Best of: The future of exercise

0:00Jonathan Long:Hey everybody, it's Russ Altman from the Future of Everything podcast. Well, the World Cup is here and we're watching some amazing athletes on a global stage. And as we watch them, we might wonder, what is all that exercise doing to their body? That led us to think, hey, let's rerun an episode with Stanford biochemist Jonathan Long. Jonathan studies the chemistry of exercise. When you exercise, what chemicals are released by your body and why? His studies are finding some pretty cool things that may lead to new treatments for obesity and diabetes, and maybe, just maybe, an exercise pill. So as you're watching the athleticism on the pitch, you might want to re-listen to this episode about the future of exercise.

0:44Jonathan Long:Before we get started, a reminder that if you're enjoying the show, please consider sharing it with friends, family, and colleagues. Personal recommendations are the best way to spread the news about everything.

1:00Jonathan Long:We all know that there's an epidemic of obesity in the United States and really increasingly worldwide. We also know that it's related to type 2 diabetes, and we all know that exercise is good for you and that diet and exercise is one way to lose weight, avoid diabetes, and feel good. And yet it's so hard. Moreover, we don't really fully understand in a specific way how exercise affects our physiology and leads to all these benefits. In fact, if exercise was a pill that you could just take, it would be very popular. We would have muscles, we would have less fat, we would feel great. But alas, we don't have those pills yet.

1:40Jonathan Long:But Jonathan Long from Stanford University is a professor of pathology, and he's an expert at exercise, metabolism, obesity, and diabetes. He's going to tell us that there's more than you think understood about exercise, and he's going to tell us that there might be a future, not soon, where there is an exercise pill. So Jonathan, it seems like effective weight loss drugs have just exploded on the scene in the last couple of years. What happened? Well, thanks for having me, Russ. I mean, it's really crazy what's been going on with the Zempic and semaglutide and all of the GLP-1 receptor agonists.

2:19You know, the history of this whole class of medicine is really fascinating, starting from very, very classical endocrinology back in the 1980s, when it was discovered that, you know, you could cleave these peptide hormones out and that they existed. And, you know, it's really been a 40-year journey from that initial basic science to what we now know today as like a pretty safe and remarkably effective weight loss drug. Really over the last 10 years is when people started to really understand the therapeutic potential of these medicines. Because what happened was they got put into people initially for diabetes.

2:59And then when they put these drugs into people for diabetes, this was around 2010 or so, they started to see some modest weight loss. And that was interesting. And it was good that the folks at Novo and Lilly decide to pursue that further because upon optimization now of those medicines, you just got bigger and bigger and bigger weight loss without any sort of untoward side effects. And so it's really been a remarkable journey starting from basic science four years ago to really the last 10 years of pharma taking an initial signal in people and translating that into an incredible medicine.

3:34Jonathan Long:You know, I love that story. And thank you for that synopsis, Because what it tells us is that this, even though in the public consciousness, they just hit the market like in the last couple of years, the fact that this is basic science discovery and multiple decades of research is an important lesson really for everybody about patience and having faith that by understanding the basics, and this is what we're going to get into next, understanding the basics of how things work, you wind up with these kind of blockbuster discoveries. So now let's step back. And you're an expert in metabolism, metabolic diseases, the effects of exercise, especially on physiology.

4:14Jonathan Long:So tell me a little bit about how your lab approaches these questions. Sure. So by background, I'm a chemist by training. But sort of unlike most chemists, I have a fundamental and very deep interest in metabolism and human physiology. And so that's sort of where the types of problems that we work on. But we approach these problems not from sort of a more medical view, but from a chemical view. And the way it works in chemistry is you always start with molecules. OK. And molecules are the key because molecules provide you clean handles to start to understand complex processes. And so when we start to think about exercise, which is a complicated state, involves many different things.

4:54I mean, some people can't even agree on what physical activity is. What we try to do is we try to find molecules associated with that state that are uniquely associated with that state, ideally, and then to use those molecules as very, very clean tools to access some subset of that state so that we can study it.

