Plain English with Derek Thompson - "Exercise May Be the Single Most Potent Medical Intervention Ever Known"

Episode Date: August 30, 2024

Exercise is a conundrum. On the one hand, physical activity is clearly one of the best interventions for preventing physical disease and mental suffering. On the other hand, scientists don't really understand how it works inside the body or what exactly running, jumping, lifting, and squatting do to our tissues and organs. That's finally changing. Euan Ashley, a professor of genomics and cardiovascular medicine and the chair of the Stanford Department of Medicine, is a member of a new research consortium that studies rats and humans to understand the molecular changes induced by exercise. Today we talk about the earliest findings from this new consortium, how exercise might have disparate effects in men versus women, why nature’s most effective cardiovascular intervention also seems to be nature’s most effective mental health intervention, as well as whether it will one day be possible to identify the molecular basis of exercise precisely enough to develop exercise pills that give us the benefits of working out without the sweat. If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek Thompson Guest: Euan Ashley Producer: Devon Baroldi Learn more about your ad choices. Visit podcastchoices.com/adchoices

Hi, I'm Tara Palmieri. I'm Puck Senior Political Correspondent and host of Somebody's Got to win. Brought to you by The Ringer and Spotify. The 2024 election has been upended with Joe Biden off the ticket and Donald Trump facing a new challenger, Kamala Harris. If you want to hear what the insiders are really saying about the race, join me Tuesdays and Thursdays as I break it all down with lawmakers, journalists, and political strategists.

We'll go deeper than the headlines to the anxieties at the highest levels of power. And of course, we'll chew over all. a hot political gossip as we head into this historic election. Be sure to follow, somebody's got to win at Spotify or wherever you get your podcasts. Today, why exercise is the single greatest medical intervention ever known and a look inside a new mammoth scientific effort to understand why. In 1958, two British researchers, Jerry Morris and Margaret Crawford, launched a study in what was then known as the British Medical Journal.

They got wind of an idea that some English jobs came with a remarkably short lifespan. These weren't jobs filled with obvious danger, like firefighters. They were normal jobs, even boring ones. Drivers of London's double-decker buses were more likely to die suddenly from heart disease than train conductors. Government clerks were more likely to die from rapidly fatal heart attacks than postmen. It seemed to Morrison Crawford that men in physically, in a physical, in a heart attack, Inactive jobs had a much higher incidence of heart disease in middle age than men inactive jobs.

The researchers followed bus drivers who sit all day and train conductors who mostly stand or walk up and down steps throughout the day. They compared the cardiovascular health of these workers. And their finding was as clear as it was eventually famous within medicine. The sitters died early. The standers and the stair climbers lived. One conclusion of the study was that, that sedentary jobs might be associated with higher risks of heart disease, but a separate

conclusion might be the exact opposite. That exercise is an intervention. And dose for dose, it might be the most powerful intervention we've ever invented. 76 years after that study was published, in May this year, the scientific journal Nature published the latest and most advanced effort ever undertaken to understand the effects of exercise on our bodies. A new research consortium, studying the effects of exercise on rats, found that exercise entirely transformed their bodies from the inside. Every tissue, every organ, every blood test, was transformed by regular physical activity. One leader of that consortium is you and Ashley.

He summarized the findings of their first batch of research like this. Exercise may be the single most potent medical intervention ever known. One reason that I like this summary by Professor Ashley is that there is value in remembering that exercise is an invention, which is to say it is an unnatural departure from everyday modern life. The sociologist Daniel Lieberman, who has appeared in the show, has explained to us that exercise is not a near reenactment of ancient human behavior. It is an awkward simulation, a cartoonish imitation of ancient human behavior. His book, Exercised, has a compelling subtitle,

why something we never evolved to do is healthy and rewarding. The treadmill itself, Lieberman reminds us, was not invented for the purpose of helping suburban moms and dads shed the weight they gained by eating ice cream with their kids. The treadmill was invented in Victorian England, as a mild form of torture for prisoners in debtors' prisons who were placed on the earliest treadmills to walk in place without moving, like Sisyphus on a flat line to make sure they weren't enjoying themselves there.

If Jim sometimes feels to you like torture, you may be relieved to know that its machines were occasionally designed to inflict that very psychological pain you might be feeling. But at a cellular level, exercise is the opposite of torture. It is optimal stress and nature's miracle drug. but to me there is something incredibly interesting and even powerfully bizarre about the science of exercise. On the one hand, it is the most obviously healthy thing in the world. On the other hand, nobody seems to understand exactly why it works or how it works.

And that's finally changing. Today's guest is you and Ashley, a professor of genomics and cardiovascular medicine, and the chair of the Stanford Department of Medicine. We talk about why it's so hard to study the mechanism of exercise, the earliest findings from his new consortium, how exercise might have disparate effects in men versus women, why nature's most effective drug also seems to be nature's most effective mental health intervention, and finally, whether it will one day be possible

to identify the molecular basis of exercise so specifically that we could develop an exercise pill that gives us the benefits of working out without the sweat. I'm Derek Thompson. This is plain English. You and Ashley, welcome with the show. Well, thanks for having me. Great to be here. Tell us a little bit about what you do.

