 max up. And I tell them exactly what you've described. Sometimes I tell them Five minutes and three minutes rest, sometimes, whatever. People that are fitter sometimes only take, like, I would only take two minutes of rest. But four times four is terrific. So you would do something if you were thinking about running? I would tell people to do something that would be right at their sort of 5k race pace, maybe a little faster, or you would do the first one a little slower than your 5k race pace, the next one, you know, a little faster than that, the next one a little faster, the next one faster than your 5k race pace. And depending on how fast you're running, if you're going pretty fast, then you would just jog in between. And if you were not going so fast, you would walk in between. So that would be the sort of thing that I would describe to people. The classic training, you know, among elite runners is mile repeats. You know, four or five times one mile, and then they jog a quarter mile or half mile in between. And I personally have seen really good runners do, you know, 430, 425, 424, 15, 410, 405. But I mean, these were people getting ready for the Olympics.

But sort of for the average person, the hard part that I think requires a little bit of coaching up front is, you know, you and I have done this our whole lives, so we sort of know what four minutes all out feels like. At 30 seconds in, you shouldn't be hurting too much. If you are, you've gone out too hard. It takes a little bit of work to coach somebody to understand what you're going for is a constant four minutes. But the suffering is disproportionately in the last 90 seconds.

When you get done with the last one, the fourth one, you do not want to be bending over. If you'd have gone a little bit of faster, you want to be bending over. So I call it the no bend over rule. And then what people have to recognize, both for the four times four minutes and within the four minutes is a good interval workout. And this sounds completely masochistic, is like putting your hand in warm water and then slowly increasing the temperature in the water to where you can barely stand it anymore, and then leave it in for a while, and then you turn it down, let your hand cool off, and do it again. One of the things I think we've learned from the cyclists is a terrific phrase called manage your suffering. You know, you need to learn to manage your suffering. And I think that's the other interesting thing about this type of training. Is to the extent, you know, people can have these sort of religious experiences, exercising this sort of interval training is one way to get them.

No, I completely agree. I mean, obviously we're cut from the same cloth in this way, but I think that there really is something wonderful about experiencing your limits and understanding that level of discomfort.

And if you're able to maintain your rhythm and tempo, Peter, while you do it, that's when you can have these sorts of experiences. I mean, one of the most beautiful things ever. And it wasn't a total endurance, you know, event, it was a little bit short, a couple minutes. But to watch Michael Phelps swim the butterfly and watch his stroke, he was good at everything, but he was especially good at the butterfly. Most people's stroke is falling apart and they end up taking more strokes. The last 50 of a 200 meter butterfly, you know, his stroke count, the second, third and fourth lap didn't change because he had that rhythm, that tempo. And if you listen to the old school coaches talk about interval training, they're constantly talking about tempo. What is your rhythm, what is your tempo and why you're doing it while you're suffering, Peter, Why you're pushing it while it's hurting, while it's burning. The goal was to not lose your form and not lose your tempo.

I used to watch Michael Phelps train before he kind of broke out in the early 2000s, I lived in Baltimore because I did my residency at Hopkins and he used to train at a place called North Baltimore, Ohio Aquatic. Now Michael, of course, within the swimming world was already an unbelievable prodigy because he had gone to the Olympics in Sydney, placed fifth at age like 15.

Or something, which is quite young for a man.

That's right. He became the youngest male to ever set a world record in a time sport. In early 01, he was still 15 when he, yeah, set the record for the 200 fly. So watching this 16 year old swimming at North Baltimore Aquatic NBAC, which his signature event of course was the 200 fly, now it's 200 long course butterfly. I would put that up there with the 200 breast and the 400 IM as the three worst races in all of swimming.

To me it's like doing an 800 meter intermediate hurdles on the track. The event doesn't exist.

It's insane. Suffer. But here's the thing, Mike, his training, you never once saw him do a 200 fly. It was lots of 75s, lots of 75s. And his coach, Bob Bowman, was really adamant about perfect form because if I recall, Michael had an unusual rhythm, which is that he breathed on every stroke. And when most people swam butterfly, it was every other. You were head underwater for one stroke, head up for one, down for one. Michael. I'm pretty sure he would breathe every stroke, but as you pointed out, no one's form could rival his. And that's why he was usually the last guy to hit the wall at the 50, yet would come back and just devour everybody.

