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An Enzyme That Increases With Exercise Can Improve Memory In Mice, And Maybe People

Mice that exercise produce more of an enzyme that can improve memory and other brain functions.
Owen Franken
Getty Images
Mice that exercise produce more of an enzyme that can improve memory and other brain functions.

Scientists say they've identified an enzyme that could help explain how exercise can slow or even reverse some signs of aging in the brain. "Exercise in a bottle" isn't around the corner, but it's not out of the question either.

The idea builds on an observation a few years ago that certain parts of the brain can actually grow, even in older people.

"Just because you have an old brain, it doesn't have to stay that way," says Saul Villeda, who researches aging at the University of California, San Francisco. "And one of the best-known interventions that has a benefit on the brain is exercise. The problem is many of the elderly are frail. They can't physically do the exercise."

So Villeda and his colleagues have been on the hunt for factors in the blood that are induced by exercise and can improve memory and other brain functions.

"Can we actually then transfer the benefits of exercise without actually having to do the physical component of the exercise itself?" he asks.

The team of researchersreported Thursday in the journal Science that it thinks it has a great lead.

The researchers took blood plasma from mice that got plenty of exercise and infused it into older sedentary mice. Sure enough, those mice showed improvements in their brains and in mental tasks in a maze.

The scientists then narrowed their search to about a dozen proteins in the blood. One in particular, an enzyme called GPLD1, seemed to be key. When scientists revved up the production of this enzyme in older mice, nerves grew in part of their brains, and the animals performed better in the maze.

"Exercise causes this protein to be produced in the liver," Villeda says. And among other things, when this enzyme enters the bloodstream, it seems to tamp down aspects of inflammation, which contributes to age-related brain damage. "The result of that is that you actually have improvement in cognitive function in these older mice."

The research team also looked at a group of older people at the UCSF Memory and Aging Center. Researchers measured their physical activity with Fitbits. Those who exercised more produced more of this enzyme.

Aging and exercise are both complicated, involving all sorts of variables that interact in unexpected ways. So Villeda had to think hard about whether a single protein could really have a big effect.

"I was definitely surprised that one protein could have that much effect," he says. But when he realized GPLD1 is changing about 100 other proteins, it seemed plausible.

Scientists are nowhere near understanding the complex relationship among all these interacting parts.

"It's a long step between identifying this enzyme and, say, making a pill out of that," says neuroscientist Bradley Wise at the National Institute on Aging. But he finds the results intriguing — and in keeping with a line of research his institute is actively encouraging. "This is one piece of the puzzle."

The team at UCSF is eager to see if it can find its way to making a medication out of its now-patented discovery. Villeda says the discovery at least suggests a path forward.

"We don't have that exercise pill right now," he says. "This lets us know that this is a viable thing to pursue, but we're not there yet. My mom gets really excited — she [says], 'Oh, exercise in a bottle!' "

But that is not around the corner. "I wouldn't rush out and make GPLD1 and give it to people," says Willard "Bill" Freeman at the Oklahoma Medical Research Foundation and the Department of Veterans Affairs medical center in Oklahoma City. Freeman co-wrote a commentary about the paper for Science.

He's encouraged by the new findings but cautions that almost nothing is known about the potential downsides of tinkering with this enzyme and the complicated system it affects.

"There's a lot more research to be done. And in the meantime, one of the things we can all do is exercise. We have that within our own power."

Exercise has all sorts of health benefits beyond the brain, from strengthening bones to helping control blood pressure. So if this discovery ever does lead to a medication, it would be most helpful for people who, through injury or old age, simply can't exercise on their own.

You can contact NPR science correspondent Richard Harris at rharris@npr.org.

Copyright 2021 NPR. To see more, visit https://www.npr.org.

Corrected: July 9, 2020 at 12:00 AM EDT
A previous version of this story included a photo of a gerbil that was mislabeled as a mouse.
Award-winning journalist Richard Harris has reported on a wide range of topics in science, medicine and the environment since he joined NPR in 1986. In early 2014, his focus shifted from an emphasis on climate change and the environment to biomedical research.