I'm a professor of cardiovascular medicine and genetics and data science at Stanford University in California. I study a variety of things. love the extremes, extremes of human behavior, including exercise, something we're going to talk about today. I feel like it's interesting. Your work straddles two different buckets. On the one side, you're looking into genetic mysteries that tell us things we don't know about the world in our bodies. And with your work and exercise, you're helping us to more deeply understand the molecular basis of something we do know, or at least we should know or suspect to be true,

which is exercise is pretty good for us. At the highest level, why is it important to understand how exercise is good for us and how exercise actually works at the molecular level? I think it's because it's just such a potent intervention. I mean, I think of it as an intervention, you know, as a doctor. Exercise is just the single most important intervention you can think of for your health. There are plenty of other important ones. I'm sure we could talk. about diet, we could talk about sleep, we could talk about other things, but I truly believe that nothing is more important among those than physical activity and exercise, and that there are deep-seated reasons within our human history to believe that that's a reasonable assumption to make.

And if we were going to describe the effects of exercise in a precise way, what would we say are the major benefits? Like, imagine we're making an advertisement for a new pill that's being marketed during Sunday football games. And that pill is called exercise. And at the end of the advertisement, there's a fair balance disclaimer. You know, exercise may cause injury and shortness of breath.

If you're sedentary, please talk to your doctor before using exercise, et cetera, et cetera. But before we get to that fair balance disclaimer, the makers of this drug, exercise, are going to proclaim its wonder to the viewing public, with as much specificity as possible.

What would they say in this advertisement? what in what way is exercise the most potent medical intervention ever invented yeah well first thing is they'd have to pay a lot for the advert because it would it might go on for a long time if you were going to list all of the things but i mean you name the system in your body and exercise improves it and makes their chance of disease in that system less 60% less likely to have heart disease 50% less likely to have diabetes 70% less like to fracture your hip 50% less likely to have colon cancer, 25% like to have breast cancer,

I think 25% of life like to get depression. 70% of people who are active in their daily lives report better sleep. I know for many years, you're much less likely to die. So, I mean, you pick your system exercise. It really is the magic pill.

And having read your research and your interview with Eric Topol, I think you might be leaving the killer one liner on the cutting room floor here, which is, and I believe I'm quoting you, One minute of exercise buys you five minutes of extra life. I'm just going to repeat that because it's astonishing to read, and I want you to confirm that it's true.

But one minute of exercise buys you five minutes of extra life. So if you do the brief math on this, if I work out for one hour a day, four days a week, for 40 years, under this assumption I would buy myself an extra four years and nine months of extra life. Number one, does that calculation feel directionally accurate to you? And number two, is this equation even true in the first place? Yeah, directionally accurate, absolutely.

Quantitively about right, sounds about right to me. I'd have to double-check your math, but yes. And is it true? Yes, I mean, it is true. I will make the caveat that almost everything that we have that speaks to the longevity of humans is data from observational trials, which is to say that we take large populations of people,

and in this case you wanted to make sure it's the largest population you can. This data is based on a population of more than half a million people, so that's pretty big, who were followed for over 10 years. And then we basically, not me, there's not my work,

I'm reporting the work of others, but those investigators basically looked at the amount of exercise that was done. It was generally moderate to higher intensity exercise. But, you know, a brisk walk plus, and looked at the number of minutes every day that those people exercised and then looked at how long they lived. And there was a very clear correlation.

And when you looked at how much that exercise bought you in terms of extra life, it did indeed map that one minute of exercise at a brisk walking sort of pace would buy you five minutes. In fact, if you exercised at a higher intensity, you could get seven or eight minutes of extra life. And so it is a stunning statistic. and it's just not really the way we normally think of it. I think most people have you said to them, do you believe exercise makes you live longer? They'd probably say, yeah, probably.

My doctor's telling me it's healthy for me. I believe that. But I think just having the rawness of the statistic and really seeing it when you think about your life and trying to juggle the minutes of your day and how you might be more physically active to help your health, that seems plausible, but also a little bit abstract. How am I going to fit it into?

today, you know, what's on my calendar today. And it's very hard to connect what you're doing today with your life in the long term. But I think that's one of the things that the statistics seem so arresting because it really contrasts what you're doing today and what you might do right now if you stand up and walk around with your ultimate length of life and what you could get and what you have time to do in those years that you gain. There's already so many questions that are popping in my head, like optimal way to exercise and timing and whether it's about exercising

for a certain number of minutes all at once versus spread throughout the week. But I actually want to put all those questions about what the science is telling us about the optimal way to exercise. I want to put that in the refrigerator for a second, and we're going to open the fridge door in half an hour. But I feel like there's already a really interesting tension

at this point in the show. We have extreme confidence in the effects of exercise. You just testified to our confidence that exercise is doing all of this work. But your research is also a clear testimony to the fact that we don't understand how it's doing this. It's a little bit like in technology history, some progress nerds are obsessed with the fact

that we invented the steam engine before we understood the laws of thermodynamics. Like the mechanism ran ahead of the science. Why don't we understand how exercise size works. If it's such an obvious effect, why has this still been a hard question to answer? Yeah, I think part of it is just that we haven't really studied it properly. I mean, I think it's at some level as simple as that. I think you're surprised that we haven't understood it to date is justified because if it's something that, you know, we're talking about experiments that were done in the