And you see that with Edwin Moses, 13 steps between hurdles and the 400 hurdles in the late 70s with that innovation. You see these people, you saw it with Kipchoge, doing it for two hours. Their ability to maintain this form and tempo. And as you watch it, as you watch it, Peter, you are awed by this sense of great effort and simultaneous relaxation. It's a real paradox. You see that in other sports, too. You see it when golfers get hot, how far they hit the ball, both violent and relaxed at the same time. You sit there and watch Steph Curry or Klay Thompson start launching balls, and it's just incredible, the tempo, the rhythm, the form and the effort. But again, just how relaxed they are. It's just wild to think about.

Even now, going back to our very, very recreational person who's never trained in their life. We don't use lactate testing on people at that level. We basically do the whole thing off RPE and we try to get 80% of their time, which might start out at two to three hours per week. As we want you to be able to talk but not enjoy it. I don't want you to be any higher than that. And then once we build up a bit of a reserve in that, after maybe six months of that kind of training, we're sort of ready to move them to that next phase of, hey, once a week I want you to do kind of four on, four off for four rounds. Do you think that once a week doing four hard intervals is sufficient to boost VO2 max?

It will increase it for sure in the vast majority of people, especially if they're doing the other stuff you're talking about. What I really like about what you describe and what people don't realize, especially when you're going to advocate relatively hard training for citizens, is that sometimes you have to train before you can really train.

That's right. You got to train to train.

You certainly have seen that in some studies with people that are really 60, 70 years old, is that they almost have to do three or four or six months of sort of pre training before they are Fit enough to train hard. So I think you're spot on there. My guess is after they been able to do it for, you know, once a week for a while, you build them up to two times per week. I think the one thing that people need to recognize, and this comes from a man named Stan James, who I think is still practicing medicine. He's in his 90s, one of the pioneers of sports medicine, orthopedic surgery. He's not operating anymore. The last I checked, he was alive and well out in Eugene, Oregon. He worked with coach Bill Bowerman, you know, the great organ coach, one of the founders at Nike, the waffle shoe guy, you know, and they got into this hard, easy thing, which is sort of what I do. And I, you know, Dr. James would tell you that once people start doing more than about five or six hard sessions every two weeks, you're beginning to ask for some sort of load management issue, whether it's orthopedics, whether it's just you're fatigued, whether it's this, whether it's that. So I do think, I can't remember the last day. I didn't do anything. You know, it's probably been years. But my guess is the number of times I do something hard is, you know, 120, 130 times per year. And my guess is I never go more than a week without doing something relatively intense.

When you think about these sort of exceptional elite athletes, the kipchoge's of the world, do you believe they have a finite number of exceptional performances in them?

You know, people used to drift into the world rankings and they'd last, you know, maybe two Olympics, six, seven years. So they'd come in, kind of emerge right before one Olympiad, do well, do well in the next one, and kind of fade. But I think there's two things that have really changed. The first is that again, sports medicine is better. So if people do get injured, they can do things about it. I think the second thing is just become so professionalized, people can, that are really, really good can now make enough money to make it worth their while to continue. You know, you see this in terms of the age of Olympians. You know, it used to be very unusual to have women over age 20 in swimming. There was no college swimming. There was none of this, there was none of that. So there was a lot of teenagers. Now you see that drifting up, and you see people like Katie Ledecky having extended careers. You, Phelps going 2000, 2004, 8:12 and 16, going to five Olympics. Yeah, that would have been inconceivable previously for swimmers. You know, people hung around and maybe stayed for one additional Olympics when they got done after college, sometimes two, but eventually they had to go do get a job. But again, among the most elite who can now monetize this, people can last longer. And you see it also in quote, the major unquote professional sports. You know, before orthopedic surgery was good and every knee surgery was an adventure, you know, somebody like Tom Brady.

Yeah, his career would have been over in 2009.

And the other thing, Peter, is if you're making $100,000 a year, why keep playing? If you're making, you know, 23 million or however, whatever the number is, you know, why not keep playing? And you look at, in sports like running, swimming, cycling, you know, it's less of a, kind of a journeyman group. But if you look at the NBA, the NFL, Major League Baseball, the salary scales are pretty good. And if people can play another couple of years, you know, this can be millions of dollars, millions of dollars for them. So they're very motivated to do this. If you can be the eighth man on an NBA team and give people 15, 20 quality minutes a game, you know you're going to have a job for a long time. And again, if you're LeBron, you know, who apparently spends some huge amount of money on training and cook and all that other stuff, if you start thinking about spending X per year for a, a 40x paycheck, why not? Why stop?

