The drumbeat of exercise’s brain benefits may sound familiar. Most of us know that getting our move on can mean a boost to mental and neurological health. But what if, through understanding these biochemical processes, we could get all of that brain gain without going through the exercise pain? Mouse experiments have already demonstrated the feasibility of such a shortcut. And there is a hint that the results in rodents could work in humans as well.
When plasma from well-exercised mice is injected into their idling counterparts, the sedentary rodents have improved memory and reduced brain inflammation. The blood of Olympic athletes is not about to be transfused into the arms of sofa spuds—at least not yet. But people with mild cognitive impairment who exercise for six months show increases in a key protein identified in the runner-mouse plasma. The same protein may be able to whisper its chemical message across the notoriously choosy blood-brain barrier and trigger anti-inflammatory processes in the brain.
These findings, published on December 8 in Nature, offer new details of how exercise benefits the brain and how molecules boosted by physical activity communicate across the organ’s strict gatekeeper. The results also hint at a surprising role for the liver and anticlotting systems in these effects and possibly point the way to a futuristic scenario of exercise in a pill—or perhaps a plasma injection.
“Puzzle pieces are coming together,” says Saul Villeda, an associate professor in the department of anatomy at the University of California, San Francisco, about these hints of multisystem involvement in exercise’s effects on the brain. Villeda, who was not involved in the new study, and his colleagues previously identified a protein in exercised-mouse plasma that refreshed neurons in the aging mouse brain. “We’re starting to identify factors in the blood that can target different facets of decline or pathology, and this one really highlights blood factors affecting inflammation in the brain,” he says. “The word that keeps popping into my head is ‘convergence.’”
On the path to convergence, behavioral scientist Zurine de Miguel, now an assistant professor at California State University, Monterey Bay, and her colleagues at Stanford University and the Department of Veterans Affairs Palo Alto Health Care System first had to let mice exercise. The animals ran their heart out for 28 days, and then their plasma was transferred to mice that had not touched a running wheel during that time. The recipient animals showed improvements in learning and memory after they had received the “runner plasma.” Their brain, in turn, revved up genes that produced proteins that facilitated memory and learning and showed a dampened inflammatory response. When the researchers deliberately induced brain inflammation in the animals, the runner-mouse plasma dialed back that response, too.
The team next looked at what the runner plasma contained. They found increased levels of anticlotting proteins, including one called “clusterin,” which helps to clear cells of debris. Homing in on this protein, the investigators tested the effects of stripping it from the runner plasma. Brains of sedentary mice receiving clusterin-free plasma showing much less anti-inflammatory activity.
The team also found that clusterin readily attached to the cells that form the blood-brain barrier. When they mimicked the effects of physical activity by injecting the protein into the circulation of mice genetically modified to have neurodegenerative disease, the animals’ brain inflammation also declined.
Finally, the researchers wanted to see if exercise causes clusterin elevations in people. They measured the protein in 20 veterans with mild cognitive impairment before and after six months of structure physical activity and found that the levels increased.
De Miguel notes that in her and her colleagues’ study, results differed somewhat between male and female mice. Despite similar anticlotting protein profiles between the sexes, the females showed more variability. The hormones they make can affect anticlotting factors, de Miguel says, and the possibility that some female mice were in a sexually receptive stage during the study might explain this greater variation.
The experiment illustrates a growing recognition of the brain’s dependence on assistance from outside the neural no-fly zone. The liver and heart are the most likely sources of clusterin, the authors say. The results implicate both organs as sources of beneficial molecules resulting from physical exercise, de Miguel says. “They all seem to be cross talking to the brain,” she adds.
Villeda says that his group’s work with “runner plasma” in aging mice also implicates the liver. The organ produces an enzyme linked to cognitive improvements in the animals, and the same enzyme was also increased in the blood of older active people. The liver connection “was surprising to us because it wasn’t usually what you focus on when you think about exercise,” he says. With the liver connection, “these mechanisms are starting to converge and come into a similar space.”
Although physical activity is closely linked to good health, it may be possible to overdo exercise. There are hints that some people who engage often in highly strenuous physical activity may have increased risk for amyotrophic lateral sclerosis. “There is some information out there that says that too much exercise can impair some of your immune response and make you susceptible to opportunistic infections,” de Miguel says.
How will “runner plasma” be used as a therapy if these effects in mice bear out in people? “I have more hope now than when I started my lab because it was difficult to think about identifying all of these factors,” Villeda says. “But now we have candidates, and when you have those, you can start thinking about small molecule development.”
De Miguel says that a possible first step might be testing which exercise protocols trigger the biggest increases in proteins that carry a brain benefit. As with mice, someone in need of the brain-boosting power of physical exercise could simply receive an injection of “runner plasma,” getting a runner’s gain without the ensuing pain.