Slacker mice don’t have to lift a paw to reap the brain benefits of exercise. All they need are injections of blood from their fellow rodents that have been working out, a new study reveals. The research suggests a molecule in the exercisers’ blood can replicate some perks of physical activity, including reducing the brain inflammation that may promote illnesses such as Alzheimer’s disease.
That molecule is “very promising and targetable” for potential treatments, says neuroscientist Christiane Wrann of Harvard Medical School, who wasn’t connected to the study. By highlighting another compound that could lead to new therapies that improve brain health, she says, the study makes “an important contribution.”
The work stems from more than a decade of research by neuroscientist Tony Wyss-Coray of Stanford University and colleagues. They revealed in 2014 that blood from young mice rejuvenates elderly rodents’ brains, sharpening their memory.
Scientists have long known that exercise is also an elixir for the brain. It stimulates production of new brain cells in rodents, boosts learning and memory, and soothes brain inflammation, a possible culprit in Alzheimer’s disease and other conditions of the aging brain.
So in the new study, a team led by Wyss-Coray and his then-postdoc Zurine De Miguel tested whether blood from exercising mice could transfer these brain benefits to their sedentary peers.
The researchers placed one group of young mice in cages with running wheels. The animals became gym rats, running about 10 kilometers per night. A second group of young rodents lived in cages with wheels that did not rotate. These mice got some exercise by scurrying around their cages, but far less than the animals with working wheels.
After 28 days, the scientists removed blood from the running mice and from the sedentary rodents and separated out the plasma, which is rich in molecules that may influence the brain. They then injected the plasma into another group of nonexercising animals every 3 days for 28 days.
Doses of runners’ plasma triggered many of the same brain effects as 28 days of vigorous activity, the team reports online today in Nature. It boosted cell survival and division in the brain, for instance. Mice that received plasma from the jogging rodents also performed better on memory tests than did those injected with plasma from the sluggards.
In one memory test, the researchers allowed the mice to learn the location of a platform in a tank of water. When the scientists returned the mice to the water the next day, the animals that had received plasma from runners seemed to have a better recall of where the platform was. They spent about one-third more time searching in the correct portion of the tank than did the mice that received plasma from nonexercisers.
When the scientists analyzed gene activity in the brains of the recipient mice, they discovered that injecting plasma from runners quieted multiple genes that promote inflammation. To confirm that plasma from the runners quells inflammation, the team injected mice with bacterial molecules that spark inflammation and then gave the animals plasma from runners or nonexercisers. Again, the plasma from the mice that had worked out dialed down the activity of inflammation-promoting genes in the brain.
Which molecule (or molecules) in the protein soup of plasma caused these improvements? To find out, the scientists analyzed changes in the levels of different proteins in the running animals. The abundance of four proteins with roles in immunity or inflammation increased by a large amount after 1 month of exercise. This foursome included clusterin, which is part of a molecular system that defends the body against pathogens and helps control inflammation.
The researchers eliminated each protein from the runners’ plasma and gauged the impact on inflammation. “When we removed clusterin, the anti-inflammatory effects of runners’ plasma were diminished the most,” says De Miguel, who is now at California State University, Monterey Bay.
The liver produces much of the body’s clusterin, which then infiltrates the brain. “Exercise can affect the brain through molecules that are being produced in the body,” says neuroscientist Fernando Gomez-Pinilla of the University of California, Los Angeles, who wasn’t connected to the research. The study, he says, “provides a mechanism by which this can happen.”
The work makes a strong case for clusterin’s involvement, but the molecule is not the whole story, Wrann says. She and other researchers have pinpointed at least nine additional molecules that may account for some of exercise’s impact on the brain.
Even if clusterin is key, it’s unlikely to make a good treatment alone because large doses are necessary to produce an effect, Wyss-Coray notes. But he adds that the molecule seems to suppress brain inflammation by stimulating receptors in the lining of blood vessels, and these receptors could be targets for new drugs.
Researchers in Norway who are not connected to the study have launched a clinical trial to test whether blood from human runners benefits patients who have early Alzheimer’s disease. The results of this 4-year study could reveal whether humans, like mice, can gain from exercise without leaving the couch.