5:10Jonathan Long:Okay. So that's very clear as well. So this is super fun. And I'm exploding with ideas because exercise is something that's on everybody's mind. So the first basic question is, do you have to do these studies in humans or I'm hoping mice, rats, other kinds of animals have very similar responses to physical exertion? Or is that a dangerous thing to assume? You know, I think it cuts both ways. I think that there are examples of processes that are human specific. And I think there are examples of processes that are common to physical activity across all different types of organisms that move. So, for example, in some of our work, we found an exercise-inducible metabolite that makes you stop eating.

5:51We think that this is the reason why, for example, after a very hard workout, you don't feel very hungry. And it turns out that this molecule, which is called LAC-Phi, is induced by…

6:05Jonathan Long:LAC-Phi. I'm going to just pause because I want people to know. It's L-A-C-P-H-E. Exactly. Right. Don't forget this molecule. Okay, keep going. This particular molecule, it turns out, is turned on after high-intensity exercise across basically any animal that moves. So we originally found it in mice. It turns out it's true in people. It turns out it's true in racehorses that are racing. We've done other studies in the sled dogs that are running across the Iditarod. Basically, any animal that moves turns on this molecule. So that's an example of a molecule that's conserved across different types of physical activity.

6:41But there are also other types of examples of molecules that are human specific or only in certain types of animals, too.

6:47Jonathan Long:Great. So one of the things that I might imagine would be different for human and is I know that when I'm getting ready to like go on a long bike ride or do a run, like I have to get psyched up for it. And I'm wondering, are we anywhere near understanding the process of like psychological preparation for exercise, which I might imagine would be different. That's why I'm asking it right here is that I might imagine that mice are a little bit more ad hoc in their exercise, whereas I'm sitting around planning my whole weekend. So what do we know about that? I think that's a really, I mean, one of the most mysterious areas of exercise science, right?

7:25So the other way of sort of asking what you've asked about, for example, is if you look at marathon runners, okay, and you ask why is it that they can't go faster? Because at the end of a race, it's not that their muscles are exhausted, right? Because they're still walking around. So there's some important psychological aspect of all of sports and activity that we don't really understand well. Now, what I can say is that there are starting to be emerging studies to try to find molecular and genetic underpinnings of, for example, motivation to exercise or preparation to exercise or pushing the limits of exhaustion.

7:59So, for example, there was a beautiful study that came out a few years ago that described how endocannabinoids, which are a class of lipid neurotransmitters, are involved in the motivation to exercise. And that's very interesting. And so, you know, so people are starting to do those types.

8:16Jonathan Long:I just want to highlight, you just said the word cannabinoid as in some of the molecules related to marijuana. Is that correct? Exactly. So, you know, when you smoke marijuana, the reason that you have some of the pleasurable and also other psychoactive effects of that drug is because you have a receptor in your brain, the cannabinoid receptors. And it turns out that you have natural ligands, natural molecules that activate those receptors. And those are called the endocannabinoids. And so there's a paper talking about motivation exercise. And what they showed was that the motivation exercise is determined by the natural rise of endocannabinoids in your body.

8:54And that's an important factor in what you were just describing in terms of getting yourself psyched up.

9:00Jonathan Long:Fantastic. Okay. So let's go back to lack fee because it was one of your big discoveries. It got a lot of press. People are excited about it. Tell us what it does. So I think the first thing you told us is that it is pretty universally present, I believe, at the end of exercise. And do we know, is it just telling us that exercise happened or is it doing important signaling to the body that it should start other things like building back the muscle or recovery? What is it doing? Right. So, LAC-V is a molecule that's derived from lactate. Okay. So, lactate, high lactate levels cause the production of LAC-V.

9:38And that's why it rises so dramatically after sprint exercise. And then what we found, it probably does many, many things. But the first thing that we found it does is it goes to the brain to suppress your food intake and suppress feeding and appetite. Okay. And so, as I mentioned, we think that this is why, for example, you don't feel hungry after a very hard workout. Now, we've since learned that where this molecule is actually made is in your gut. So it turns out there are intestinal epithelial cells in your gut that make LACFY. And so this represents sort of a gut to brain axis that's controlling feeding behaviors.

