In the thick of graduate studies at the University of Chicago, Constanza Cortes Rodriguez remembers feeling burnt out. “Nothing was working in the lab, and I was very stressed,” Rodriguez says. That’s when she joined the school’s Ballroom and Latin Dance Association and fell in love with salsa and bachata. She soon found herself practicing nine or more hours a week, flawlessly executing moves on three-inch heels.
Dancing siphoned hours away from her research, and yet Rodriguez, who’s now a neurobiologist at the University of Alabama, quickly realized that it was making her a better scientist. “The time I did spend in [the] lab was so much more efficient; I could feel myself thinking differently and remembering things better.”
Her experience showcases an emerging trend in our understanding of cognitive health: Molecules made by muscles in motion can influence the structure and health of the brain. Scientists used to think that the brain controlled the body, and while the body transmitted signals of sensation back to the brain, the brain was isolated and in charge. But research in the last few years has flipped that notion on its head.
The data really show that the brain is not this unidirectional organ that dominates the rest of the body, says Christoph Handschin, a muscle researcher and professor of pharmacology at the University of Basel in Switzerland. “Rather, there’s a mutual interaction between these systems.” This emerging evidence has big implications for how exercise can affect cognitive health.
”We’re still scratching the surface, but it’s super exciting that we can now address some of the epidemiological links long observed between activity, brain health, neurodegenerative diseases, depression, and mood disorders, which so far have not been understood at all,” says Handschin.
Saul Villeda, a neuroscientist at the University of California, San Francisco, who studies how factors in the blood rejuvenate the brain, agrees. “The body of a 20-year-old is inherently different from the body of a 70-year-old. And somehow, something about exercise can cause a benefit in all these contexts.” The key, Villeda says, is that exercise’s impact on the brain is multifactorial—activity seems to increase the brain’s capacity to regenerate neurons, calm inflammation, and enhance neuron-to-neuron communication.
People in their 60s, 70s, and 80s already recognize that regular exercise is key to remaining mentally sharp and independent, according to the “Second Half of Life” study conducted jointly by the AARP and National Geographic. In an online and telephone survey of 2,580 adults ages 18 and older, people in those age brackets reported a greater appreciation for the value of exercise compared with people in their 30s, 40s, and 50s. Respondents also reported that brain health is consistently a top concern for people of all ages.
Researchers are now eager to figure out exactly how and why exercise improves brain function to develop better recommendations and treatments.
“The ultimate goal would be to develop a drug that can mimic exercise’s effects in the brain,” Rodriguez says. This becomes especially important in populations that can’t just hop on a treadmill, like people with mobility issues or frailty.
The brainy benefits of staying fit
Decades’ worth of research links physical activity and exercise with positive changes in the brain in a variety of contexts.
In children, for example, physical activity is associated with better cognitive performance as measured by IQ tests and academic achievement. Epidemiological studies on older adults show that regular exercise reduces the risk of developing Alzheimer’s. And imaging studies confirmed that the volume of the hippocampus—a region of the brain important in learning and memory—is larger in individuals who are more aerobically fit compared to their sedentary peers. These subjects, who ranged in age from 59 to 81, also performed well in spatial memory tasks.
Moreover, exercise helps patients whose brain function has already begun to falter; it sparks improvements in learning, attention, and memory in people with early stage Alzheimer’s disease, schizophrenia, or brain injury. Psychologists have noticed exercise’s benefits for their patients, too.
“Exercise can alleviate symptoms of anxiety and depression in pretty significant ways,” says Juli Fraga, a psychologist based in San Francisco. “It’s so beneficial that psychotherapists often prescribe it to their patients, and some even offer walk-and-talk therapy.”
Despite the mounting evidence for exercise’s benefits to the brain, an explanation for the mechanisms behind them has eluded researchers. But as scientists learn more about what happens to the brain as it ages, or when the brain turns on itself in the throes of neurodegenerative diseases, some exciting theories about how exercise impacts this vital organ are emerging.
The first clues to muscles affecting brains
Understanding how exercise generates molecules that directly benefit the aging brain began 25 years ago with the publication of a pair of papers by Henriette van Praag, a postdoc at the Salk Institute for Biological Studies in California. Those papers examined the brains of adult mice that spent time on a running wheel versus those that did not. The data showed for the first time in mammals that exercise induced the birth of new neurons, or neurogenesis, in the brains of adult mice. Those changes were accompanied by improvements in spatial memory and learning.
Van Praag, who is now an associate professor at Florida Atlantic University’s Stiles-Nicholson Brain Institute, says there was some serendipity in the discovery. In a previous study, researchers had seen signs that some component of an enriched environment—where mice had access to various stimuli, such as places to hide or toys—generated new neurons. So she set out to find the critical factor. “Running was actually just one of the controls in my study,” she laughs.
“Van Praag’s work is seminal in linking running to neurogenesis and enhanced brain function—important not only for the neurobiology community, but also paving the way for exercise and muscle researchers to study the crosstalk between training, muscle, and the brain,” says Handschin.
In 2002 Bruce Spiegelman, a cell biologist at the Dana-Farber Cancer Institute and Harvard Medical School, was studying a protein called PCG1-alpha that regulates the body’s metabolism by switching genes on and off. He discovered that boosting the amount of this protein in mice made their muscles stronger, redder, and packed with more blood vessels—it was as if the animals had been training hard at the gym without ever setting foot on a treadmill.
