In this episode, chemist Jonathan Z. Long discusses his recent discovery of a new molecule produced when we exercise that appears to be linked to health benefits from regulating appetite to boosting learning and memory.
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We all know exercise has all sorts of benefits beyond just making us stronger and fitter. It lowers and inflammation. It buffers stress and anxiety. It clarifies our thinking. In fact, regular exercise is one of the few things we know with reasonable confidence can help extend our healthy lifespan.
But for all the evidence of the benefits of exercise, it's a bit surprising that we don't know more about how exercise does all these great things for our bodies and our brains.
Today's guest, Jonathan Long, recently discovered a new molecule produced when we exercise a compound called Lac-Phe. Lac-Phe appears to be linked to a number of health benefits from regulating appetite to boosting learning and memory.
Long is a chemist by training — and an institute scholar of Sarafan ChEM-H, the Institute for Chemistry Engineering and Medicine for Human Health, our sister institute here at Stanford. So I started our conversation by asking him how his background as a chemist informs how he thinks about studying exercise and human health.
NOTE: Thanks to everyone who's tuned in to our first season! We're going to take a break for the summer to get ready for next season, but we'll have more tales from the frontiers of brain science for you in the fall.
Learn More
Organism-wide, cell-type-specific secretome mapping of exercise training in mice (Cell Metabolism, 2023)
- Understanding how different cell types respond to exercise could be key step toward exercise as medicine (Wu Tsai Human performance Alliance, 2023)
An exercise-inducible metabolite that suppresses feeding and obesity (Nature, 2022)
- ‘Anti-hunger’ molecule forms after exercise, scientists discover (Stanford Medicine)
- Why Does a Hard Workout Make You Less Hungry? (New York Times)
- An exercise molecule? (American Society for Biochemistry and Molecular Biology blog)
Mechanistic dissection and therapeutic capture of an exercise-inducible metabolite signaling pathway for brain resilience (Innovation Award from the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute)
Episode Credits
This episode was produced by Michael Osborne, with production assistance by Morgan Honaker, and hosted by Nicholas Weiler. Art by Aimee Garza.
Episode Transcript
Nicholas Weiler:
This is From Our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University. On this show, we crisscross scientific disciplines to bring you to the frontiers of brain science. I'm your host, Nicholas Weiler.
Quick note, I just want to take a moment to say thanks to everyone who's tuned in to our first season. We're going to take a break for the summer to get ready for next season, but we'll have more tales from the frontiers of brain science for you in the fall. So with that said, here's the sound we created to introduce today's topic, exercise, and the brain.
We all know exercise has all sorts of benefits beyond just making us stronger and fitter. It lowers and inflammation. It buffers stress and anxiety. It clarifies our thinking. In fact, regular exercise is one of the few things we know with reasonable confidence can help extend our healthy lifespan. But for all the evidence of the benefits of exercise, it's a bit surprising. We don't know more about how exercise does all these great things for our bodies and our brains.
Today's guest, Jonathan Long recently discovered a new molecule produced when we exercise a compound called Lac-Phe. Lac-Phe appears to be linked to a number of health benefits from regulating appetite to boosting learning and memory. Jonathan is an assistant professor of pathology and an institute scholar of Sarafan ChEM-H, the Institute for Chemistry Engineering and Medicine for Human Health, our sister institute here at Stanford. I started our conversation by asking Jonathan how his background as a chemist informs how he thinks about studying exercise and human health
Jonathan Long:
Exercise in a way is like medicine because it provides a therapeutic benefit that we can measure and see. But unlike a medicine, we don't have a definition of what are the molecules associated with those effects. And what about things like pharmacokinetics and pharmacodynamics and adverse effects.
Nicholas Weiler:
Even without molecules, you probably can't prescribe a specific dose of exercise.
Jonathan Long:
Exactly right. So my approach to this whole problem is a chemist is find the molecules first. And once you find the molecules that will give you a clean entry point to study what is otherwise a very, very complex and poorly defined phenomenon, physical activity. So we were on the hunt for really robust molecules that were always associated with physical activity across many different modalities of physical activity across many different types of species. It was unclear by the way that such molecules would even be found because you can imagine that walking around the block is very different than running hard upstairs and is very different than running a marathon is very different than you running and a mouse running and dogs running and horse running.
So to our surprise, we actually found that all animals that move, which include mice that are running on treadmills, which include humans that are running on treadmill fuels, which include dogs running the Iditarod, which is that race across Alaska, which include horses run a golden gate field across the bay, all the animals when they sprint, they increase in their blood the same molecule. And it tells you that there's some fundamental, very conserved aspect of physical activity that's related to this molecule.
