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The effects of exercise on the brain

Lessons in Lifespan Health

Release Date: 04/13/2023

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Connie Cortes is an assistant professor of gerontology at the USC Leonard Davis School. Her work straddles the fields of neuroscience and exercise medicine, and she recently spoke to us about her research seeking to understand what is behind the beneficial effects of exercise on the brain with the goal of developing what she calls “exercise in a pill” therapies for cognitive decline associated with aging and neurodegenerative diseases. 

On brain plasticity and brain aging

Brain plasticity we define as the ability of the brain to adapt to new conditions. And this can be mean something like a disease, it can mean something like stress, it can mean something like learning, and it can also mean something like aging. Our brain is actually quite plastic and can respond to a lot of these stimuli. Now, brain aging is a slightly different component to that where we think about what happens during the brain as we get older, the normal wear and tear. What are the differences and the similarities as well between a 75-year-old brain versus a two-year-old brain? 

What we've come to understand is like most other aging tissues, an aging brain begins to suffer from wear and tear just like a car would and that's where regular maintenance and regular checkups come in. … But essentially things at the biological level begin to slow down and as they slow down, that can affect the way our neurons fire and therefore we get age-associated decline in cognition and memory.

On why exercise is good for the brain health

That’s one of the questions that my lab is trying to answer, but in the field of exercise medicine, we've come to appreciate that exercise is very good for the brain, and it appears to do so in multiple ways. It can affect your cardiovascular health, which has a direct impact on the brain as far as blood flow and essentially clearing the brain out of things it doesn't need. The other way is delivering, metabolites and essential nutrients to the brain during exercise we make a lot of these things that get into our blood and eventually transfer through the blood-brain barrier into the brain. And so as far as the biological mechanisms of how exercise is good for the brain, we really, truly don't know yet. But that is why this field is so exciting and I think we're poised to answer these questions in the next five to 10 years. 

On whether exercise can prevent or slow cognitive decline or diseases like Alzheimer's that are associated with aging

For actually many decades now, we have had anecdotal evidence from the clinics that aging populations that are active, physically active, and or exercise have significantly lower levels of age-associated neurodegeneration, as well as just age-associated cognitive decline. And it's only been in the past, I would say 10 years that we've come to appreciate that it is truly the exercise activity. And so what we find is that consistently, no matter what markers of brain health we look at, those aging populations that are sedentary tend to do worse than those that are physically active. And so the field now is extremely interested in trying to understand why this is happening and can we kind of use these mechanisms and these targets as new therapies down the road.

On efforts to develop “exercise in a pill” therapies

We all know a hope that exercise is good for us. However, the most at-risk populations that we are trying to help, especially here in the school of gerontology, are populations that usually cannot engage in the level of exercise required. Now in the field, we're still trying to define what an exercise prescription is, but you may have heard you know, three times a week, 90 minutes a day, uh, some sort of cardio. And something that raises your heartbeat, uh, that is, has come from exercise studies in young people. However, elderly populations are sometimes suffering from additional medical conditions or sometimes there's a financial constraint or even an accessibility constraint, and they just cannot engage in that level of exercise. And so what we are trying to figure out is can we design exercise in a pill to perhaps allow them to receive the benefit without having to get on a treadmill three times a week?

On when to begin exercising

So that's the good news. It doesn't matter when you start, you will always get benefits. So for those of us that are a little bit more on the sedentary side, that's the good news. Now the better news is, is that yes, the earlier you start, the better. But this goes back to this concept of brain plasticity. The brain will respond to these interventions that promote neurotrophic signaling no matter how old you are, which is great for us from a therapeutic standpoint. And so the recommendation of remaining physically active is, start as soon as you can. And today is a good day to start.

On the muscle-brain axis and how our muscles and brains communicate

One of the challenges that we face in the field of exercise medicine is that exercise changes everything. And so we are always stumbling around this roadblock of, are the changes that we're seeing in our studies, the chicken or the egg, is it a cause or a consequence? Are they driving the benefits that we see or they just a response of the system? And so by narrowing down how different tissues communicate with each other during and after exercise, we're trying to answer this question of who is responsible for driving the benefits. And we focused on skeletal muscle because as you can imagine, it's one of the biggest responders to exercise. You need it to get on the treadmill, you use it to start lifting weights. And so where, first of all, trying to figure out how skeletal muscle responds to exercise and also how this changes with age.

And what we have come to understand is that during exercise skeletal muscle secretes messages into the blood circulation that we believe are essentially talking to the brain and telling it to do better. And if we can identify these messages, then we can probably deliver them in the form of medication and therapy. And so this muscle-to-brain axis we believe is essential for the brain benefits of exercise, and we're hoping to use it to start, uh, prioritizing some of these targets for therapy.

On exerkines

The field of skeletal muscle physiology has known for a very long time that it's an endocrine organ, that it secretes things as it communicates with the rest of the body but the fields of exercise, medicine, skeletal muscle physiology and neurobiology have only started talking to each other in the past five years. And so there's an entire field of research now, um, called the field of exerkines, exercise-associated cytokines, things that come out of skeletal muscle and other tissues during exercise that may be some of these responses that were going after.

On rethinking Alzheimer's as not only a disease of the brain

Since Alzheimer's disease, was first identified over a hundred years ago now, we've thought about it as a disease of the brain, but recently we've come to appreciate that it may be a disease of the body and the brain is just the most sensitive organ to it.