1950s and 60, the classic experiments of the London bus drivers that some of your audience may have heard of where they basically compared the conductors on the London buses to the drivers. Here's one group of people in the same environment. They're breathing the same air. They're being paid by the same employer. They're waiting the same uniform. But one group walks up and down the stairs all day long and one group sits in the driver's seat driving. And there was a 50% lower risk of developing coronary heart disease, heart attacks in the conductors than there was in the drivers. So that was an experiment from the late 40s in 1950s. So you're right. We have known the power of exercise for 70 years. Why is it taking us this long to really deeply delve

into the molecular basis of it? I don't actually have a good answer for you, except that in general we tend to study disease more than we study health. We've tended to think, well, what's killing us is heart disease. So that's where we should put our research dollars, and whether that's on the pharmaceutical side or on the National Institutes of Health side, we've tended to focus on disease. and I think we do miss a trick by doing that because we miss the idea of understanding prevention. But it's also maybe the part that people say, well, we know how you exercise.

To your example just a moment ago, as long as we know how you exercise and we know what the right kind of exercise is and we'll get to that later, does it matter if we understand exactly how it works? Now, I argue that we can learn a lot from that, but I also hear from the perspective of the people who want to achieve the game,

that you don't necessarily have to know every single thing about how the mechanism of an intervention works to recommend that intervention and see the benefit from it. I like the way that you put that. And I think I agree that you don't need to understand how jogging is affecting your metabolic health in order to jog for 20 minutes a day, let's say. But if we did understand more acutely what jogging was doing to our mitochondria, it might help fitness scientists develop better exercises that would allow people to get better bang from buck within their busy lives.

And so, again, we're going to connect this back to lessons for optimal exercise in the end of the episode. Let's do a quick pit stop on methodology. Tell us how you're studying the question of what exercise is doing to us slash doing to rats, whose biology we can translate to ours to a certain extent, and tell us about this research

consortium motorpack that you've put together to take on this question. Yeah, and there's a large group of people came together, funded by the National Institutes of Health. And I would say, first of all, testament to the people who lobbied the NIH over many years to say, if this is something we haven't studied enough, we should study it. And then the NIH put the money towards it, decided a large consortium would be the right way to do it. It was the right moment in time, and then funding that consortium. And now there's a large group, 17 or 18 sites, there's 35, 30, I think are more principal investigators in this work.

So it's a very large group of people working together. The consortium, as you mentioned, is called Motorpack, which is probably the best-named consortium that I'm involved in, because it's, for once, speaks a little bit to the actual focus of the study. But molecular transducers of physical activity consortium is where we get the acronym Motorpack. And we basically are interested in building the molecular map of exercise. not something that's been done before. And to do that, you have to bring experts in measurement

technology, people who know how to measure genes, people who know how to measure proteins, people who know how to measure metabolites. And you have to then bring them together with people who are very expert in making both humans and, in this case, rats, run and do strength training and sort of really understand exercise. So it's a very different group of people who are not always, who haven't many cases collaborated before, who then came together to try to understand exactly what the molecular basis of exercise was. It's essentially to build a map, like one of those underground maps from the London Underground or the New York subway, wherever. We don't have that for exercise. But if we bring together that right group of people, those who can measure and those who

understand the right tissues to look at and the right protocols under which to put those animals or humans, then we can for the first time really understand how exercise works. So that's the consortium. We came together several years ago. We got a bit interrupted by COVID. So the human study that is coming got a little bit behind, but we're catching up rapidly. And the recent paper was the first sort of major landmark paper from the group. And that was describing the effects of aerobic training on rats. And so happy to chat a little bit more about that one. Well, there's a couple questions I have about methodology on this paper too, but I also want you in this next answer to tell me what you found. First off, it sounds like you put rats on

treadmills over several weeks, which immediately raises the question of rat treadmills. How does this work? How does one keep a rat in a treadmill? But, you know, it seems like this was an incredibly comprehensive, even invasive exam. You took tissues, you performed dozens of different measurement platforms on these rats. You tested them in every possible way after making them go on this 20-minute run on a tiny little rat treadmill. So first, brief, disfews. description of what the hell are we talking about, rat treadmill, and then maybe dilate on what is it that you found? What were the main findings of these rat exercises that should make us so excited? Yeah, yeah, so you're right. Tradmills for rats, they exist, and they like to run. I mean, actually,

rodents, you know, if you see them in the wild, they definitely run. And so it's not actually so hard to make them run. They started with 20 minutes a day of exercise up to 50. minutes, usually some slope on the treadmill too. So those of you who dial up the slope in your treadmill when you go to the gym, these rats were doing the same thing. About 75% of VO2 max. So VOTOMX, sort of your maximum aerobic intensity.

So that would give some of your listeners, I think, an idea of the intensity. And then it would be for one, two, four or eight weeks. And then we're looking at kind of the chronic effects of acute exercise. So we'd wait a couple of days until after the last acute bout and then basically look at the tissues at that point. So that's basically the study.