Nicholas Weiler:
So I wanted to dive in on that a little bit. So you wanted to understand are there different molecules involved in different kinds of exercise? And do you see the same thing in different species? So you started on the mice on treadmills, you were looking for molecules that increased in the blood following exercise, and basically you found one. You had a signal there's something here.
Jonathan Long:
It was a very clear signal. The top hit across every mouse experiment we ever did. It was the same molecule and it was that lacing molecule.
Nicholas Weiler:
So tell me about how you extended this to other animals. How did you go about that?
Jonathan Long:
Well, so the next one we actually looked at was humans because there's a lot of blood from a lot of people that are in clinical trials being exercised in various ways. One of the most common ways that you can do that is to put people on a treadmill and ask them to keep going until they say stop. That's called a self-limited cardiopulmonary treadmill exercise. And we had blood banked from our colleague Mike Snyder from these humans that were on treadmills. And we saw that the Lac-Phe molecule was also one of the top hits that was induced after exercise in the humans as well. And then we started to think, well, if we see it in mouse and we see it in humans, maybe we should just look very broadly. So one of the animal models that I had become very interested in were race horses.
Race horses have a long history in exercise research. They have a measurement called a VO2. This is a measurement how much oxygen they take in and horses increase their VO2 by more than any other animal ever recorded, which is 40 fold during a race. So they're a model of extreme exercise. So then we decided to look at racehorses. It turns out getting blood from race horses is also surprisingly easy because they're routinely drug tested. So all the A samples get sent out at the drug testing lab. The B and C samples came over here to Stanford. We put them on our instruments, we were looking, and lo and behold, the Lac-Phe molecule was again the top hit. And as we kept looking across all sorts of different animal models, we looked at racks, we looked at sled dogs that run across Alaska. In all these cases, Lac-Phe is dramatically induced after a single bout of exercise.
Nicholas Weiler:
Okay. So now you have this molecule and Lac-Phe that's a combination of lactate, and that's the molecule that makes your muscles sore when you exercise. And then phenylalanine, do I have that right? That's just a common amino acid, like a building block of proteins?
Jonathan Long:
So the Lac-Phe name refers to the two parts of the molecule that compose the entire entity. The molecule is a combination of lactate, which is, as you mentioned, the byproduct of exercise associated with sprinting and also the very common amino acid fentanyl elevate.
Nicholas Weiler:
So you've got this molecule Lac-Phe. I guess the next question is, well, what is this doing now we know this is elevated? One of the key things you looked at is its effect on appetite. Why did you focus on appetite?
Jonathan Long:
Yeah. So we were thinking very broadly about what Lac-Phe might be doing. Exercise has all these different effects across all sorts of different organ systems. The truth of the matter is that we made a bunch of synthetic Lac-Phe and we're putting it to animals. And then we started to measure all of the different physiologic parameters looking at various benefits of physical activity. So we were thinking about benefits for weight control, benefits for glucose metabolism and other cardiometabolic traits. And we were looking very broadly, the effect that was most prominent was the effect on feeding behaviors. And what we saw was that if you gave animals last feeding that they would eat less. And we knew that effect was specific because their movement was the same. They would drink the same and we could do all sorts of other tests to tell that it was very selective in terms of the suppression of appetite without basically any other effects generally in metabolism.
Nicholas Weiler:
So this is counterintuitive in a way because we usually think of there being an energy balance, calories in, calories out. So in a way you'd expect that exercise would make you eat more because you're using more energy.
Jonathan Long:
Yeah. I think you're absolutely right that the effect of exercise on your appetite is extremely complicated depending on the type of exercise, the duration of exercise, and many other factors. And there's no doubt that there's many such exercise regulated hormones that regulate your feeding behaviors. But with Lac-Phe, evolutionarily we think about it is that Lac-Phe is highest after a single bout of sprint exercise. When levels of lactate are also highest, that's like high intensity interval treat or running stadium stairs. So we think that lack means associated with the appetite suppression that you get after a really, really hard workout. And then evolutionarily, the way that we think about that sprint exercise is that before there was modern society, you would be sprinting away from predators that want to eat you.
And what you think about in that context is the autonomic nervous system response where you want to shut down digestion so you can fuel your muscles so you can run away. So we think that the lactate molecule plays into that type of system where it's a parallel chemical signaling system to your autonomic nervous system to help you in ancient days flee away from predators. And nowadays is associated with the feeling bad after high intensity interval training.
Nicholas Weiler:
Yeah. Your trainer is your predator maybe. Okay. No, that makes sense. I was thinking about doing a long hike or a bike ride or something like that, and I usually come back and eat maybe unwise numbers of calories after that. But I'm clearly just not going hard enough. So one of the things I thought was interesting, I mean, you saw a bunch of health benefits. Do I have this right? You found that if animals don't have Lac-Phe, then even really intense exercise does lead them to overeat and gain weight.
