What if something in the blood of an athlete could boost the brainpower of someone who doesn’t or can’t exercise? Could a protein that gets amplified when people exercise help stave off symptoms of Alzheimer’s and other memory disorders?
That’s the tantalizing prospect raised by a new study in which researchers injected sedentary mice with blood from mice that ran for miles on exercise wheels, and found that the sedentary mice then did better on tests of learning and memory.
The study, published Wednesday in the journal Nature, also found that the type of brain inflammation involved in Alzheimer’s and other neurological disorders was reduced in sedentary mice after they received their athletic counterparts’ blood.
Scientific results with mice don’t necessarily translate to humans. Still, experts said the study supports a growing body of research.
“We’re seeing an increasing number of studies where proteins from outside the brain that are made when you exercise get into the brain and are helpful for improving brain health, or even improving cognition and disease,” said Rudolph Tanzi, a professor of neurology at Massachusetts General Hospital and Harvard Medical School. He led a 2018 study that found that exercise helped the brains of mice engineered to have a version of Alzheimer’s.
The most promising outcome would be if exercise-generated proteins can become the basis for treatments, experts said.
“The demonstration that there are transferable factors in the blood that seemed to convey beneficial effects on the brain that improve learning and memory is by far the most interesting aspect of the work,” said Dr. Madhav Thambisetty, a neurologist and senior investigator at the National Institute on Aging, who was not involved in the new research.
The study, led by researchers at Stanford School of Medicine, found that one protein — clusterin, produced in the liver and in heart muscle cells — seemed to account for most of the anti-inflammatory effects. But several experts noted that recent studies have found benefits from other proteins. They also said more needs to be learned about clusterin, which plays a role in many diseases, including cancer, and may have negative effects in early stages of Alzheimer’s before brain inflammation becomes dominant.
“It’s far too premature to conclude that higher or lower levels of clusterin might be either beneficial or not,” said Dr. Thambisetty, who has studied clusterin. “I don’t think we’re at the stage yet where people can trade in their treadmills or cancel their gym memberships for a clusterin pill or a clusterin injection.”
The study was led by Tony Wyss-Coray, a professor of neurology and neurological sciences at Stanford, who had previously done research finding that the blood of young mice can reverse age-related cognitive impairment in old mice.
Dr. Wyss-Coray said he wanted to see “if exercise produced factors that would also accumulate in the blood and that you could then transfer them.”
The study involved mice that were about three months old — roughly the equivalent of 25-to-30-years-old for humans. Some of the mice, nocturnal animals that love to run, could freely use exercise wheels in their cages and logged about four to six miles on the wheels each night. The wheels were locked for other mice that could scoot around their cages but could not get an extended cardio workout.
After 28 days, the researchers took a third group of mice that also did not exercise and injected them with blood plasma, the liquid that surrounds blood cells, from either the runner mice or the non-runner mice. Mice receiving runner blood did better on two tests of learning and memory than those receiving blood from the non-runner mice.
In one test, which measures how long a mouse will freeze in fear when it is returned to a cage where it previously received an electric foot shock, mice with runner blood froze 25 percent longer, indicating they had better memory of the stressful event, Dr. Wyss-Coray said. In the other test, mice with runner blood were twice as fast at finding a platform submerged in opaque water, he said.
The team also found that the brains of mice with runner blood produced more of several types of brain cells, including those that generate new neurons in the hippocampus, a region involved in memory and spatial learning.
A genetic analysis showed that about 1,950 genes had changed in response to the infusion of runner blood, becoming either more or less activated. Most of the 250 genes with the greatest activation changes were involved in inflammation and their changes suggested that brain inflammation was reduced.
The team tested whether removing any of the four most significant proteins in the runner blood would matter, and found that if clusterin was removed, anti-inflammatory effects disappeared. And when mice engineered to have a type of brain inflammation or a version of Alzheimer’s were injected with clusterin, it lessened their brain inflammation.
In the only part of the study involving humans, 20 military veterans with a pre-dementia condition called mild cognitive impairment who had participated in a six-month exercise program were found to have high levels of clusterin in their blood.
Kaci Fairchild, associate director of the Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education and Clinical Center, and an author of the new study, said the veterans, ranging in age from 50 to 89, exercised three times a week, combining cardio with weight training.
Dr. Fairchild said that in results that have not yet been published, besides having elevated clusterin, the veterans did better on tests involving word memory and story recall.
“Across the board, veterans had improvements in cognitive function, largely related to learning and memory,” Dr. Fairchild said. Noting that some people have disabilities or limitations that prevent them from exercising, she said she hoped that “the implications from this clusterin is that we can develop a medication targeting this protein for persons who weren’t able to engage in physical activity.”
In the brain, clusterin binds to cells that line the blood vessels, cells that become inflamed in Alzheimer’s disease, Dr. Wyss-Coray said, suggesting that a potential drug might bind to those cells and “mimic the anti-inflammatory effects.”
Still, experts who study Alzheimer’s disease and neuroinflammation said much more research is needed before therapies can be developed.
“Not everything that works in mice works in humans, and we don’t know if there are other unexpected side effects that could make it untenable in humans,” said Mark Gluck, a professor of neuroscience and public health at Rutgers University in Newark, N.J., who was not involved in the study.
Dr. Michael Heneka, the incoming director of the Luxembourg Centre for Systems Biomedicine who was not involved in the study, said the role of inflammation in diseases processes can change over time, being protective early on and detrimental later, so it is important to target inflammation at the appropriate time.
It’s also unclear if clusterin is the optimal protein for a therapy.
Other proteins linked to physical exercise have been shown in recent studies to improve cognition in mice. One, irisin, released by muscles, was found to reduce neuroinflammation and help mice perform better on memory and learning tests. Another, called Gpld1, an enzyme produced in the liver, was shown to increase after exercise and to correlate with better cognitive function in elderly mice.
Whichever proteins end up being promising, it would be safer to develop a medication than to try to transfuse blood, which would contain other things beside the proteins, said Dr. Tanzi, who was not involved in the new study. “The big question,” he added, “is which proteins are the winners and how do we take advantage of them to provide new therapies?”