So where do you think we are today, Mike, in performance enhancing drugs in sport? So cycling is probably the sport I would follow the closest of the major endurance sports. I guess I follow swimming as well, though not nearly as much as I did for 15 years prior. I think when you go back and look at the cycling data. I love the way Lance talks about this. Right. You know, I think he's very open, right, to say, look, as long as there has been a Tour de France, there has been a graying of the line. But there is a difference between the kind of high octane cheating that was done in Lance's era and sort of the low octane cheating that was done in Eddie Merckx's era when they were using a little bit of mfet.

Here's what I would say about where we are with doping. So the testing has gotten better both in terms of the frequency of testing.

And the ability to detect.

Yeah, you know, the actual chemistry of the test, you know, the machines, the analytics. If you look at the way. What's called an abnormal test is called. It's not like what we call an abnormal test or an out of range test in clinical medicine. There are typically many standard deviations above average for these things and they're typically designed so there's not a lot of false positives. They don't want to have any false positives. So that gives people, people a room, some room to micro dose. And that's why you have relatively few positive tests. But occasionally there'll be people, you know, caught through investigations, judicial mechanisms, the police. And historically, many of the biggest busts have been the police. What I would simply say is that the era of industrial strength doping is over. You know, people doing like the East Germans did and androgenizing females to the extent that they really look like men. So I think that that is done.

You say that even in light of what the Russians did as recently as less than a decade ago.

I think what the Russians did was again, relatively low dose by comparison. So I think there's plenty of room for microdosing, plenty of room for the kinds of manipulation, systemic manipulation, if there's a motivated government to do it. And there's plenty of room for other forms of corruption. But I do think that industrial strength doping has largely been, quote, stop, prevented. I think there are probably a bunch of novel compounds that are out there, you know, small peptides that cause this to be released or that to be released, which would be very, very difficult to detect. They'd have vanishingly short half lives and so forth, and they would just boost your endogenous production of hormone X, Y or Z. You know, something like a growth hormone releasing factor, you know, something caused testosterone levels to go up or so forth. It's a cat and mouse game, I think, for the kind of the big three. Amphetamines, epo, blood doping and anabolic steroids, growth hormone. I think that testing has gotten better and industrial strength doping is over. We don't know what we don't know about these novel compounds. And I think what we learned from the BALCO situation is that there are all sorts of clever bathtub chemists who can make all sorts of things at home, in the garage, wherever it is, in a very unregulated environment. And the barrier to entry for that kind of do it yourself sort of stuff is quite low. You can buy, you know, all sorts of laboratory equipment and reagents and all sorts of things so you don't have to be, you know, a big farmhouse to make interesting things. That's where I'd say we are with doping.

How familiar are you with BALCO and.

The agents that work balco and Patrick.

Arnold, you know Patrick?

I don't know Patrick, but I know who he is. The tragedy of Patrick Arnold, this tremendous guy with a master's degree, I believe, in organic chemistry, that he wasn't working for one of the big pharma companies making anti aging anti sarcopenia compound.

I've met Patrick a number of times. I've spent a lot of time speaking with him in a very unemotional way and just a very frank way. He can explain in great detail exactly how he modified these androgens.

The guy has encyclopedic knowledge apparently of everything that's ever been synthesized in the androgen field and what it does in terms of half life and that metabolism and that sort of thing. If you think about Victor Conte Jr. You know, a refugee from the tower of power, junior college educated rock jazz musician who's one of the great autodidacts ever out there. So I think with both of these individuals, step back from the legal ethical ramifications and say what do they know? And try to be a little bit objective about that. With doping you get into all sorts of other sort of areas in the cultures those people were operating in what was considered the cultural norm. Lance was not the only person doing industrial strength doping. Was he doing it better than other people? If there were six ways to dope and person X was doing two and you were doing three, was Lance doing all six? That sort of thing. The other thing people have to recognize about doping in these incredibly competitive situations with these incredibly competitive people, competitive organizations or people that have, you know, foreign policy, our country is better than yours because we won more medals, is that there's always going to be some sort of arms race mentality. And you see it with training, you know, if you're in there lifting an hour a day, I'm going to go lift an hour and ten minutes a day. And so where does it stop?

