An intriguing new study from UC San Francisco scientists has identified a protein produced by the liver after exercise that could protect the brain from age-related cognitive decline. As well as helping explain the neuroprotective benefits of exercise, the research points to the possibility of generating this same effect by taking a drug.
The new research arose out of several studies investigating how transfusing blood from young mice into older mice strangely rejuvenated the brains of the aging animals. While these “fountain of youth” studies into the beneficial properties of youthful blood have homed in on some compelling prospective anti-aging compounds, a couple of graduate students working on the studies wondered if the same research process could be deployed to detect any specific blood-borne factor underpinning the beneficial effects of exercise.
So the first stage of the research was simple. Take two cohorts of aged mice. One group gets a running wheel in their cage for six weeks while the other gets just nesting materials. Six weeks later both cohorts were examined and the exercising mice showed increased growth of new neurons in the hippocampus and memory improvements.
This part of the research wasn’t especially surprising. A number of recent studies have illustrated both the short- and long-term brain-boosting benefits of exercise. However, the next question was whether transfusing blood from the exercising mice would deliver the same neurological benefits to the sedentary mice.
The sedentary mice received eight injections of blood from exercising mice over three weeks. Incredibly, the brain benefits seen in the exercising mice did indeed appear in the sedentary mice after receiving the blood. A control group of sedentary mice receiving blood from other sedentary mice did not show similar responses, confirming the presence of something in the exercise-primed blood was generating those effects.
So the researchers closely investigated the exercise-primed blood to look for novel proteins that increase following physical activity. After generating a shortlist of 30 potential proteins, the team ended up focusing on one liver-derived protein called Gpld1. Senior author on the study Saul Villeda says they homed in on Gpld1 specifically because there has been little research investigating its function.
"We figured that if the protein had already been investigated thoroughly, someone would have stumbled upon this effect," says Villeda. "I like to say – if you're going to take a risk by exploring something new, you might as well go big!"
Mice were engineered to overproduce Gpld1, and to the researchers' surprise, after three weeks of heightened Gpld1 production the brains of the sedentary mice resembled those of the mice receiving the exercise-primed blood. New neuron growth was seen in the hippocampus and animals showed improved responses in learning and memory tests.
"To be honest, I didn't expect to succeed in finding a single molecule that could account for so much of the benefits of exercise on the brain,” says Villeda. “It seemed more likely that exercise would exert many small, subtle effects that add up to a large benefit, but which would be hard to isolate. When I saw these data, I was completely floored."
The new study also notes increased Gpld1 blood levels can be detected in healthy, physically active older adults. This suggests the mechanisms observed in the animal studies may be present in humans, although further research will be needed to verify this.
Several questions do remain unresolved. Most glaring is the observation Gpld1 does not seem to be able to cross the blood-brain barrier. So whatever neurological effect it is exerting on the brain must be a result of it activating other, still undiscovered, pathways.
Further research will work toward exploring whether this mechanism can be therapeutically targeted with a drug that directly exerts these beneficial effects on the brain without the need for exercise. The goal would be to help older adults unable to engage in physical activity maintain optimal brain health.
"This is a remarkable example of liver-to-brain communication that, to the best of our knowledge, no one knew existed,” says Villeda. “It makes me wonder what else we have been missing in neuroscience by largely ignoring the dramatic effects other organs might have on the brain, and vice versa."
The new study was published in the journal Science.