We did it importantly in male and female rats, and this is something we'll come back to in a moment because in general, in science, all of science, we have studied male humans and male animals much more than we've studied females. And so it's important part of the design of the study that we did both. Let's go into the tissues.

Tell me what tissues in organs were most changed by exercise. and feel free to use some of the language from the nature paper, hormesis, heat shock, protein aggregation. But if you do use these words, please just at least pause to define each of them. But what did we find? What organs and tissues were most changed by exercise? For me, the overall most interesting finding and the kind of headline finding is that these animals really turned into different beings after exercise.

I mean, the rats on exercise look completely different. to rats that are sedentary. And humans, we have to assume are the same, and soon we'll have the data for humans as well. Every single organ that we looked at, and we studied essentially every organ in the body, changed dramatically with exercise. And we're often used in science to thinking, you know, how big a study do we need to do to find this size of finding? And particularly if we're looking for small findings, you need big studies to be able to have statistical confidence that you can find that. Turns out with exercise, the signal is so large. You don't need a particularly big study to find it.

But what we were finding were very big changes. And some of them were in tissues we'd absolutely expect to find changes. So you go and look in the skeletal muscles or you look in the heart and the whole metabolism of those muscles and the makeup of those muscles has changed. And that's not that surprising because we think, well, exercise changes is good for heart disease. And obviously you build muscle by exercising. But some of the other organs were really dramatically different in a way that we didn't expect. So, for example, the small intestine, you know, that's the part of your intestine that's at the top that does a lot of the nutrient absorption.

We weren't particularly expecting that the small intestine would change much with exercise. In fact, the traditional teaching has been during exercise, all the blood goes to your exercising muscles, and none goes to your gut, because it's just shutting down when you exercise. But it turns out that's probably not true. Or your adrenal gland that produces adrenaline. Maybe that's less surprising to your listeners that that might change. change, but we think of that as a gland that just sits there and either turns up the adrenaline or turns it down. We don't think of it as having almost like a molecular personality that changes according to how much exercise you generally do, but the adrenal gland changed a lot.

Of course, the adipose tissue, which is fat, basically, a couple of different kinds of fat you have in the body, standard white fat that basically stores energy, and then brown fat is much more involved in metabolism and is localizing specific areas in the body. Both these kinds of fat changed dramatically. And that's actually one of the places where we saw a big difference between male and female rats. It was in the fat tissue. Even at rest, actually, before we started exercising them, there were big differences in

the signaling, so the intracellular circuits, if you like, in white and brown fat tissue in the males and female. And then those differences were accentuated after exercise. And so a big finding, I think, a really, you know, it's a sense. second sort of headline finding from our work was that we have to study male and female animals whenever we do, I think any studies, frankly now, but particularly, of course, for exercise, because they really, those two groups were very different. And in almost every analysis we did, we could find differences between the male rats and the female rats and their response to

exercise. I'm summarizing this for myself as a three-parter, number one, that you saw changes in many different tissues and organs. Enough tissues and organs that you say the rats that exercised were essentially entirely different creatures than the rats that didn't exercise. As you were talking, by the way, it occurred to me that maybe one reason that we haven't done these kind of studies in humans

is that it's probably very difficult to put a human on a treadmill and then get tissue from their small intestine. Some humans might not necessarily want to be cut open and share the small intestine while they're bent over and heaving after you've pushed them to their VO2 max. The second takeaway from this is that there's large differences between males and females,

and I want to get back to that in a bit. And then you mentioned white fat versus brown fat. I think we might also want to recircle there as well. But I definitely want to make sure that we talk about this idea of hormesis. I think I'm pronouncing that correctly. The idea that one benefit of exercise is that we, our cells, experience this kind of recurrent stress, and that recurrent stress does something to our proteins or to our mitochondria or to both that is really good for us. And I'd love you to address this concept of cellular stress through this curiosity

that I've had about how exercise works. So my mental model for why exercise works has always been an extension of the Nietzsche principle that what doesn't kill you makes you stronger. So caloric restriction, right? What normal people call diets. You stress out your cell with a diet, the cell thrives under conditions of optimal stress, and caloric restriction, it turns out, is probably good for us to a certain extent. Exercise stresses us out too, and that cellular stress, that hormesis seems to be good for us. But this principle of stress can't extend to everything, because if I have a plan to become addicted to heroin for a few months and then to suddenly stop using heroin. I'll have withdrawal symptoms that will absolutely feel like stress, but I somewhat doubt

that hard drug withdrawal is good for longevity. What is the difference between good cellular stress, hormesis that actually works, and bad physical stress, like a hangover or a painful chemical withdrawal? This is a really good question. And actually, a question that I've thought quite a bit about in the past because there are definitely parallels between the stress of exercise and the stress that you know you mentioned a couple of them I mean I think that the stress of caloric restriction is a little more complicated we could come back to that but I but in my mind when I was thinking of stress you think of some of the things that happen in exercise and some things that happen like if you have to sit an exam or something then there's definitely overlap there and