Do you still think that growth hormone, human growth hormone, which is of course not something that can readily be tested for, is still one of the more utilized agents probably even today for performance enhancement?

There's probably some of it going on. My guess is people probably have drifted back to more short acting androgens, low dose short acting androgens and hope for the best? That would be my guess. The same would be true with low dose epoxy and or sort of related compounds or other factors. When you learn about growth hormone, it's Typically because person X says that they're sending FedEx packages to Athlete Y, you know, that kind of thing. So much of this has a judicial slash investigatory element to it. When you get to the big scandals.

Why do you think some sports seem more effective than others? So, for example, swimming as a general rule seems less impacted than say, cycling or even running, even though the demands are still pretty high.

Hard to know. And how cultures head one way or the next, tribalistic behaviors, what's normal, what's not normal, and so forth. I think that that's key to understanding that sort of thing.

We started this discussion, Mike, by talking about the miracles of exercise, right? We went through all of these things that exercise is doing physiologically and how the net impact of these things is so profound on the length of your life and the quality of your life. There's no shortage of pharma companies out there that are trying to understand how can those benefits be put into a pill?

Exercise pills, sure.

Exactly. What is your level of optimism around the idea that some of the benefits of exercise could be basically captured by a pharmaceutical strategy?

The efforts for exercise mimetics so far have been primarily things that increase mitochondrial biosynthesis. And that appears like it at least works in animal models. And then you always, how do you translate it from one to the next? But as I pointed out, exercise, sure, it makes your mitochondria better or makes more of them, but making your mitochondria better isn't going to make your autonomic nervous system better, isn't going to make your blood pressure better. Better isn't going to necessarily make the lining of your blood vessels better, so on and so forth. So it's not going to make your heart bigger, so on and so forth. So I think at least so far, at least so far these have been sort of one trick ponies. And while you might be able to get some benefits for people that are wheelchair bound or whatever, quadriplegics, let's put it that way, not even wheelchair bound can exercise for some other reason that may be helpful. I think the jury is really still out. I'm not particularly enthusiastic about it. I don't think you're ever going to get one that does any more than a little bit. I think more interestingly, I like to tell people, you know, at some level, there's already an exercise memetic out there. It's called the poly pill. If you look at the data on people who get a combination, one pill a day of low dose statins, low dose blood Pressure meds and maybe one or two other components. It causes pretty nice reductions in risk factors in most people because doses are low, the side effects tend to be low and so forth. But again, none of this is patentable. But if people don't want to exercise, can't exercise, you know, a better choice than trying to find some mythical exercise mimetic is to use a poly pill, which would do the same thing. She give them a statin, their cholesterol goes down and maybe their endothelial function gets better. You do a tiny bit of metformin, maybe their glucose tolerance gets better. You do a bit of beta blockers, their heart rate is lower, that sort of thing. And again, I'm not advocating this, but there's all sorts of data out there that a polypill data and speculation and modeling suggesting a polypill is a, quote, legitimate, unquote, whatever that means, potential public health strategy for lifestyle diseases. I would encourage people to exercise and do the sorts of things you're talking about, but I think polypills have been understudied.

Mike, what is it you're most excited about right now? What is the question you're most interested in trying to answer?

I'm excited about a lot of things. We've got some interesting data with Sarah Baker on sex differences in blood pressure regulation. I'm quite interested in human performance. As you know, Peter, the first thing they teach in medical school is that a right shift in the oxygen hemoglobin dissociation curve is good for you at altitude. Well, all animals that are genetically adapted over centuries, millennia to high altitude llamas, the birds that fly over Mount Everest and so forth are left shifted. We've been doing some really cool hypoxia studies in people with rare left shifted hemoglobins. I'm super interested in that. Just as sort of a physiological question.

Can you explain to folks what the right and left shift looks like on the hemoglobin dissociation curve?

