AdventHealth neuroscientist Kirk Erickson has always been active. As a kid, he played sports, did martial arts, and ran track and field. Exercise was just something he did for fun. But now, after more than 20 years of researching exercise’s effects on the brain, he’s come to appreciate the magnitude of its importance. 

“There's pretty unequivocal evidence that exercise affects the brain and the risk for numerous neurocognitive disorders. We're talking about neurodegenerative conditions and psychiatric conditions,” said Erickson. “It reduces the risk for depression, reduces the risk of Alzheimer's disease, reduces the risk for Parkinson's disease and the risk for normal age-related cognitive decline.”

Exercise seems to cause structural changes in the human brain linked with cognitive benefits as well. When Erickson and his fellow researchers assigned healthy older adults to perform aerobic exercise three times a week for one year, the hippocampus, which is critical for learning and memory, actually increased in size by about two percent, while adults assigned to a stretching intervention experienced hippocampal shrinkage (1).

Exercise may be a goldmine for drug discovery: hormones, peptides, and other proteins produced in the body during physical activity could prove to be valuable therapeutics for treating many neurodegenerative or psychiatric disorders. But scientists are only beginning to understand the many mechanisms by which exercise benefits the brain. Some of the benefits likely come from physiological changes that happen during and after exercise; for example, blood flow to many areas of the brain, including the hippocampus, increases (2). Cerebrospinal fluid movement through the brain’s glymphatic system, through which the brain disposes of waste products including amyloid beta, also increases (3). Benefits likely also stem from exercise-induced synaptic plasticity (the ability of neurons to alter their connections with each other) or neurogenesis (the creation of new neurons).

While exercise-induced neuroprotection is beginning to be understood at the cellular level, much less is known about the molecular mechanisms. Elucidating molecular mechanisms is crucial if scientists want to develop therapies that mimic the brain benefits of exercise; it’s all very well to say that exercise exerts these effects through neurogenesis, but scientists can’t put neurogenesis in a pill.

Back to the beginning

In 1982, Swiss neurobiologists discovered a protein in pig brains that boosted neuron survival. They named it brain-derived neurotrophic growth factor, or BDNF (4). BDNF is crucial for neurogenesis and neuroplasticity and is one of the most extensively studied links between exercise and brain health. While many scientists initially had high hopes for BDNF as a therapeutic, clinical trials testing it for treating neurodegenerative disorders have not yet succeeded, possibly due to difficulties with delivering enough of the protein to the appropriate parts of the brain (5).

Fortunately, researchers like Tara Walker, a neuroscientist at the Queensland Brain Institute, are hard at work identifying other signaling molecules that link exercise and brain health. Walker is an avid runner herself, and has recently completed her first trail ultramarathon. Her love of running plays a major role in her work as well as in her personal life. “My running impacted my research rather than the other way around,” she said. “I became fascinated with trying to understand how exercise positively affects the brain.”

She knew that neurogenesis likely linked the two. “Exercise is one of the strongest physiological ways that we can increase adult neurogenesis,” she said. And while BDNF is important in this process, there is more to the story.

Exercise is one of the strongest physiological ways that we can increase adult neurogenesis. 
– Tara Walker, Queensland Brain Institute

Walker hypothesized that the benefits of exercise might originate not in the brain, but outside it. “Exercise is a full body action, so we figured that there must be something released into the blood that is somehow mediating this response,” she said.

She’s not the only one to have this hunch: two other researchers have since demonstrated that transferring plasma from mice that have exercised to sedentary mice transferred some of the benefits of exercise, including increased neurogenesis, improved cognition, and reduced neuroinflammation (6,7). Other researchers are currently attempting to treat patients with early stage Alzheimer’s disease using plasma donated by people who exercise regularly (8).

In order to identify these beneficial bloodborne factors, Walker and her team compared the plasma from running mice to that of sedentary mice. They found significant differences in the amounts of dozens of proteins between the two groups (9).  Since several of the proteins elevated by running were related to platelets, Walker decided to investigate these tiny blood cell fragments further.

Walker found that exercise increased a cytokine produced by platelets, called platelet factor 4 or PF4. In mice, PF4 didn’t seem to increase neuronal proliferation when Walker’s team infused it into the hippocampus, but it did increase the survival of immature neurons, which is an important part of the process of neurogenesis (9).

While scientists have studied PF4 in the context of blood coagulation and immune function, “there’s not really much else known about PF4 in the brain, so it’s uncharted territory,” said Walker. “That’s why we’re really interested in it.” She is currently studying the effects of PF4 on the brain in the context of aging.