when we talk to patients I'm a cardiologist as I mentioned at the top so I talk to patients about life stress quite a lot. And it's very clear that life stress, chronic life stress is bad for you. And yet it does contain some of the same triggers that exercise stress that is so good for you has. Now, there's a chronic versus acute, there's an intermittent versus constant element there that we could deal with with those sorts of life stresses versus the stress of exercise. But I think they're also fundamentally different at a molecular and an organismal level when you really start to study it. And this is maybe one of the first times we've studied in this much depth and what exercise is doing. And we mean one simple example is when you're stressed about an exam,

your blood pressure goes up and it goes up because your adrenaline goes up and it goes up in a way that we think overall chronically we'd lead to harm. When you exercise, your blood pressure also goes up. But it goes up in a different way. It goes up not because you're tightening your blood vessels. You're not. You're actually loosening your blood vessels. Your vasodilating for thermoregulation to keep you cool. But what happens is you have increased flow because, of course, your legs start squeezing and your arm starts squeezing, and more blood is squeezed back to the heart, and the heart responds by squeezing more blood out to the body. So the flow, your cardiac output, goes up, and then your blood pressure

goes up. So our measurement doesn't reflect the fact those are two fundamentally different things when we say your blood pressure goes up in both. So I think that there are some of those overlaps that are really more kind of apparent than real. Like when you dig a bit deeper, they're actually quite different. But yeah, this concept is fascinating to me because it really, to me, underlies the, why is exercise so good for you? And we think about the history. I mentioned this a little at the beginning, the sort of history of humanity and the fact that we do believe that exercise is almost certainly linked to our evolution as a species. You know, 10 million years ago, we were mostly on all fours, a couple of million years ago. We were more upright, but we still had a lot of

hair in our bodies. We weren't particularly good at running. And, you know, in the last few hundred thousand years, we learned persistence hunting, the idea that, you know, you could spend over the course of days or even longer, you could hunt down a four-legged prey. You know, on a short sprint, you're never going to keep up as a human. We just don't sprint that quickly. But we're very good at thermal regulation, for example. We're very good at endurance running. And if you combine those two things and you can keep your prey in sight, then over the course of days, you're very good, you can tire out the prey because if your prey is on all fours

and covered in fur, its thermal regulation processes are much less good. They don't sweat. They have to pant. And so they can run really fast, but then they have to stop. And so that's a lot of the thought

about how we move from mostly hunting and gathering to the point where we could get very high density, caloric food, in other words, meat. And that allowed our brains to expand. Now, of course, this is ultimately speculation

about our history, but there's good reason to believe that those two things are connected. And so aerobic endurance, specifically our ability to run and thermoregulate may well be tied directly to the expansion of our brains that allowed us to be human and to operate at a higher level than our closest cousins, let's say, chimpanzees. I find that very interesting. And I've had Daniel Lieberman on the show, whose book exercised. I believe the subtitle is something like, why something we weren't devolved to do is necessary for life or something along those lines.

And his point, which is a different angle of attack on the issue, but ultimately arise at the same place as your description, is not that humans were evolved to exercise, but rather that at a certain level of literalness, humans were not evolved to, quote, exercise. We weren't evolved to walk into a room and take part in a kind of costume drama of hunter-gatherer, of physical activity, right?

The first treadmill, he points out, was not invented to simulate chasing a lion in the savannah of Africa. It was invented by Victorian sadists to outfit debtors' prisons in England so that they could be tortured to run the same place and feel like they weren't getting anywhere. So treadmills invented to be mildly torturous, but nonetheless turn out to be the sort of thing that's very useful for us to simulate the kind of activity that essentially couldn't constructed the bodies that we find ourselves in, right? That sets your point. We're sort of built to sweat, but we live in air temperature controlled environments that are designed to minimize

sweating. And so we have to depart from our life in order to simulate the sort of activities that are cellularly salubrious to us, which is just a bizarre situation to be in, but nonetheless, it is our lot, and it's probably better than the situation you were in 10,000 years ago. I want to talk about gender and sex for a second, because you lightly glossed the idea that we saw different effects in male rats versus female rats. Talk a little bit more about what those differences are and how exercise might produce, again, rats not people in this study, but how exercise might produce subtly different effects in males versus females. Yeah, one example of that, I think I mentioned a moment ago with related. to the signaling pathways that were enriched in the white fat, so the storage fat. And they were enriched both in a rest and in exercise and with bigger changes after exercise.

And in women, for example, in this case, women rats, so female rats had signatures. And this is across multiple, we call these different measurement modalities omics, because we have genomics and proteomics. And it really just means we're measuring a lot of proteins and a lot of genes all at once. So we talk about the different omic signatures, and the signatures that we saw across those different measurement platforms were enriched for insulin signaling. So that's a bit like diabetes signaling,

or the creation of fat molecules were more enriched in the females at rest than they were in the males. Whereas if we looked at the genes that were previously known that were enriched in the male fat, it was actually genes more related to aerobic metabolism. So it's essentially almost like exercise itself. So there was a little bit of a change even there where there was a tilt towards fat production at rest in the female rats

and a tilt towards sort of exercise genes in the males. And then these changes were either preserved or amplified during and after exercise. And so, you know, I certainly, my wife and I exercise plenty together and we're often comparing what Apple or Fitbit thinks we've done in terms of calories and then how that actually relates to whether we are able to lose weight or not. I think that's the specifics of those signatures, I don't think map very well to two individual males and male and female living in the same house

trying to exercise. But the principle that we do inhabit different bodies and we need to pay attention to that in the world and especially as healthcare providers is I think underlying by these very specific molecular changes that we're seeing. One of your studies found that training, exercise, these rat treadmills, upregulated or accelerated, the immune response to different diseases, like liver disease or type 2 diabetes. And I want to slow down on this part in particular, because this was among the more surprising findings of your paper.