Around this time, scientists had begun to realize that moving muscles cranked out hormones and other molecules—called myokines—that get released into the bloodstream and provide benefits to faraway organs. So the PGC1-alpha find led Spiegelman to wonder: If that protein makes muscle look like it’s been exercised, then “maybe it’ll also prompt muscle to secrete things that are produced during exercise.” He could then use the protein to help him find the molecules responsible for the valuable changes in metabolism and immune function that exercise precipitates.
The hunt culminated in 2012 when Spiegelman and colleagues discovered irisin, a myokine released by exercised muscle. They figured out that irisin transforms white fat into beige fat. Since beige fat burns calories—unlike white fat, which stores them—Spiegelman thought irisin could be key to how exercise combats obesity and diabetes.
More pieces of the puzzle fell into place the following year when Christiane Wrann, then a postdoctoral researcher working with Spiegelman, showed that muscle was “talking” to the brain during exercise. When muscle cells produce irisin, it boosts levels of another protein called the brain-derived neurotrophic factor (BDNF) in the hippocampus, one of the first regions of the brain that changes in neurodegenerative diseases. There, BDNF promotes the health and growth of synapses and neurons, helping them mature and enhancing synaptic plasticity.
Just last year Wrann, now a neuroscientist at Massachusetts General Hospital and Harvard Medical School, tested irisin’s role in exercise and cognitive function. Her team compared mice who were genetically engineered to lack irisin with control mice who could still produce the molecule. After exercise, the control mice performed better on a task that relies on spatial memory and learning. The irisin-deficient mice didn’t show this same improvement, suggesting that irisin is what promotes these cognitive skills.
When Wrann’s team examined the mice’s brains, they saw that both groups of mice produced neurons in response to exercise, but the new neurons in irisin-deficient mice were abnormal, affecting their ability to form connections. When the gene to produce irisin was added back into the brains of mice lacking the protein, the mice had an easier time distinguishing between two similar patterns, a skill humans find useful for locating a car in a parking lot, for example.
Exercise and neurodegenerative disease
Wrann’s team also discovered that irisin seemed to play a role in protecting against neurodegeneration. The researchers bred mice that lacked irisin and had Alzheimer’s-like symptoms. These doubly afflicted mice experienced symptoms more quickly than mice that had only Alzheimer’s-like disease, and they showed cognitive improvements when irisin production was restored.
Wrann suspects that one way irisin helps is because it dampens inflammation caused by malfunctions in the brain’s immune system. This system is made up primarily of cells called microglia and astrocytes, which are normally tasked with reducing brain infection and cleaning up debris after an injury. As mammals age, though, these cells can remain active after the acute danger has passed and interfere with neuronal function, first by destroying connections between neurons and then by killing the cells themselves.
This activity causes chronic brain inflammation that has been implicated in many neurodegenerative diseases, including Alzheimer’s and Parkinson’s. But lab mice treated with irisin had less inflammation in their hippocampuses, and their microglia and astrocytes shrank, suggesting that irisin helped curb the haywire immune response.
So do these results apply to humans? Perhaps, according to preliminary work conducted in Wrann’s lab and by other teams. Irisin has an identical molecular structure in mice and humans, she says, which suggests that it serves similar functions in both species.
The results have exciting implications for the neurological benefits of exercise, since studies show elevated levels of irisin in people’s blood after a workout. On the flip side, post-mortem analyses of the brains of Alzheimer’s patients reveal a 70-percent reduction in irisin’s precursor molecule compared to age-matched controls, suggesting that irisin may be neuroprotective.
From a therapeutic perspective, “irisin certainly is promising,” says Handschin, “especially given the data about its effect in the brain.” But he cautions that irisin hasn’t yet passed the gauntlet of tests that line the road to drug development. “Whether this pans out in human patients remains to be seen.”
Depression, anxiety, and mood disorders
Handschin is personally interested in the interactions between muscle, exercise, mood, and motivation. In as-yet unpublished work, his group examined the effect certain molecules produced by exercised muscle have on mice’s willingness to run on a running wheel. Animals lacking these factors are capable of running, but they choose not to—a behavior that’s atypical for mice, which usually run up to six miles a day.
“There must be something in muscle that signals back to the brain and somehow reduces this drive to run for running’s sake,” Handschin says.
The field’s promise for treatments of mood disorders—particularly severe depression—also interests Spiegelman, who calls it one of medicine’s great unmet needs. “Severe depression is the number one cause of suicide, and it’s especially prevalent in young people,” he says. Currently, he and colleagues are evaluating irisin’s impact on anxiety-induced depression in experimental models with mice.
And the brain’s conversation during exercise isn’t limited to muscles. Its interaction with molecules—mostly proteins—secreted by the liver, fat, and bone remodels the brain to sharpen our thinking, stave off depression, and more.
With viable pharmacological candidates like irisin and others on the horizon, the University of Alabama’s Rodriguez believes that “we’re on the cusp of a great age of discovery that is finally going to translate into the clinic.”
But the explosion of research in muscle-brain crosstalk offers both rewards and challenges, cautions Karina Alviña, an assistant professor of neuroscience at the University of Florida College of Medicine. The salient molecules affect multiple systems in multiple ways, which means their potential reach is huge, but untangling their various dependencies can be a headache. Designing a drug that won’t have unintended consequences will be a big challenge, she says.
Still, Alviña finds a measure of hope in the research she and others are conducting, since it suggests “the environment and our lifestyle choices can have a big effect on the way we age,” Alviña says. That means it’s within our power to get older in a healthier way and maintain a higher quality of life for longer.
“So if I had to say one thing, it would be, Keep yourself active—even if it’s walking a few minutes a day. If you can, then do that.”
