Scientists at UC San Francisco have uncovered a long-sought biological pathway explaining how physical activity shields the aging brain from decline. A liver enzyme produced during exercise travels through the bloodstream to the brain’s blood vessels, where it clears out a harmful protein that weakens the brain’s protective barrier. Published in the journal Cell on February 18, 2026, the discovery could lead to new treatments for Alzheimer’s disease — including a drug that may replicate exercise’s brain benefits for people who cannot stay physically active.
For decades, doctors have recommended exercise as one of the best ways to maintain a sharp mind. Physical activity stimulates the growth of new nerve cells, enhances learning, and reduces brain inflammation. But the precise biological steps connecting a workout to a healthier brain have remained frustratingly unclear — until now.
The Brain’s Protective Barrier
The human brain is guarded by a dense network of tightly packed blood vessels called the blood-brain barrier. Acting like a security checkpoint, this structure filters out toxins and harmful substances circulating in the blood, protecting delicate brain tissue. With age, the barrier deteriorates and becomes permeable. Dangerous compounds leak in, sparking inflammation closely associated with cognitive decline and disorders like Alzheimer’s disease.
Six years ago, the UCSF research team took an important first step toward solving the mystery. They discovered that exercising mice produced elevated levels of an enzyme called GPLD1 in their livers, and that GPLD1 appeared to rejuvenate the brain. There was just one puzzle: the enzyme cannot cross the blood-brain barrier, so scientists were left wondering how it reached the brain in the first place.
The Liver-to-Brain Connection
The new study answers that question. The researchers found that GPLD1 works by targeting another protein, called TNAP. As mice age, TNAP accumulates on the cells forming the blood-brain barrier, weakening it and making it leaky. When mice exercise, their livers release GPLD1 into the bloodstream. The enzyme travels to the brain’s outer blood vessels and acts like molecular scissors — snipping the excess TNAP off the cell surfaces. With less TNAP present, the barrier seals up, inflammation subsides, and cognitive function improves.
“This discovery shows just how relevant the body is for understanding how the brain declines with age,” said Saul Villeda, PhD, associate director of the UCSF Bakar Aging Research Institute and senior author of the study.
What the Experiments Showed
To confirm TNAP’s role, the researchers conducted a series of targeted experiments in mice. When young mice were genetically engineered to carry excess TNAP in the blood-brain barrier, they developed memory problems resembling those of aging animals. This showed that high TNAP levels alone can drive cognitive decline.
When the team then used genetic tools to dial down TNAP levels in two-year-old mice — roughly equivalent to a 70-year-old human — the blood-brain barrier became less permeable, brain inflammation decreased, and the mice improved on memory tests. “We were able to tap into this mechanism late in life, for the mice, and it still worked,” said Gregor Bieri, PhD, a postdoctoral scholar in Villeda’s lab and co-first author of the study.
A Drug That Could Bottle the Benefits
Not every older adult or person with a physical limitation can exercise regularly. That reality gave the team a practical motivation: could a drug replicate what exercise does? They tested a compound called SBI-425, which blocks TNAP activity directly. Aged mice treated with SBI-425 showed similar improvements in memory and blood-brain barrier function as those given GPLD1 itself. Crucially, the drug does not enter brain tissue — it acts only on the outer vessel walls, which may reduce the risk of unintended side effects inside the brain.
Hope for Alzheimer’s Treatment
The findings extend to Alzheimer’s disease as well. Mice genetically engineered to develop Alzheimer’s-like brain plaques and behavioral problems showed a reduction in plaque density and improved behavior after being treated with either GPLD1 or the TNAP inhibitor.
Human tissue data added significant weight to these results. When scientists analyzed brain tissue samples from deceased individuals, they found that people who had Alzheimer’s disease carried higher levels of TNAP in their brain blood vessels compared to those without the condition. This correlation suggests the same mechanism observed in mice may also be at work in the human brain.
“We’re uncovering biology that Alzheimer’s research has largely overlooked,” Villeda said. “It may open new therapeutic possibilities beyond the traditional strategies that focus almost exclusively on the brain.”
While the findings are encouraging, human clinical trials will be necessary to confirm whether TNAP-targeted therapies are safe and effective in people. TNAP also plays roles elsewhere in the body — including bone mineralization — meaning any future drug would need to act precisely on the brain’s blood vessels without disturbing other systems. Still, this research offers a compelling new blueprint: the liver, long known mainly for its role in digestion, may be one of the brain’s most important allies in the battle against aging.