Jonathan Long:
That's exactly right. So what we can do is we can genetically engineer mice so they can't produce Lac-Phe. And in those genetically engineered mice, instead of having this Lac-Phe break to stop you from eating after an intense workout, they don't have that break anymore. So they continue to eat and they get obese after exercise trading. So that's really, I would argue the strongest evidence that we have that this Lac-Phe molecule really is involved in the suppression of appetite after a hard workout.
Nicholas Weiler:
So you see Lac-Phe elevated in many different animals after exercise. And we were just getting into talking about what happens if you don't have it. But I wonder if you could just briefly mention what were the health benefits that you see associated with Lac-Phe in these animals?
Jonathan Long:
Yeah. So our lab in the initial discovery of Lac-Phe has mostly focused on the energy balance aspects, on the appetite control, on the body weight effects. But we are now starting to ask broader questions about might Lac-Phe be doing other things related to the salutary effects of physical activity. One area where we've looked, and one area that's been very interesting is just generally in the brain. We know that Lac-Phe is acting in the brain because that's where your appetite control is being regulated. And now we're looking very broadly at other areas of the brain to see if Lac-Phe is also activating any other regions, for example, related to anxiety, depression, sleep, and those other types of behaviors and aspects that are associated with the health benefits of exercise.
And what we're starting to see in very, very early studies that are ongoing now is that Lac-Phe does seem to activate other pathways in the brain beyond just feeding control alone. For example, the mice that can't produce Lac-Phe also have reduced learning and memory, and that's quite interesting. We have different assays for learning and memory, including, for example, a water maze where mice try to find a little platform in the water. And what the animals that can't produce Lac-Phe seem to do is that they seem to have more difficulty finding the platform. That suggests that in addition to appetite control, Lac-Phe as an exercise has inbistrol molecule might be mediating other health benefits, especially associated with brain health. And that's an active area that we're trying to understand right now.
Nicholas Weiler:
And I wanted to ask you about that. So your group has recently received support from the night initiative for brain resilience here at Tsai Neuro to look into whether Lac-Phe as a molecular mediator of exercise could help enhance healthy brain aging, reduce the risk of neurodegeneration. I mean, this is such a fascinating line of research. There's this temptation to think of this as like, "Maybe we could make a drug. That means I don't have to go work out. I'll get all the benefits of exercise. I'll stay thin. I'll have a long lasting healthy life." I think listeners are probably rightly cynical because we've heard about miracle molecules before. Sometimes things pan out, often they don't. What to you makes this different?
Jonathan Long:
So I agree and share the concerns of your listeners here. This is a complicated area where we are approaching it cautiously and from just a basic scientific principles, chemical principles, and trying to understand the system. What is exciting for me is the fact that this metabolite Lac-Phe is so well conserved across the entire animal kingdom. Anything that moves turns on Lac-Phe. That tells you that somehow nature and evolution has built this in a very, very fundamental way. And what that exactly means in terms of the basic sides or in terms of translation to new medicines, I don't know but it tells you there's something very, very deep.
Just to give you a sense of this. I mean, it's very rare, and I've never had it happen to me before as a basic scientist where you do different experiments, a mouse running, a human running, a horse running, and God comes back and hands you the same answer. And when that happens, you got to listen. And my attitude of the whole thing, which is whatever it is, it's fundamentally tied to movement in animals. It's fundamentally tied to a key metabolite lactate, and it's fundamentally tied to the brain signaling and behavior and how that knowledge then might be translated to clinical practice or to new medicines that's still many, many years away.
Nicholas Weiler:
I really love the way that you put that and we have to follow the clues that nature or God drop on our trail and see where they lead.
Jonathan Long:
And I'm saying that as someone who's not very religious, but the feeling of seeing different experiments gave you the same answer, it feels like you're looking at God's hands. That's how it feels. Yeah. When you see that, then you feel like, okay, I just got to follow the science here. I share that caution that you raised, and at the same time, I'm trying to balance that caution with just the remarkable finding that nature has revealed to us.
Nicholas Weiler:
Well, that's beautiful. So one of the things I find so fascinating about this is that people have been studying exercise for a long time. Why was this discovered now? I mean, why hadn't this been found before?
Jonathan Long:
This is a great question, and I can tell you it's because no chemists have looked at this problem. So there's many molecules in our bodies. We know that, they're in textbooks, and those are all the standard molecules. But there's something that's changed in the last 10 years, which is a technology called mass spectrometry. And mass spectrometry allows you to measure all the molecules in your body, whether you know about them or not. And what we have learned is that there's many, many molecules in our bodies that are not in the textbooks, probably upwards of like 80% are not in the textbooks. And most scientists then just ignore that 80% because it's chemically hard to figure out what is it? Let's just focus on the ones that we know about. When we did the experiments, what we did differently was instead of just focusing on that 20% of molecules that you know about, we opened up our amount specs to look at everything in a totally unbiased way.