10:11But of course, the gut to brain axis controls many, many other things, including, for example, feelings related to anxiety and depression or happiness or different types of motivations over behaviors. And so we're -

10:25Jonathan Long:We all have had a stomach ache when we're nervous about something that's about to happen, right? That's part of the same phenomenon. And so we are actively looking at other things that lactate might be doing related to the gut-brain axis. But one thing it does for sure is feeding and probably many other things in the brain as well. And presumably the lack part is from the lactate. That's provided by the muscles that are producing and it kind of goes to the gut. The gut creates this molecule. How long does the molecule last before it's like down to baseline levels? You know, in humans, it lasts a really long time.

10:57So if you, for example, have a person and you give them what's called a cardiopulmonary treadmill test, okay? You basically put them on a treadmill and tell them to run until they want to stop, okay? So they'll run for 10 minutes, be very exhausted. Lactate levels are through the roof. Lactate levels are through the roof. And if you now look at one hour later, the lactate levels will have come back down to baseline, but lactate levels still remain high. If you check six hours later, It's still very high. OK. And it only comes back down after 12 hours or 18 hours in people. And so it lasts a very, very long time after a single bout of acute exercise in people.

11:31And what's so interesting about that, by the way, is that what that means is this is, I think, part of our body's sensory system that can convert a very, very short stimulus, like a high intensity interval training session, into a very long and profound effect physiologically. Right. This is part of the logical logic by which that happens.

11:53Jonathan Long:Yeah, yeah, that really is. That's very helpful because that does make sense because the question is, okay, I only did it for 10 minutes and an hour later, I'm back on the couch watching The Simpsons. Why am I still getting benefit? And now you're beginning to understand that these molecules are hanging around. So what happens if you're – what's the difference between the response in a very well-trained athlete and a weekend warrior or a couch potato? That's a great question that we've just started to look at because we've only started to recently get access to those type of samples. And what I can tell you is that it all has to do with how they metabolize lactate.

12:26So in a very well-trained individual, they typically have very, very developed very good systems for metabolizing and handling their lactate. What that means is in those individuals, actually, the lactate doesn't go up as high. Whereas if you take an untrained individual who does not have those systems built in now after training to handle their lactate, their lactate spikes through the roof and their lactate also spikes through the roof. And so we think that there's a more pronounced effect to this whole pathway in untrained individuals versus trained individuals.

12:57Jonathan Long:fascinating okay so i want to get to diabetes because you study you study exercise but you're all part of your motivation if i understand it correctly is trying to understand metabolic disease and kind of the the king or queen of metabolic diseases in many ways is type 2 diabetes it's a scourge in our population it's becoming a global a global problem um what what are we learning about diabetes and the relationships to exercise and metabolic physiology and maybe these these molecules. Like you haven't mentioned whether LACF has anything to do with diabetes directly. So where are we in understanding that?

13:32Jonathan Long:And because we started out with the discussion of these drugs, many of which started out as diabetes drugs. Exactly. So, you know, you're absolutely right that, for example, diabetes and exercise and obesity all go hand in hand in hand, right? And in fact, diabetes complications are one of the major problems associated with being obese. You can't control your blood sugar. You have diabetic retinopathy. You have all sorts problems associated with uncontrolled blood sugar. Now, right now where we are is it's very clear with the new drugs that are available, Zempic and all the other GLP-1 receptor agonists, that as you start to control your body weight, that alone is sufficient to confer control over diabetes.

14:13And so now, instead of, for example, thinking about these as separate things, now more of the thinking is, how do we start to lower body weight safely and effectively? Because if we can do that alone, we start to resolve some of these obesity-associated problems, which include, for example, diabetes, include fatty liver disease and hepatosteatosis, which include dyslipidemia and cardiovascular complications. And so we've been mostly focused on the energy balance side of things. Now, you asked about lack-fee and diabetes. So it turns out that if you give lack-fee to obese animal models, what happens is they start to lose weight.

14:47And actually, their diabetes resolves, okay? But we think that that's not necessarily a direct effect of lack-fee on the glucose control systems, but as a secondary effect to the fact the animals are now leaner and therefore metabolically healthier more generally.