So in Alzheimer's disease patients if you examine some of their blood markers, some of their heart markers, some of their muscle markers, they're actually very different compared to healthy control populations. And so we are coming to appreciate the fact that despite the fact that the brain resides behind the blood-brain barrier and we thought it was isolated from the rest of the body, it's actually in direct communication and conversations with the rest of the body and the periphery. And so in our lab, we truly believe that skeletal muscle can influence the rate at which the brain ages and or develops things like Alzheimer's disease.

On differences in how males and females respond to exercise

It is only recently that the field is realizing that we don't know what the female brain does in response to exercise. However, from the clinical perspective, we do have some indications that women might be in a position to receive the most benefits from exercise interventions. And this comes from the current understanding that, for example, uh, women are the most at risk for developing Alzheimer's, and exercise is such a potent intervention against it. And so in our lab, we're currently beginning to tease out the sex differences associated with brand responses to exercise and trying to see what might be different. And we have some really interesting findings where, um, after exercise, the hippocampus particularly, which is the area that degenerates during aging and during Alzheimer's disease, it's where we store memory and cognition and it's also the, the brain region that responds the most to exercise. We have tremendous differences in the way the hippocampus is remodeled after exercise. So the biological responses might be unique to one sex or another, which again, provides us unique areas for intervention for either men or women or perhaps combinatorial approaches across sexes.


On future work looking at circadian rhythm and exercise

Yeah. So, I mentioned we're very interested in sex differences to exercise interventions. Genetics is another huge one. In the lab, we are constrained by our genetic homogeneity of some of our animal studies. And so integrating some of the human studies to bring in this genetic diversity is going be fascinating and then circadian rhythms is another one. Some of the listeners may actually notice by themselves that they prefer to exercise in the morning or at night, and that has to do with your own circadian rhythm as well. And so perhaps we could also identify not just the best type of exercise for you, but also the best time to do it to maximize the benefits that you may receive. So in the lab, the way we are approaching this is we're using this integrated approach of neuroscience, exercise physiology and gerontology, but also using across platforms.


So we go all the way from basic cellular biology to animal modeling to human studies, and then all the way back to cells in a dish. In particular, I'm very excited about a new animal model we've created that despite never running on a treadmill throughout its entire life, the brain is responding as if it's exercising. And so by using this animal model that doesn't need to exercise, but displays the benefits of exercise in the brain, we hope we can start to prioritize this chicken and the egg question that I mentioned -  what is important and what is driving the benefits? And we're going to use these animals as a platform to prioritize drug targets to start testing in the near future.


On small changes to promote brain health

It's never too late to start. It's never too late to change some of your behaviors and your habits. And the power of very small things to have a huge effect is something that I don't think we quite appreciate. So something as simple as going on a walk around the block once a day, just getting some sunshine, especially now that the rain is finally breaking, that is incredibly helpful, changing your diet a little bit. You know, drinking one less soda a week can have a huge impact on different outcomes in your body. And so thinking about small changes rather than radical, big changes that are very difficult to maintain can help a lot.


On the importance of mentorship, access and diversity

This is an essential component of who I am as a lab leader and as a scientist, I'm a strong believer in, um, opening doors for those coming up behind me, uh, simply because one of the reasons I'm here is because mentors open doors for me. And so I'm returning the favor. I'm particularly passionate about historically excluded minorities in STEM. I myself am a Latina scientist, and there are not enough of us out there and I truly believe that all of us belong here, and it's through diversity of ideas that we're going figure out these big questions with major impact to human health. And so ever since I was a grad student, I've worked tirelessly to, like I said, uh, bring in junior investigators, mentor junior investigators, and make sure that my lab is a welcoming place for anybody that's interested in the research that we do. I've mentored, undergraduate students, graduate students, postdocs, and now other junior faculty.  I've spoken at multiple of my professional societies. I've given career mentoring workshops. Sometimes I've come to realize a lot,  a very small thing, like I mentioned earlier, can make a huge difference. Students that look like me, that see me up there on the podium realize that they can do it too. And so that's commitment to science. Accessibility and diversity in science is a huge thing for me as well.

On her Minute Science video series

I started the very video series a couple of years ago because I kept seeing all of these misconceptions around science and especially about the brain. It's something I've been interested in since I was an undergraduate student, and I love the brain and so I realized that sometimes, especially as scientists, we tend to use language that's very difficult to follow. We love our acronyms, so many acronyms all the time. And even in talking to my parents and talking to my husband, they will give me a very confused look. And I've realized I've defaulted to using very complicated language, and I came to appreciate that it doesn't need to be that complicated. We are not an ivory tower anymore. We need to share our science with the public. Our research is funded by federal tax dollars, so the federal taxpayer should know what we're doing and they should be able to communicate with us and learn about what we do. And so that was the purpose of my minute science video series that I hope to continue sometime soon, um, once my schedule clears up a little bit.

And so we talk about things like, you know, is it true that you, you only use, you know, you don't, you never use your entire brain at the same time. Or is it really true that you can be right brain and left brain, but not both? But does it mean when people, people say the lizard brain, um, is it true that your olfactory system is the first one to respond to memory and why? Things like that.