Liver enzymes released during exercise were recently shown to repair aging brain blood vessels and restore memory in mice.

This new discovery reframes how physical activity protects cognition by tracing its benefits to repair processes at the brain’s outer borders, rather than within neurons themselves.

Leaky blood vessels are associated with aging

In older mice, the blood vessels that cut off the brain from blood flow became porous, allowing small molecules to escape into surrounding tissues.

Dr. Saul Villeda of the University of California, San Francisco conducted a study by tracking these leaks in aging animals.U.C.S.F.) demonstrated that a surge in the liver enzyme GPLD1 coincides with tightening of blood vessel walls and strengthening of memory.

Instead of entering the brain tissue, this enzyme acts on the surface of blood vessels, removing deposits that accumulate with age.

Because the protective factors never entered the brain itself, this mechanism resided at the barrier, and we needed to take a closer look at what was being removed from aging blood vessels.

Leaky brain barrier negatively affects thinking

Cells lining brain blood vessels form the blood-brain barrier (BBB), blood vessel walls that block many blood molecules.

When the BBB seal loosens, unwanted compounds can pass through and nearby brain cells can react to stress signals and damage memory.

one person study They tracked increased barrier leakage in older adults and linked it to worse thinking scores.

Similar leakage patterns have been reported in the early stages of Alzheimer’s disease, and BBB health is on the short list of targets.

Protective enzymes are released when you exercise.

Six years ago, a UCSF team showed that exercised mice improved their cognitive performance through blood. plasmaEven if the recipient stays still.

That work was selected GPLD1a liver enzyme released into the blood after exercise, that can cleave over 100 types of proteins.

However, GPLD1 was unable to enter brain tissue, leaving researchers without a strong signal and clear delivery route.

“This discovery shows how important the body is in understanding how the brain declines with age,” Villeda said.

Aging damages cerebral blood vessels

As the mice grew, the sticky enzyme began to build up on the cells lining the brain’s blood vessels, loosening the tight seal that normally protects the delicate tissue.

In clinical tests, the exercise-related enzyme GPLD1 ignored most surface proteins but consistently cleared this age-related accumulation.

Young mice, engineered to carry extra amounts of deposits in their brain blood vessels, began to struggle with memory tasks and behaved more like older animals.

Focusing on this single change gave the researchers a direct way to test whether removing the deposits could restore the brain’s protective boundaries for the future.

Liver enzymes repair the brain barrier

GPLD1 released from the liver during exercise traveled through the bloodstream to the blood vessels surrounding the brain.

It separates enzymes that have accumulated on the surface of blood vessels, reducing the burden on the barrier between the blood and the brain.

Older mice that received additional GPLD1 retained much more dye in their blood vessels during testing, indicating a strengthened barrier.

Within these same blood vessel cells, many age-related genetic changes reverted to more youthful patterns, signaling broader repair.

Memory and vessel restoration

Generally speaking, with a mouse equivalent In humans aged 70 years, there was less accumulation in blood vessel cells and less barrier leakage.

Following this reduction, brain inflammation decreased and the animals regained their previously diminished strength on memory tasks.

Returning the accumulated material to the aging vessel eliminated many of GPLD1’s benefits, highlighting how central this target had become.

Still, the experiments showed that vascular repair can explain much, but not all, of the effects of exercise on memory.

New treatment goals

The researchers also tested compounds mixed into food that reduced accumulation on blood vessel surfaces without entering the brain.

Treated older mice had stiffer blood vessel walls and performed better on object and spatial memory tests, consistent with the increase seen in additional GPLD1.

This compound acts outside the brain itself, highlighting vascular surfaces as a realistic therapeutic target.

The same enzyme plays a role in other tissues, and long-term blockade may be risky, so future treatments will need to be treated with caution.

Enzymes reduce Alzheimer’s disease

In mice bred to develop Alzheimer’s disease-like plaques, enhancing GPLD1 reduced Alzheimer’s disease-like plaque deposition. Hippocampusan area essential for memory.

Blocking blood vessel accumulation caused a similar reduction, lowering overall plaque burden in the brain.

Brain samples from older adults with Alzheimer’s disease also showed high levels of similar accumulations on blood vessels.

These findings point to making blood vessels healthier as one way to reduce stress on neurons, but only clinical trials can prove whether this strategy works in humans.

Treatments other than exercise are also possible

For people who can’t exercise much, treatments targeting vascular surfaces could one day mimic some of their training biology.

big cohort Researchers have linked increased activity to a lower risk of dementia, but they cannot prove the cause alone.

“This could open up new therapeutic possibilities beyond traditional strategies that focus almost exclusively on the brain,” Villeda said.

Before the drug reaches the clinic, UCSF scientists must test its safety, timing, and whether other GPLD1 targets are also important in humans.

Work is connected exerciseliver chemistry, and brain blood vessels into one chain of cause and effect, altering memory.

This chain of events is leading researchers toward protecting the blood-brain barrier later in life, recognizing that regular exercise is currently the safest and best-proven strategy.

The research will be published in a journal cell.

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