When I think of exercise, again, my mental model, as the non-scientist, is, a bit like I'm fortifying the walls of my castle. I'm preventing bad things from happening to me. But once I'm sick, every bone and cell in my body is telling me to not get up. Don't exercise. Don't stress yourself out. This research suggests that at least for some diseases, it might be important to counteract that impulse and to strain ourselves a little bit. If we can't get out of bed, obviously we shouldn't exercise ourselves to death, but that there is something about the cellular mechanisms of exercise that trigger a response that's doing the immune work for us that we might typically expect from like a disease-fighting drug. Do I have that right? Is it possible that

a reasonable finding of your paper or reasonably articulated finding of your paper is that exercise doesn't just prevent disease? It can also fight disease that you have? I think that's a really interesting take on real findings in the paper. And I don't want to say that that isn't true. I would certainly, you know, as the doctor in me would say, you know, you've got to be a bit careful when you feel sick. You know, you should rest. I don't, I don't think I would change as a result of our findings in this paper any of my advice around what you do when you feel sick. But what we can say, and you as an individual, of course, could make that leap. I don't want people getting COVID or the flu this winter,

and having heard this podcast say, well, you know, Derek told me to run a mile, even though I'm sweating from a seated position and there's snot coming out of my nose. Not my suggestion. And you are the doctor here, so people should absolutely take whatever your response is. But I am interested in this disease-fighting potential of exercise.

Yeah, no, and I think that it is, you know, if the hormesis that we just talked to at this idea of recurrent stress leading ultimately to disease prevention and protection is one of the things I was most fascinated to kind of dig into with this paper as the results came through. In some ways, this inverse of disease question that we're talking about now was kind of my second most interesting thing. Like, okay, so we build them like our map of exercise. Not just what does it look like, but what doesn't it look like? What is it the mirror image of? And it turned out when we'd asked that question. It was the mirror image for certain organs and certain systems. It was the mirror image of

some very recognizable diseases like diabetes, like cirrhosis, which, and if diabetes was maybe a little less surprising, because again, we think of exercise as being very powerful in helping avoid and if you like defeat diabetes, it isn't necessarily something we connect to cirrhosis at all. So seeing a mirror image finding of something that we think of as being more related to liver or, sorry, certainly liver but more related to, let's say, things like alcohol or hepatitis related to infections, things that aren't necessarily cardiometabolic in their origin, was I think particularly interesting. So we were seeing these mirror image findings in the liver. And one of the things is that there are organelles, so those are the little parts that are inside lots of cells.

And you've mentioned mitochondria earlier, which were the little batteries that live inside of all our cells that create the energy. we had one deep dive paper just on the mitochondrial cross-tissue responses. And so those mitochondria exist in cells across lots of tissues. And we saw a lot of signals, again, that were different within the mitochondria. So these little batteries that live inside our cells are different in different tissues and respond differently to exercise. Not surprising again for muscle, but quite surprising for liver. We think of the liver as part of our GI system again that is helping us deal with the

food that we eat and we think of that system as being shut down during exercise. But, you know, like so many things in science, I think, you know, we were just wrong. I'm very interested in mental health and have done so many shows on the anxiety surge throughout the country, especially among young people, the rise in depression, the rise in loneliness. What about the mental health benefits of exercise? Are there studies that, for example, compare the effects of exercise, and the effects of exercise, to say SSRIs, Prozac, Lexapro? Because right now what we're talking about is not just exercise as fortifications

for the wall of the self, don't get sick, don't develop an anxiety disorder. We're talking about exercise as treatment. Are there studies that compare these sort of treatment effects of exercise to SSRIs? Yeah, there are, at least there are clear studies using a randomized approach,

which is our top level, highest level of evidence where we toss a coin and you get the intervention or you don't and as much as possible you and the person judging its effect are blinded to which you had. Of course, whether you exercise or not, it's hard to blind the individual to that. But there are those randomized trials demonstrating clear benefit at a similar level and in some cases greater level

than drug therapy for benefit in various mental health conditions. depression being the one that has most been studied. And so it's not just protection, as you say, it's not just that exercise gives you the armor against these diseases, very important if you can avoid them. But in the case, particularly in depression, but some other mental health illnesses as well, there are actual studies looking at exercises of treatment.