Exercise also boosts another protein: selenoprotein P, a selenium transport protein that is critical for transporting selenium from blood to the brain (10). When the researchers deleted this protein, mice no longer experienced exercise induced neurogenesis. Further studies showed that dietary selenium boosted neurogenesis in aging mice and protected cognitive abilities after an injury to the hippocampus.

Walker cautioned that selenium has a narrow therapeutic range. While tiny amounts of selenium are essential, the recommended daily allowance for humans is only 55 micrograms, approximately 1000 times smaller than the mass of one grain of rice; higher doses can be toxic (11). Instead of long-term selenium supplementation, she thinks that short-term treatment after brain injuries will likely be the most promising application, an idea that she continues to explore.

Learning how muscles talk

While Walker is a neuroscientist who took an interest in exercise, Bruce Spiegelman, a cell biologist at Harvard Medical School, studied energy metabolism in fat and muscle cells for years before he became interested in the brain.

Although he didn’t realize it at the time, this journey began decades ago with his discovery of PGC-1α, an important protein for energy metabolism, in 1998 (12). Exercise increases PGC-1α in muscle tissue, but the protein also appears to mediate many of the downstream effects of exercise (13).

“In 2002, we put [PGC-1α] in muscle and we discovered that it gave muscle many of the attributes of muscle that had been exercised,” said Spiegelman. “It occurred to us that maybe this work could be extended. It was known that muscle talks to other tissues… And so, the question is if we dropped PGC-1α into muscle cells in culture or into muscle tissue in vivo, could we make a simplified system that would allow us to discover factors secreted by muscle that may carry some of the benefits of exercise?”

Spiegelman’s team found that PGC-1α expression in muscle tissue caused the muscle cells to secrete a previously undiscovered hormone that they named irisin; follow-up studies showed that mice and humans produced irisin during exercise as well (14). Spiegelman’s team next determined to find out if muscles used irisin to “talk” to other tissues, and if so, what message they sent.

As one of her first projects as a postdoctoral researcher in Spiegelman’s lab, Christiane Wrann, who is now an exercise and metabolism researcher at Massachusetts General Hospital, measured irisin in different tissues in the body. “It's not just very high in skeletal muscle; it's also very high in the brain, in the hippocampus,” she said.

This got her thinking. “We do know irisin is an exercise hormone and we do know exercise is good for the brain. Is it possible that irisin is one of these important connectors — how exercise is improving brain function?” Together with her team, Wrann showed that in mice, boosting irisin in the blood increased BDNF gene expression in the hippocampus, suggesting potential brain benefits (15).

Wrann continues to study the effects of exercise on the brain. She recently discovered that increasing irisin in the body improves cognition and reduces neuroinflammation in a mouse model of Alzheimer’s disease (16).

Since neuroinflammation is involved in many types of brain dysfunction, Wrann is excited about the potential to investigate irisin for Alzheimer’s disease and other neurodegenerative diseases.

In the context of Parkinson’s disease, Spiegelman’s team found that irisin reduces α-synuclein accumulation in mice, resulting in increased dopaminergic neuron survival (17).

There are still some hurdles to overcome before irisin makes it to the clinic. One snag may be its relatively short half-life in blood (18). While researchers have tested using viral vectors to elevate irisin expression in mice long term, gene therapy for humans is still in its infancy, so the pharmacokinetics of irisin will likely need to be assessed prior to human use. According to Spiegelman, pharmacokinetic profiles of irisin within the brain may be different than in the blood; they are currently examining this. Depending on the results of those tests, scientists may need to modify the protein to produce a longer half-life without abolishing the therapeutic value.

Other next steps for irisin research include expanding into nonhuman primate models of neurodegenerative diseases as well as examining the efficacy of irisin in mouse models of other diseases, such as depression.

Many Threads to Untangle

A handful of other proteins, including adiponectin, cathepsin B, clusterin, Gpld1, and lactate also mediate the effects of exercise on the brain. Even more may be awaiting discovery (6,7,19–21).

“I think that the reason exercise is so beneficial is that there isn't a single molecular pathway that's not affected,” said Erickson. “We know that exercise is affecting thousands of different pathways and every organ system in the body.”

Even with further discovery, it is unlikely that a single molecule will ever mimic all of the benefits of exercise; scientists developing drugs to mimic the effects of exercise don’t intend them to replace regular exercise throughout a person’s lifetime, but rather to be used in specific circumstances.

“Our long-term goal is to understand how exercise increases neurogenesis and try to develop novel ways to mimic that exercise induced neurogenesis for people who can’t exercise,” said Walker. “Obviously you can’t tell someone who’s just had a stroke or who has Alzheimer’s to go out and run a marathon.”

While there’s still a lot to learn, researchers hope that by unraveling the secrets of exercise, they will one day provide desperately needed therapeutics for devastating neurodegenerative and psychiatric conditions.

References

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