Physical activity protects the brain from age-related cognitive decline. It’s one of the most potent ways to improve cognition in individuals at risk of neurodegenerative disease. However, some people can’t exercise due to physical limitations. To help these people, scientists have been looking into what it is about physical activity that causes positive effects on the brain.
According to a new study in mice coming from the UC San Francisco Eli in collaboration with Edythe Broad Center for Regeneration Medicine and Stem Cell Research, there is a little-studied protein that may be responsible. Their findings could lead to the making of a pill that delivers the same neuroprotective effects of exercise, without having to exercise.
Saul Villeda, Ph.D., the study’s senior author and a UCSF assistant professor, said:
“If there were a drug that produced the same brain benefits as exercise, everyone would be taking it. Now our study suggests that at least some of these benefits might one day be available in pill form.”
The protein – called GPLD1 – is produced by the liver and secreted into the blood after physical activity. The higher the level of this protein there is in the blood, the more protected the brain is from age-related cognitive decline. What’s more, the experiment with mice showed that by merely increasing the amount of GPLD1 in the blood by injection, the mouse experienced many of the same brain benefits as regular exercise. Furthermore, blood tests from elderly humans found that the enzyme is elevated in the blood of those who exercise regularly.
The Experiment
- Two cohorts of aged mice were employed for seven weeks. One was given a running wheel, the other only nesting materials.
- When the seven weeks were over, they examined the mice from both groups.
- Then, they transfused the blood from the exercising mice into the sedentary mice to see if the blood alone would deliver the same neurological benefits. They received eight injections over three weeks.
The Results
- The exercising mice showed memory improvements and increased growth of new neurons in the hippocampus.
- The blood transfusions delivered the same brain benefits as exercising in the sedentary mice. (For this phase of the experiment, they had a control group of sedentary mice receive blood from other sedentary mice. They didn’t show similar responses.)
- The experiment confirmed that the presence of something in the exercise-primed blood was generating positive effects.
Next, the researchers analyzed exercise-primed blood. They were looking for novel proteins that increase following exercise. They found 30 potential proteins and decided to hone in on GPLD1 since there had been little research investigating its function.
Villeda said:
“We figured that if the protein had already been investigated thoroughly, someone would have stumbled upon this effect. I like to say – if you’re going to take a risk by exploring something new, you might as well go big!”
The team then used genetic engineering to get the livers of aged mice to overproduce GPLD1. They wanted to see if the protein itself could drive the benefits of physical activity. The results were impressive. After three weeks, they tested the animals and found the treatment produced an effect similar to six weeks of regular exercise. Not only that but there was a dramatic increase in new neuron growth in the hippocampus.
Villeda said:
“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. 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.
Through this protein, the liver is responding to physical activity and telling the old brain to get young. This is a remarkable example of liver-to-brain communication that, to the best of our knowledge, no one knew existed. 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.”
One big mystery remains, however. GPLD1 doesn’t pass through the blood-brain barrier – a protective element that keeps toxic or infectious agents traveling in the blood out of the brain. Therefore, the neurological effects the protein exerts on the brain must be via activating other pathways – such as by reducing inflammation and blood coagulation throughout the body. The lab is currently working on pinpointing precisely how GPLD1 interacts with other biochemical signaling systems to produce its brain-boosting effects.