And it is particularly good at treating mental health illness. And of course, you know, we would always recommend you work with a doctor to get the right combination of, therapies for you, but most doctors will recommend exercise as part of a treatment plan for depression and, you know, maybe along with a medication, but most doctors, the evidence is at that point where it's absolutely accepted by the community that it can help. And I think for most people who feel that exercise improves their mental health from whatever starting point they're at, I think it's not not that surprising to hear that. And maybe this concept of the exercise high,

that's at the other end of the spectrum, that, you know, those who are maybe feeling good about life and everything's going well, and then you have time and energy and exercise, and they feel even better afterwards, I think it's maybe not surprising when you realize that that's a common finding among people, I mean, very measurable finding that people have greater mental health in the short and long term after exercising, that that would also apply to those who, at a starting point, much lower and that there could be a real therapeutic benefit. Is your consortium looking at how exercise might be able to fight anxiety depression or ward off anxiety or depression? If you're already studying the mechanics of what exercise is doing at a tissue by tissue level within the body, can we also look at what mechanical effect exercise is having on certain

markers of depression? Yeah, and I think that the question speaks to a challenge that we've had, of course, in studying the hardest organ in many ways to study in our body, which is our brain. And it's because we do have a link between certain chemical pathways and mental health state. And we know that, and we've talked about depression. We talked about SSRIs as one class of drugs. but I think the link between the disease state and our understanding of it at a molecular level is much more fuzzy in neurology and brain science, neuroscience, than it is in many other.

I mean, we have this banter back and forth among doctors as to whose organ is more important, as you might imagine. And one of the challenges, I think, with the brain Nobody debates that it is our most important organ in many ways. But we have much more limited ability really to treat brain malfunctions because there's such a long distance between the sort of tools that we currently have, including molecular tools like the ones we've used here in Motorpack,

and those disease processes. Our understanding is much more fuzzy. I do hope that there are going to be elements of Motorpack that can inform on those questions. again, because of the power of exercise in improving mental health, the power of exercise in treating mental health disorders, that we can find molecular pathways that can help us find new treatments that can be used in parallel.

But I think the distance we have to travel to get to that is just much further. Right. It's interesting. You're talking about making a map, but when it comes to the brain, we don't even understand the territory. So how do you make a map? It's like you mentioned liver cirrhosis and diabetes. I would expect without being a doctor or having spent a single solitary millisecond medical school, you can probably get liver tissue and a blood sample and say, aha, that's liver cirrhosis, right?

That's diabetes. With the brain, you can't cut a little slab of brain off and then say, oh, that's clearly generalized anxiety disorder. We're very, very far from being able to do tissue samples, that lead to specific psychotherapy diagnoses. So I absolutely take your point that there's some work in neuroscience and brain science that we have to do first before we connect the molecular effects of exercise to some kind of endpoint in brain science.

And we just don't have that yet. But hopefully we will. Let me finish with some practical questions about exercise. Does timing matter? and does consistency matter? So, for example, do you see evidence that there is, say, a universally optimal time of day to exercise?

Maybe some of these rats worked out in the morning and some of them worked out at 10 p.m. at night just before they were supposed to go to bed and you found some huge difference in terms of how it affected their metabolism. I'm laughing, so maybe I don't expect much from that question, which maybe is my fault for not asking a very good question. But the second bit is I'm very curious about.

Is there a metabolic difference between, you know, me running 30 minutes a day, four days a week, versus me playing two hours of basketball with the boys on Sunday? So maybe just take both of those in the same answer. Does time of day matter and does time chunking throughout the week matter? Yeah. No, all really interesting topics. And some we can speak to. First of all, on the rats, they exercise when we said they should exercise. So we decided when they do exercise.

And in fact, most rodents are active at night. They're nocturnal. So actually, to study them during the day when our technicians are awake, you know, we have to reverse their night and day cycle. So we probably shouldn't take anything from this particular study on the timing of exercise. But fortunately, there's been quite a few other studies, including in humans and cycling, some digital health studies that we've done. In our group, we also have studies where we use watches and other wearables to learn about cardiovascular health factors. So you talk specifically about timing, first of all. And I think it's clear that there is no clear answer to the question of timing.

So there are studies that come out every other month with slightly different findings. What is very clear is that doing the exercise is what matters. There is some data to suggest earlier morning is a good time. But there's equally a little different data, a little different intent, but there's also good data to suggest that exercising after dinner is good, for example, insulin. resistance if you fill your belly with food a good time to exercise is just after that and so there's metabolic benefits to that there might not be digestion benefits to that a lot of people find it convenient including me to exercise first thing in the morning and there is some support for that and then for the effect lasting during the day when you're otherwise up rather than say lasting at night

when it might be somewhat disruptive to your sleep to have had a higher adrenaline period even if it's exercise just before you try to shut down your body and go to rest. So I think if people ask me what I do or what I think I would recommend, I probably would veer towards earlier morning rather than later in the day. But the most important thing is that you do it and you spoke to consistency. So consistency is what is key, getting into a habit of exercising and whether that's just getting up and moving around more actual walks, actual runs are playing pickup basketball, doing it consistently is what counts. And then the other element of timing that you mentioned was daily versus weekend warrior. And we've actually studied this. And there's a reason to believe

and there's some suggestion that there has been some suggestion that a weekend warrior sort of approach might be even harmful. Like, you know, sitting around all day and then just getting out on the weekend and pounding three or four hours on a mountain bike might not be the best idea. Now, there are other reasons why it might not be the best idea relating to coordination and falling off a mountain bike and then various other reasons for that. But actually, when we've looked and some others have done this too, we find just as much benefit at sort of piling it all on at the weekend as we do during the week. And so I think hopefully that is optimistic news for those who really can't find the time

