Protein from blood of exercising mice rejuvenates brains of ‘couch potato’ mice | Science

A protein found in the blood of exercising mice could help explain why working out sharpens cognition in elderly people.


It’s well established that exercise can sharpen the mind: People and mice who work out do better on cognitive tests, and elderly people who are physically active reduce their risk of dementia. Now, in a surprising finding, researchers report that blood from a mouse that exercises regularly can perk up the brain of a “couch potato” mouse.

This effect, traced to a specific liver protein in the blood, could point the way to a drug that confers the brain benefits of exercise to an old or feeble person who rarely leaves a chair or bed. “Can your brain think that you exercised, from just something in your blood?” asks aging researcher Saul Villeda of the University of California, San Francisco (UCSF), who led the rodent research.

The study grew out of research in Villeda’s lab and others suggesting blood from a young mouse can rejuvenate the brain and muscles of an old mouse. Some teams have since claimed to find specific proteins that explain the benefits of this “young blood.” Graduate student Alana Horowitz and postdoc Xuelai Fan in Villeda’s group wondered whether  exercise—not just youth—could confer similar benefits via the blood.

It was easy to enough to test: Put a wheel in a cage full of mice, and the mostly inactive animals will run for miles at night. The researchers collected blood from elderly or middle-aged mice that had an exercise wheel in their cage for 6 weeks and then transfused this blood into old mice without a wheel in their cage.

Couch potato mice receiving this blood eight times over 3 weeks did nearly as well on learning and memory tests, such as navigating through a maze, as the exercising mice. A control group of couch potatoes receiving blood from similarly old, nonexercising mice saw no boost. The rodents getting the blood from the active mice also grew roughly twice as many new neurons in the hippocampus, a brain region involved in learning and memory, Villeda’s team reports today in Science. That change is comparable to what’s seen in rodents that directly exercise.

The researchers then looked for proteins that go up in the blood of mice when they exercise and homed in an enzyme called glycosylphosphatidylinositol specific phospholipase D1 (Gpld1) that’s made in the mouse’s liver. When the scientists injected Gpld1’s gene into the tail vein of couch potato mice, delivering it to their livers and thereby making the organs crank out the enzyme, the rodents’ cognitive performance and brain neuron growth improved after 3 weeks by about as much as if they had received blood from exercising mice. The team also showed that Gpld1 blood levels were significantly higher in a group of elderly people who regularly exercised than in those who didn’t, suggesting the mouse results may hold up in people.

The researchers couldn’t find much Gpld1 in the brains of the exercising mice, however—it doesn’t seem to cross the blood-brain barrier. Instead, its brain-boosting effects may derive from cleaving certain other proteins from the membranes of many types of cells. Those freed molecules then enter the bloodstream and lower inflammation and blood clotting, processes tied to dementia and cognitive decline in elderly people. Villeda’s team now hopes to find a drug that could mimic this effect and be given to elderly people who are too frail to exercise.

“It’s very tantalizing,” says Princeton University molecular biologist Coleen Murphy, who studies aging in worms. “We always want people to exercise more and not everybody is going to be able to do that. To be able to give people this in a pill form would be fantastic.”

Such a treatment—or even blood from exercising people—could also help younger people who are in rehabilitation and can’t work out, suggests Willard Freeman, a University of Oklahoma, Oklahoma City, aging scientist who sees severely injured soldiers as a Veterans Affairs researcher. (Freeman co-authored a commentary on the paper in Science.) He cautions, however, that Villeda’s team has uncovered just one part of a cascade of events. “We have a lot to learn.”


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