Aging Makes the Brain Leaky but Exercise Fights Back

Exercise may protect memory by sealing the aging brain’s defenses from the outside in.

Researchers at UC San Francisco have identified a biological process that helps explain why regular exercise benefits memory and thinking skills. Their findings suggest that physical activity strengthens the brain’s natural defense system, helping protect it from age-related decline.

Aging and the Blood-Brain Barrier

As we grow older, the network of blood vessels that shields the brain becomes more fragile. This system, known as the blood-brain barrier, normally prevents harmful substances in the bloodstream from entering brain tissue. Over time, however, it can weaken and become leaky, allowing damaging molecules to slip through. That leakage triggers inflammation, a process linked to cognitive decline and conditions such as Alzheimer’s disease.

Several years ago, the research team discovered that mice that exercised produced higher levels of an enzyme called GPLD1 in their livers. The enzyme appeared to have rejuvenating effects on the brain. Yet there was a puzzle. GPLD1 cannot cross into the brain itself, so scientists did not understand how it was influencing brain health.

How Exercise Signals From Liver to Brain

The new study provides clarity. The researchers found that GPLD1 works by targeting another protein called TNAP. With age, TNAP builds up in the cells that form the blood-brain barrier. This accumulation weakens the barrier and increases its permeability.

When mice exercise, their livers release GPLD1 into the bloodstream. The enzyme travels to the blood vessels surrounding the brain and removes TNAP from the surface of those cells. By trimming away this protein, GPLD1 helps restore the barrier’s integrity and reduce leakiness.

“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.

Villeda is the senior author of the paper, which was published in Cell on February 18.

Identifying TNAP as a Key Driver of Cognitive Decline

To uncover how GPLD1 exerts its effects, the team first focused on what the enzyme does at a basic level. GPLD1’s primary role is to cut certain proteins from the surface of cells. The scientists searched for tissues that carried proteins vulnerable to this trimming process and suspected that some of these proteins might accumulate as animals age.

Cells that make up the blood-brain barrier quickly drew attention. They displayed several possible GPLD1 targets. When researchers tested these proteins individually in laboratory experiments, only one was actually cut by GPLD1: TNAP.

Further experiments confirmed TNAP’s importance. Young mice engineered to produce excess TNAP in the blood-brain barrier developed memory and cognitive problems similar to those seen in older animals.

When the team used genetic engineering techniques to lower TNAP levels in 2-year-old mice — which are the equivalent of 70 human years — the blood-brain barrier became less leaky, brain inflammation declined, and the animals performed better on memory tasks.

“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.

Implications for Alzheimer’s Disease and Brain Aging

The findings suggest that developing drugs capable of trimming proteins such as TNAP could offer a new way to restore the blood-brain barrier, even after it has deteriorated with age.

“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.”

Reference: “Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature” by Gregor Bieri, Karishma J.B. Pratt, Yasuhiro Fuseya, Turan Aghayev, Juliana Sucharov, Alana M. Horowitz, Amber R. Philp, Karla Fonseca-Valencia, Rebecca Chu, Mason Phan, Laura Remesal, Shih-Hsiu J. Wang, Andrew C. Yang, Kaitlin B. Casaletto and Saul A. Villeda, 18 February 2026, Cell.
DOI: 10.1016/j.cell.2026.01.024

Other UCSF authors are Karishma Pratt, PhD; Yasuhiro Fuseya, MD, PhD; Turan Aghayev, MD; Juliana Sucharov; Alana Horowitz, PhD; Amber Philp, PhD; Karla Fonseca-Valencia, degree; Rebecca Chu; Mason Phan; Laura Remesal, PhD; Andrew Yang, PhD; and Kaitlin Casaletto, PhD. For all authors, see the paper.

The study was supported in part by National Institutes of Health (AG081038, AG086042, AG082414, AG077770, AG067740, P30 DK063720); Simons Foundation; Bakar Family Foundation; Cure Alzheimer’s Fund; Hillblom Foundation; Glenn Foundation; JSPS; Japanese Biochemistry Postdoctoral Fellowship; Multiple Sclerosis Foundation; Frontiers in Medical Research; American Federation for Aging Research; National Science Foundation; Bakar Aging Research Institute; Marc and Lynne Benioff.

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