either early morning or later the day during the week, but do find they have more time at the weekend. I think personally what I recommend for most of my, certainly my patients and then others who whom we're trying to prevent disease, is to get a regular cadence. And particularly if you have a combination of high-intensity exercise and more moderate exercise to mix that up as well. So sometimes during the week, it's less time. You're trying to fit it into just a period early in the day. You know, make that your brisk walk. And then after dinner, maybe do another brisk walk. See if you can keep that up during the day, during the week, sorry. And then maybe you're more intense exercise,

which might be basketball or tennis for the kids or something. That might happen at the And so, but it's whatever, you know, it's whatever you can fit into your life because what's really clear is the key is that some exercise and preferably some exercise most days is better than none. You're a Stanford researcher. You're also an entrepreneur and co-founder of an exercise analytics company, Svexa. You seem enmeshed in both the science and the technology of this. So I have a quick dual part question for you about two trendy health topics. And your answers here can be quick. I'm going to give you the two words, and I want you to tell me either it works, it doesn't work, or we don't know. Those are your options. Okay, I'm ready. Cold plunges,

creatine. It works, it doesn't work, we don't know. Cold plunges, I don't think we really know, frankly. Cretin, yes, some evidence. Why don't you elaborate a bit in the creatine piece? Well, I mean, it's been studied over many, many years by many, many people, and there's some effect, I think what's less clear is that whether creatin supplementation is really required and really adds a huge amount extra. I don't think there's any doubt that creatine's part of your operational and metabolic system is required and you need to have that in your diet. Whether there's significant additional benefit to supplementation depends on the study, it depends on the amount. And for most people, I think with a regular diet, it probably isn't going to make a lot of

difference. A little different if you're an extreme, more extreme athlete or you're looking to have a rapid bulking of muscle. But I would say protein, and similar for protein, I don't know if you were going to ask about that, but protein supplementation is probably similar. Definitely there is evidence. It's probably a bit overplayed and I think a lot of people take protein supplementation and expect their muscles are going to grow and forget the part about straining and stressing their muscles or don't realize that that's the principal thing. In reality, if you do both, then there's some evidence for both creatine and protein, but it's probably not quite as robust or as dramatic as most people believe.

There definitely explains why stirring creatine into my water and sitting down to watch Love Island USA has not dramatically increased my musculature. But I'm going to keep trying this. My particular study of N-Equels 1 is not over. You just never know. You just never know. Is it inconceivable that we might one day invent a drug whose molecular function actually does closely imitate exercise? And that goofy example that I gave above where I said, you know, you're watching football on a Sunday and an ad comes out and it's, there's a drug that, you know, Pfizer, Glaxo just came out with.

It's called XR size. And it has the benefits of exercise that you have uncovered in your rat and future human studies. is this a total pipe dream, or is it possible you think that with a more high-definition understanding of what exactly exercise is doing to our bodies, that maybe certain drugs can pick off a part of that portfolio of effects that exercise is having on our bodies? So maybe another two-part question. Number one, is an exercise pill possible that can do everything? And number two, is it plausible that we could develop a set of pills that could somewhat simulate or imitate the function of certain effects that you're seeing in the body?

Not unlike, I guess you could say, the GLP1 drug revolution, where we are essentially imitating a gut hormone that we didn't really understand. We just discovered from a helo monster that it might have something to do with appetite suppression. And then yada, yada, yada, it turns out to be quite a miraculous. intervention. Where are we on exercise drugs? Yeah. Well, I believe in answer to question one, the answer is absolutely not. I think we have no chance whatsoever of developing a drug that can mimic all the benefits of exercise. And I hope that over the last hour, you know, our conversation has led your listeners to agree with that. It's just too many things, too many organs, too many exercise is a very unique thing. However, to your second point,

I mean, I think that's one of the reasons for building this map. I mean, there are, they, you could pick off even 10%. We talk about the ad for the exercise drug. If the benefits of exercise were even 10% of this exercise pill were even 10% of the overall benefits of exercise, that's a blockbuster drug. And to your point, I think mimicking potential positive effects of systems we now understand better,

even if it's a little bit after the fact like the JLP ones, I think that's a good approach for pharmaceutical companies to think about when we think about powerful mechanisms that can really help. And we have ended up, I think, focusing a lot on disease when we think about drug development. And sometimes it's too late. I think thinking earlier, looking, studying disease earlier, or even studying very potent,

powerful, preventive intervention like exercise, actually I think is going to open a Pandora's box of potential for pharmaceutical development. And as you say, picking off individual systems, individual diseases even using this molecular map and this kind of mirror image response with exercise. I absolutely believe we're going to see, and I hope we see, I hope this work leads to the development of multiple drugs that can start to mimic some of these just very powerful effects of exercise. I hope so too.

That would certainly help me finish the season of Love Island. You and Ashley, thank you so much. I appreciate it. Thanks so much for having you. I really enjoy the conversation. Thank you for listening. Today's episode was produced by Devin Boraldi. our summer schedule for plain English for the next few weeks.

We'll be one episode a week on Fridays. We'll see you next week.