Think of a curvilinear situation or an S shaped curve and italicizes curve. And so the idea is that if you shift it to the right, the red stuff, the hemoglobin in your blood doesn't hold on to the oxygen, so it releases it and can give the oxygen to the tissue. And that's great if it's hypoxic. Now the problem with that is it's harder for that kind of hemoglobin to get the oxygen out of the lung. And animals like llamas and like these incredible Athletes called the bar headed goose that fly over Mount Everest without acclimation, they're living in the plains of Mongolia. One day they just fly over Mount Everest and go to India. They're left shifted because they prefer to make sure that they can pick up the oxygen out of the air in their lungs at very high altitude. So we have a family of people and some other subjects that we study that are left shifted.

So right, meaning there is a family of people who genetically shift left instead of shift right under hypoxic conditions.

And there's all sorts of rare hemoglobin variants. They're not like sickle cell or anything like that. Very interesting, Peter, to be sitting in the lab having somebody breathing 10% oxygen talking to you. These left shifted people do that. It's crazy. It's just wild.

What is the FIO2 at the top of Everest, by the way?

Just for comparison, barometric pressure is about 250, so it'd be 21% of 250. So roughly about 50. So once you get into your lung, I think arterial is about in the 30s. Wow. Yeah, at 15%, which is 3,000 meters. These people exercise like, you know, they do fine. So I'm very interested in that. And then as I mentioned, you know, before we went on is through a weird collection of events. When the pandemic struck in March and early April of 2020, I somehow became the principal investigator of the U.S. convalescent Plasma Program, a program that was initially designed to facilitate in 5,000 patients, compassionate use of convalescent plasma antibody rich plasma from recovered COVID patients that we would give to people who had disease. And hopefully the antibodies would help them through all sorts of twists and turns. We ended up doing over 100,000 people. We found evidence if we gave people a whole lot of antibody early in the course of disease, we made them better. We also found some evidence that it was probably very helpful in people that were immune suppressed. And that has been the gift that keeps giving. So at age 60, you know, 162, 63, I got kind of a new career in immunology and infectious disease. And so we're pursuing that and we're especially interested in that, Peter, because whenever Covid sort of finally winds down, about 2 to 3% of the population is what we call B cell deficient. So B cells are the cells in your body that make antibodies, help you respond to fight the virus, respond to the vaccine. About 2 or 3% of the people don't have any or don't have very Many. And those people continue, will continue to get Covid and other forms of infectious disease. And antibody therapy is essential to help those folks. You know, I'm very happy that we've published papers in high profile journals, but we just learned yesterday from People magazine of all places that the actor Jeff Bridges, the Dude himself, the dude from Big Lebowski, the Dude himself, had gotten lymphoma, gotten drugs that depleted his B cells, which is typical for lymphoma patients. Got Covid, he could not clear the COVID and responded to convalescent plasma.

What's the total volume of plasma you need to give a patient in that setting?

If you get really high titer stuff, 2 to 400 MLS, that's it.

One time treatment?

Yeah, typically sometimes we give people more. And what's been helpful, Peter, is that we now have people that have been both vaccinated and they've had a breakthrough infection or they've had an infection and been vaccinated.

Right.

So they have hybrid immunity. And those people make their plasma has a whole, whole lot of antibodies in them and they're broad spectrum, so they cover all the variants. And they almost anticipate future variants because of the way the immune system works is a sort of a sloppy replicator. And so they cover a lot of the variants, they cover potential future variants. And as monoclonal antibodies, which have been super helpful during the pandemic, as those get less effective due to escape variants, this very high titer plasma is still available. We're back doing exercise studies, we're back writing papers about exercise and doing our regular physiology. I think this antibody therapy has really took a bite out of me. It's like what Jim Bouton said, the great pitcher. You know, you spend your life gripping the ball and thinking about your grip on the ball, and in reality it was the other way around. The ball had grip on you. So, you know, I've been thinking a lot about antibodies and maybe antibodies have been thinking about me because it's really hard to stop thinking about it because it's so interesting. And we get reports back to us from not famous patients that are very similar to what we've heard of Mr. Bridges. So we're quite excited to pursue these solutions for our immune suppressed patients. When I started medical school in 1982, those sorts of patients, their life expectancy was quite low. Now our patients with heme malignancy, multiple myeloma, lymphoma, leukemias, a lot of those people live a long, long time.

How long after a person is infected and Recovers from infection. Are they a suitable plasma donor?

Within about two to three weeks.

When does that window close?

It goes on for three or four months, you know, probably up to six months. And it would probably reopen if they got boosted, that sort of thing.

