Exercise’s Power to Boost Brain May Be Gained with a Single Protein
Thu, April 22, 2021

Exercise’s Power to Boost Brain May Be Gained with a Single Protein


The mental benefits of exercise are just as profound as the benefits of physical health and well-being. An increasing amount of studies have highlighted how exercise can have a positive impact on depression and anxiety, relieve stress, help one sleep better, boost the overall mood, and also improve memory. A new study on mice by scientists from UC San Francisco has also found that the brain benefits of exercise may be gained with a liver protein called Gpld1.

Alana Horowitz from the Department of Anatomy and colleagues closely studied the GPLD1, an enzyme produced in response to exercise. It is a type of molecular scissors that cut other proteins outside of cells, releasing the proteins to perform other biological jobs. The team suspects that targeting these biological functions with a molecule that acts like Gpld1 may mimic the brain benefits of exercise.

Plasma concentrations of glycosylphosphatidylinositol (GPI)–specific phospholipase D1 (Gpld1) were found to increase after exercise and associate with enhanced cognitive function in aged mice, the authors said.

To come up with such findings, the team took blood from aged mice that exercised regularly for seven weeks. These blood samples were then administered into sedentary aged mice. The result shows that four weeks of the treatment produced dramatic improvements in memory and learning of older mice the same as what was observed in mice who exercised regularly. When the authors examined the mice’s brains, they found that there was an enhanced production of new neurons in the hippocampus, a brain structure that plays a major role in memory, emotion, motivation, and learning.

Horowitz and colleagues also measured the different soluble proteins in the blood of both active and sedentary mice. A total of 30 candidate proteins were identified, many of which have been previously associated with functions in controlling the metabolism and 19 of which were predominantly obtained from the liver. Two of the proteins, the Pon1 and Gpld1, emerge as important for the body’s metabolism processes. The researchers prefer to focus the Gpld1 protein because few studies had so far investigated on its function.

Saul A. Villeda, UCSF assistant professor in the departments of Anatomy and Physical Therapy and Rehabilitation Science, mentioned that their team figured that if the Gpld1 protein had been investigated thoroughly, they would have already discovered this effect. He said that if they are to take a risk by exploring something new, it would be better to go big and that is what they just did for their research.

They discovered that the Gpld1 is responsible for increasing the blood circulation of mice after they exercise. The Gpld1 levels likewise correlate with the improvements in the subjects’ cognitive performance. UCSF’s Hillblom Aging Network study also showed how there was an increase of Gpld1 protein in the blood of active and healthy elderly human adults compared to less active elders.



“Exercise in a bottle”

Villeda added that if there was a drug that could produce the same brain benefits of exercise, then everyone should be taking it. Their study now suggests that at least some of these mental benefits could one day be in the pill form. He told National Public Radio that their study result lets them know that the “exercise pill” is a viable thing to pursue. He even told his mom about it and she got excited, calling it “exercise in a bottle.”

Willard Freeman from the Oklahoma medical center’s Department of Veterans Affairs, who was not involved in the study, opined that the idea of an exercise pill is not yet around the corner. He would not rush things and make Gpld1 available to people. He said he is encouraged by the UCSF findings but cautions that no study has mentioned the potential downsides of experimenting with the enzyme. He added that in the meantime, one of the things within our power is to exercise. “There’s a lot more research to be done,” he said.

Villeda himself admitted that he did not expect they’d succeed in finding the molecule that could account for the brain benefits of exercise. “When I saw these data, I was completely floored,” he said. Before their findings, it seemed that exercise would cause many subtle and small effects that would only add up to a large benefit.

Liver-to-brain communication

Through the Gpld1 protein, the liver responds to the physical activity and it tells the old brain to get young. Villeda believes that it is a remarkable example of liver-to-brain communication that no one in the past knew existed. The team also discovered that the Gpld1 enzyme produced by the liver no longer passes through the blood-brain barrier (BBB), which is a highly selective semipermeable border of cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system. In short, the BBB protects the brain from infectious and toxic agents in the blood. The UCSF team said that Gpld1 seemed to exert its effects on the brain through pathways that reduce blood coagulation and inflammation through the body. Both blood coagulation and inflammation elevate have been associated with age-related cognitive decline and dementia and are also elevated as the person ages.

Scientific online publication Our World in Data shares that the global age-standardized prevalence of Alzheimer's disease and other dementias was at 604.86 per 100,000 people.



Prevalence of insufficient physical activity

According to 2016 data by the World Health Organization (WHO), 28% of adults aged 18 and above were insufficiently physically active. This means that they only engaged in less than 150 minutes or moderate or intense physical activity every week. Countries with the highest prevalence of insufficient physical activity among male adults based on age-standardized estimates include Kuwait  (61.3%), Saudi Arabia (44.9%), Brazil (40.4%), and Germany (40.2%).

On the other hand, Uganda is considered the world’s fittest country. Based on the WHO’s analysis of the fitness levels of people in 168 countries from 2001 to 2016, Uganda made it to the top. People in Uganda tend to like sports and make the effort to integrate movement into their daily chores and life. But being the country that exercises the most doesn’t always mean it is also the healthiest in the overall score. Bloomberg’s 2019 global health rankings show that Uganda did not even make it to the top 50 healthiest countries. This was after other factors were considered, such as environmental considerations, life expectancy, and obesity rates.

If the UCSF discovery does lead to an exercise pill, it would be most helpful to individuals who cannot exercise on their own because of old age or injury.