And what happened then was that Lac-Phe showing up and that 80% of data that everyone else is ignoring because they can't figure it out. The challenge for us, of course, in working with that 8% of poorly studied molecules is that it becomes very challenging to try to figure out what is it that you're actually detecting, but we're chemists, so we can make molecules, we can work with molecules and we can actually figure that out. But it does take some expertise in chemistry to be able to do that. I would say that most people who have been interested and approach a problem of physical activity and the salutary effects of physical activity have not been trained in very, very serious organic chemistry. I just happen to have that training and I happen to also have this interest in physical activity. So there's a very unusual combination of interest and expertise from two very different domains.
Nicholas Weiler:
And then the other thing that I wanted to ask was, we've talked a lot about the molecules and we've talked about the benefits of exercise for the body. But can you take us into the brain as you are approaching these questions about why exercise is so good for the brain, why it could potentially lead to healthier brain aging? What are you looking at?
Jonathan Long:
Yeah. The brain and exercise is a fascinating question. There are very, very few modifiable interventions to improve your brain health. One of them is exercise. First of all, a very fascinating observation that you can't do much because your brain's in here and it's complicated, but you can't move. And somehow that helps things up here. And that's a very strange idea when you start to think about that.
Nicholas Weiler:
How do your muscles affect your brain? How does your exactly cardiovascular rate affect your brain? Yes.
Jonathan Long:
Exactly right. And as you think about decline of brain health with aging, you think about, for instance, cognitive impairment. You think about neurodegenerative diseases, including Alzheimer's diseases. We are thinking about all of those different types of processes. Now, because we have a specific molecule to study, we can approach the problem cleanly from a chemical perspective. We can ask now, what is the effect of lax fee in these different types of experiments? So for example, one of the things that we're trying to do as I alluded to earlier, is we're trying to understand the effect of Lac-Phe as a clean entry point in learning and memory. And we can do that because we can directly introduce Lac-Phe to animals, or we can use those animals that don't have Lac-Phe and ask do they have any behavioral differences in learning and memory or cognition, which are of course the three domains most severely affected in Alzheimer's disease.
And in preliminary studies, we are seeing beneficial effects there. And that's very positive and we're continuing to follow that up. In other studies, we're looking at, for example, aggression. So people who, for example, have dementia and Alzheimer's disease, they also tend to have more aggression. And that's an interesting observation, and we can now ask the question again, using a clean entry point of Lac-Phe rather than some complex physical activity probation. Does Lac-Phe modulate aggression and other neuropsychiatric behaviors associated with Alzheimer's disease. We're starting to see, for example, that Lac-Phe can also seem to modulate and reduce aggression in certain animal lungs. We're also doing the standard models with Alzheimer's disease and the development of neurodegenerative phenotypes there. And we're continuing to study that now more broadly in the brain.
Nicholas Weiler:
Fantastic. All right. And I'll just do one final question. Taking a step back, we get so much advice about what to eat and how we should be exercising more and it's hard. I think we all struggle with this, some of us more than others, how to get enough exercise, how to eat, and so on. I know I do. How can understanding the mechanisms of how exercise affects the body and the brain help us just make better decisions or live healthier lives? I mean, does this give you personal insight about the value of exercise and health?
Jonathan Long:
I think that any exercise is always going to be better than not moving. And all of the regular advice that you get from, for example, the Center for Disease Control, the CDC, that you should be moving 150 minutes a week, that you should potentially add strength training twice a week. That's what I follow. What our work highlights is that maybe as you're doing some high intensity training, some of the effects that are going on in your body associated with that high intensity interval training might be just different than taking a walk around the block or other forms of activity.
From a practical point of view, that doesn't change what I do. I'm still on the elliptical and the more takes at the gym and just following the CDC guidelines. But it's interesting to think that maybe a diversity of different types of exercise could be good for you because the different types of exercise might be providing different molecules and affecting different systems in slightly different ways. And just like you want a varied diet, maybe also want very physical activity too.
Nicholas Weiler:
That's very helpful. Yeah. And just the fact that when you exercise, you're not just strengthening your body, you're doing all kinds of other favors for yourself too. Well, I could keep talking about this all day. I'd love to hear how this is going as the results come in from your new experiments. But for now, thank you so much for coming on the show.
Jonathan Long:
I'm very happy to do this. Thank you for having me.
Nicholas Weiler:
Thanks so much again to our guest, Jonathan Long. For more info about his work, check out the links in the show notes. This episode was produced by Michael Osborne with production assistance by Morgan Morgan Honaker. I'm Nicholas Weiler. Stay tuned to this feed. We'll be back soon.