Exercise is one of the most powerful ways to protect the brain from aging. Regular physical activity slows cognitive decline and lowers dementia risks, but many older adults are unable to exercise due to health limitations. This challenge has led scientists to search for ways to deliver these same brain benefits in another way. 

Research from NIH Director's High-Risk, High Reward Early Independence Award recipient Saul Villeda, Ph.D. from the University of California, San Francisco, points to a promising possibility. His research suggests that a molecule released into the bloodstream during exercise, called GPLD1, may be a key part of how exercise keeps the brain healthy.

GPLD1 is made in the liver and is released into the blood during exercise. Its function is to trim off certain proteins from the surface of a cell, impacting how the cell functions. Dr. Villeda’s research group discovered that GPLD1 removes a protein called TNAP from cells. TNAP is a protein found on the surface of cells that line the brain’s blood vessels and helps keep harmful substances out. This protective layer is called the blood-brain-barrier. While TNAP plays a role in maintaining this barrier, too much TNAP can weaken it, leaving the brain more vulnerable to damage.

Using mouse models, Dr. Villeda’s research group found that older mice had more TNAP on blood-brain barrier cells compared to younger mice. Exercise reduced TNAP levels in older mice, likely due to increased GPLD1. 

To test whether GPLD1 could produce similar benefits without the mice exercising, the team treated older, sedentary mice with a compound so that more GPLD1 was released from their livers. They found that, as a result, the TNAP levels decreased, even without the mice performing any exercise. This was also the case for mice with Alzheimer’s disease-like symptoms. These Alzheimer’s-like mice with more GPLD1 – and less TNAP – outperformed other mice of the same age during learning and memory tests.

This research demonstrates an important communication pathway between the brain and the liver, showing that GPLD1 from the liver can improve memory loss in mouse models of dementia and may replicate some of the brain-related benefits of exercise. While still early, this research suggests that future treatments might improve memory not by targeting the brain directly, but by improving the health of the blood vessels that support it – potentially offering new hope for aging populations unable to exercise.

Bieri, G., Pratt, K.J.B., Fuseya, Y., … Villeda, S.A. Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature. Cell.189, 1499-1516 (2026).