Exercise has long been celebrated for its benefits to physical health, but recent research demonstrates its surprising effects on the brain, particularly in reversing age-related cognitive decline.
While aging inevitably brings change to memory and cognitive function, evidence suggests that regular physical activity may offer a solution to mitigate these effects.
Scientists at University of California San Francisco have uncovered a process that could explain why exercise sharpens memory and cognitive abilities by strengthening the brain’s natural defense system.
The research, led by Saul Villeda, associate director of the UCSF Bakar Aging Research Institute, explored how physical activity influences the brain’s blood-brain barrier, a key structure that protects the brain from harmful substances in the bloodstream.
Some years ago, the research team discovered that “exercising mice produced higher levels of an enzyme called GPLD1 in their livers,” which seemed to rejuvenate the brain.
However, this presented a mystery: GPLD1 cannot cross the blood-brain barrier, leaving scientists puzzled about how it was able to deliver its cognitive benefits.
In the study, scientists shifted their focus to understanding how GPLD1 functions despite its inability to cross the blood-brain barrier. They discovered that the key to unlocking its benefits lies in a protein called tissue-nonspecific alkaline phosphatase.
TNAP accumulates in aging brain blood vessels and weakens the blood-brain barrier.
As mice age, TNAP accumulates in the cells that form the blood-brain barrier, weakening its protective function. This buildup contributes to the barrier becoming more permeable, allowing harmful substances to enter the brain and trigger inflammation.
The research team found that when mice exercised, the liver-produced GPLD1 interacted with TNAP, reducing its buildup and restoring the blood-brain barrier’s integrity, ultimately protecting the brain from cognitive decline.
To understand how GPLD1 delivers its protective effects, the research team focused on the enzyme’s ability to cut specific proteins from the surface of cells.
In their search for potential targets, the scientists identified several proteins on the cells of the blood-brain barrier that could potentially be affected by GPLD1.
However, in their tests, they found that only one protein which was TNAP, consistently trimmed by the enzyme.
To further test the importance of TNAP, the team exposed young mice to elevated levels of the protein in the blood-brain barrier and found cognitive decline and memory problems similar to those seen in older animals.
Contrastingly, when researchers reduced TNAP levels in 2-year-old mice, they found that the blood-brain barrier became less permeable, inflammation decreased and the animals performed better on memory tests.
This research suggests that exercise may influence cognitive health in ways not previously understood, highlighting the importance of peripheral systems in protecting the brain.
“We’re uncovering biology that Alzheimer’s research has largely overlooked,” Villeda said in a press release. “It may open new therapeutic possibilities beyond the traditional strategies that focus almost exclusively on the brain.”
Even more encouraging is the study’s findings that interventions can still have an impact in later stages of life.
“We were able to tap into this mechanism late in life, for the mice, and it still worked,” Gregor Bieri, a postdoctoral scholar in Villeda’s lab and co-first author of the study, said. Two years for mice is equivalent to 70 human years.
This suggests that protective mechanisms within the brain might remain responsive even while aging, offering hope for potential therapies that could delay or prevent cognitive decline in the elderly.