You only get sufficient antibodies from people who have had the actual infection, not from people who just go get a.

Booster initially, because there were no vaccines. We only had people that had the normal infection. Since the vaccines have become widely available in the last almost 18 months now, or 15, 16 months, we've now been able to get people who've had both. The people that have had both are really super donors. And we can work with those people to come back in and get multiple units. We collect our own blood at Mayo, we have a terrific blood bank here locally. But they're using it at Hopkins, they're using it at Harvard, using it at Einstein. A lot of their big plan places. We're working with the societies, the Food and Drug Administration and others like the Lymphoma or Leukemia and Lymphoma Society, the CLL Group, Infectious Disease or, excuse me, Immune Deficiency foundation, to make sure that we have this available for those sorts of patients. They're doing this at scale in France to about 50 patients a week, which would be about 300 a week in the U.S. if you account for population differences. So that's one of the things we're quite interested in. This is something people can donate. It's a, a way for people to give back.

Are you able to find sufficient donors? Are there enough donors that are aware?

Again, because there's so many people who've been both infected and broken through. There's always logistical issues in terms of getting the person to the blood collecting center, getting it here, getting it there, but availability should be pretty high.

And with plasma, do you still have to do a type and cross?

Gotta still be typed and cross and people are. They have to be eligible to otherwise donate blood. But during the peak of plasma use, prior to the vaccines and prior to the monumentals, 20, 30, 40,000 units a week were being used in the country. And in the weeks when more plasma was being used, the death rate two weeks later was lower. So there's a pretty nice correlation between them. But again, I think, you know, we've talked about training, we've talked about a little bit about coaching, we've talked about your participation in sport and so forth. But I think one of the things that really helped me work with the government and work with our team team, instead of do a 5,000 person demonstration project do really a treatment registry and over 100,000 patients was the organizational skills I learned from my coaches. And I used to joke with higher ups in the Food and Drug Administration. They'd say, well, how did you do that? I'd say, I'm a recovering physical educator. And that was always good for a laughter and at least a few dark hours.

Last question. Mike, given your long standing history in athletics, both personally and professionally, are you optimistic or pessimistic about the future of Americans based on the level of physical activity that we see?

We need to do something. We need to do something and I think it really reflects our society in general. I think that you have, for lack of a better word, upper middle class kids who have access to superb coaching, to superb facilities and to programmatic things. I think we've got a tremendous problem with play and unstructured play. Things that when I was growing up in the 60s and 70s that were done through the park district and the school district. I think a lot of those opportunities have fallen by the wayside. The kids who were college athletes used to come back and have open gym all over Tucson. When I was a kid, there's no open gym at the high schools in Rochester, Minnesota, a rich community in the summer. And the advantage of open gym was a, you got people off the street and they were doing things and the police knew where we were, which they're always very pleased about. If they know that all the high energy boys are in one place, it makes their life a little easier as well. Yeah, I think it's a real problem. So I think we'll have these incredible performances by the kids who have access. But I think that what we're doing in the rest of the world is problematic. I guess if I could do anything, I'd start a national open gym movement. Winter, summer, whatever. Because we have a lot of nice facilities that are used just limited number of time per day.

Could you imagine if you were czar and you could sort of do anything and you just said no matter what your lot is in life, if you're a school child, if you're a person who works in an office, if you're a person who works in, we somehow rearrange the day such that every person has a mandatory one hour activity. You could make it exercise, you can go to the gym for an hour, but it could also be, look at a minimum, you got to go out and walk.

Well, you know, it's interesting you mentioned that because in our department with remote work and so forth, this is broken down a little bit, but we had a number of secretaries. They were all women, middle aged women, and we have this huge deep bunker system at the bowels of the hospital with these huge hallways and it's about a mile around the place and these folks would go down and walk at one lunch. They'd bring their tennis shoes to work, they would meet up with their pals and go do 30, 40 minutes a day of laps at lunchtime with the secretaries all over the hospital. And it was, I think terrific for them. I think it was a social event for them and I think that they solved a lot of problems too and they actually made them way more productive.

As I said at the outset, I've enjoyed reading your papers for more than two decades and I'll continue to do so and it's been great to chat and hopefully we can meet in person at some point and do a workout together.

Yeah, I look forward to it.

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