It was recently discovered that a liver enzyme released during physical exertion aids in rejuvenating aged blood vessels in the brain and restoring memory function in mice. The study’s findings were detailed in the journal Cell.
This new revelation alters previous understandings of how physical activity safeguards cognitive abilities, linking its advantages to a repair mechanism operating at the brain’s outer border rather than within the neurons themselves.
In elderly mice, the blood vessels separating the brain from the bloodstream had become porous, enabling small molecules to seep into the surrounding tissues.
By tracing these leakages in aging animals, Saul Villeda of the University of California, San Francisco (UCSF), demonstrated that a surge in the enzyme GPLD1 activity in the liver correlated with tighter vessel walls and improved memory. Instead of passing into the brain matter, the enzyme acted upon the vessel surfaces, clearing away age-related deposits.
Since the protective agent never entered the brain tissue itself, the mechanism had to reside at the barrier border, allowing for a more granular look at precisely what was being removed from these aging vessels.
The cells lining the brain’s blood vessels form the blood-brain barrier (BBB), a vessel wall that blocks many blood components. When the BBB weakens, unwanted compounds infiltrate, and nearby brain cells respond with stress signals that can impair memory.
One human study had previously identified an increase in cognitive impairment among older individuals, a correlation found alongside declining cognitive performance.
Similar patterns of leakage were observed in the early stages of Alzheimer’s disease, placing the health of the blood-brain barrier high on the list of potential therapeutic targets.
Six years prior, a research team from UCSF had shown that exercise-exposed mice exhibited cognitive enhancement via their blood plasma, even when the animals remained sedentary.
That work isolated the liver-produced enzyme GPLD1, which is discharged into the blood following exercise and can break down over 100 proteins. However, GPLD1 could not penetrate brain tissue, leaving researchers with a strong signal but no clear delivery route.
As mice matured, the sticky enzyme began to accumulate on the cells lining the brain’s blood vessels, loosening the tight seal that normally protects the delicate tissue.
In laboratory tests, the exercise-activated enzyme GPLD1 ignored most surface proteins but consistently cleared away these age-related deposits.
Young mice engineered to have elevated levels of this substance accumulating in their brain vessels began to experience memory deficits and behaved more like much older animals.
Focusing on this single alteration allowed researchers to directly test whether removing the accumulated deposits could restore the brain’s protective boundary at an older age.
Released from the liver during exercise, GPLD1 traveled through the bloodstream to reach the vessels surrounding the brain. On the vessel surface, it dissolved the accumulated enzyme, easing the strain on the barrier separating blood and brain.
Elderly mice given supplemental GPLD1 retained significantly more dye within their blood vessels during testing, suggesting a strengthened barrier.
In these very same vessel cells, many age-related changes in genes shifted towards a more youthful profile, signaling a broader restorative process. In mice equivalent to approximately 70 human years, reducing the build-up on vessel cells lessened barrier permeability.
Following this reduction, brain inflammation decreased, and the animals regained the capacity for memory tasks that had previously declined. The re-accumulation of this substance in aging vessels negated much of GPLD1’s benefit, highlighting how critical this target has become.
Nevertheless, the experiments indicated that vessel restoration accounts for the majority, but not all, of exercise’s memory effects.
Researchers also tested a compound added to the diet that reduced substance accumulation on the vessel surfaces without crossing into the brain.
Older mice receiving this treatment showed tighter vessel walls and superior outcomes in both object and spatial memory tests, mirroring the improvements seen with supplemental GPLD1 administration.
Because this compound acted externally to the brain, it identified the blood vessel surface as a tangible therapeutic target.
Any further treatments must be approached with prudence, as the same enzyme is active in other tissues, and prolonged blockage could pose risks.
In mice bred to develop plaques similar to those seen in Alzheimer’s disease, elevated GPLD1 levels reduced the amount of these deposits in the hippocampus—a region crucial for memory.
Blocking plaque formation in the vessels led to a similar reduction in their numbers, lowering the overall plaque burden in the brain. Brain samples from elderly humans with Alzheimer’s disease also displayed higher levels of this vascular accumulation.
These findings suggest that healthy blood vessels could be one way to reduce the strain on neurons, though only clinical trials will confirm if this strategy is effective in humans.
For individuals unable to exercise extensively, therapies targeting the blood vessel surface might, in the future, mimic some of the biological benefits associated with physical exertion.
About the Author