15:01Jonathan Long:Oh, I see. So, yeah. So there is this legitimate question of what's the mechanism of action by which LAC-FEE makes these changes. So do you see, I was going to ask you, and I think now is the time, do you see LAC-FEE as being the core idea for a new weight loss drug? Or do you think we've already captured most of what it does with the existing drugs. Well, I think that this is the core, but we have to put it in the right context, okay? And the analogy I would draw is what we talked about at the very beginning with the GLP-1 drugs. The first, I mean, we understand this now is a blockbuster weight loss medicine, but the first indications that it might be something were in the 1980s with academic experiments that were done at the MGH, okay?

15:44And now, 40 years later, we translated that in a very, very successful way. What I think where we are with exercise science broadly and where we are in our current lab right now with Black V is where we were with GLP-1 in the 1980s. We're just uncovering the fundamental basic sciences and basic understanding of the pathway so that we can set ourselves up over the next decades to try to think about what parts of this pathway might be therapeutically harnessable for the next generation of weight loss medicines or the next generation of anti-diabetic medicines. So I think that's where we are. So, yeah.

16:22Jonathan Long:So, and just to finish up this segment, let me ask you about, you were talking about diabetes and the direct and maybe indirect effects of LAC-FEE. And that raises this larger question that I wanted to ask, which is, does it matter how a person loses weight or is the only point or the main point to lose the weight? So you can imagine that I could take drugs, I could exercise, I could stop eating, I could do all three of those. You and I have friends who are doing this kind of proactively for life extension reasons. Maybe we'll get into that later. From your understanding of the basic chemistry, does it matter?

16:57So I'll give you a yes and a no answer. OK, so OK, good. The no answer is if you are overweight or obese, it's always good to lose weight and come down to a normal healthy weight because the increased body weight alone puts you at risk of all these cardiometabolic complications. Okay. That's the no part of the answer. But there is an important yes part of the answer, which is that as you start to lose weight, weight in our bodies can come from two places. It can come from either fat mass or lean mass, which is muscle tissue. Okay. And what you would like to do is you would like to lose fat, but preserve your lean muscle mass.

17:39And so what that means, for example, is that you would like to keep resistance training to keep your lean mass while you're, for example, reducing your caloric intake so you can lose the fat mass. Okay. And it's very, very difficult as someone loses weight to change the body composition. So it's very, very difficult to maintain the fat loss while keeping all your lean mass. But to the extent that you do want to do that, that would be the ideal situation. OK, so to summarize and to answer your question, what you want to do is if you're overweight, you want to lose weight. And ideally, you want to do it by losing fat mass without losing lean mass.

18:17But that's a very difficult thing to do. And it depends on sort of where you're starting from.

18:22Jonathan Long:This is the Future of Everything. And I'm your host, Russ Altman. More with Jonathan Long next.

18:37Jonathan Long:Welcome back to the Future of Everything. I'm your host, Russ Altman, and I'm speaking with Professor Jonathan Long of Stanford University. In the last segment, Jonathan told us about this very exciting molecule, LAC-F, that builds up after exercise, suppresses your appetite, and is involved in all the signals that tell your body that you just had a good exercise session. In the second segment, he's going to tell us about what's the possibility of a pill for exercise. Is exercise like a medicine? Why is everybody taking metformin? And how is this all going to play out in the years to come? So Jonathan, I wanted to ask you about this idea that exercise is like a medicine.

19:16Jonathan Long:And I've heard people talk about this before, but it sounds like you're in a particularly good position to tell us if it really makes any sense. Yeah. So I think this is one of the most interesting ideas that's been proposed and has been around for very long, right? Exercise is medicine. Okay. And even you'll read about it in the Washington Post, you'll read about it in the New York Times all over. And I think it's a very interesting comparison because nobody digs just one level down. People say exercise is like medicine because if you move, you start to lose some weight. This provides benefits for your body weight, for your blood pressure, for your cardiometabolic risk factors.

19:52All of that is true. But the next level down is in what ways is exercise not like a medicine? And to answer that question, we have to talk about what is a medicine, okay? In a modern-day medicine, okay, if you take a torvostatin or you take a blood pressure medication or you take a metformin, you take any of these things, what happens? you're taking a defined drug substance, a defined chemical entity that has a defined pharmacokinetic and pharmacodynamic profile with a defined pathway and a defined receptor engagement or target engagement. You know, when you should take it, you know, when you should not take it, you know, who is contraindicated, you know, all these things about modern day medicines.