The results of research in mice suggest that a little-studied liver enzyme called Gpld1 may be responsible for the well-known benefits of exercise on the aging brain, and that its regenerative effects may be transferrable directly from one animal to another. The studies, headed by scientists at the University of California, San Francisco (UCSF), Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, showed that when aged, sedentary mice received plasma transfusions from regularly exercising mice, they gained the same beneficial neurological effects without having to hit the running wheel themselves.
The findings could feasibly lead to new therapies that confer the neuroprotective effects of physical activity on people who can’t exercise due to physical limitations. “If there were a drug that produced the same brain benefits as exercise, everyone would be taking it,” said Saul Villeda, PhD, a UCSF assistant professor in the departments of anatomy and of physical therapy and rehabilitation science. “Now our study suggests that at least some of these benefits might one day be available in pill form.” Research lead Villeda is senior author of the team’s published paper in Science, which is titled, “Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain.”
Exercise is one of the best-studied and most powerful ways of protecting the brain from age-related cognitive decline. Exercise has been shown to improve cognition in individuals at risk of neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia, even for individuals who carry rare gene variants that inevitably lead to dementia.
“In the context of dementia-related neurodegenerative diseases, exercise is correlated with reduced risk for cognitive decline in the elderly, improves cognition in populations at risk for AD, and is associated with better neurobehavioral outcomes even in autosomal dominant AD,” the scientists wrote. However, not everyone is able to exercise regularly as they get older, perhaps due to physical limitations or other disabilities. “Despite the evident benefit of exercise, its application is hindered in the elderly, as physical frailty or poor health can decrease a person’s ability or willingness to exercise,” the authors continued. Researchers have long searched for strategies that could confer some of the same neurological benefits of exercise to people with low physical activity levels.
Villeda’s lab has previously shown that biological factors present in the blood of young mice can rejuvenate the aging mouse brain, and conversely, factors in the blood of older mice can bring on premature age-related cognitive decline in young mice. “… transfer of blood from young animals, either by heterochronic parabiosis (in which young and old circulatory systems are joined) or by administration of young blood plasma, improves regenerative capacity and cognition in aged mice,” the authors noted.
These previous results led Alana Horowitz, a graduate student in the Villeda lab, and postdoctoral researcher Xuelai Fan, PhD, to look for blood-borne factors that might also confer the benefits of exercise, which is known to rejuvenate the aging brain in a similar fashion to that seen in the lab’s “young blood” experiments. “Given parallels between the effects of exercise and young blood, we tested whether exercise-induced circulating blood factors could confer the beneficial effects of exercise on regenerative and cognitive function in the aged brain,” the scientists continued.
To do this Horowitz and Fan took blood from aged mice who had exercised regularly for seven weeks and administered it to sedentary aged mice. They found that four weeks of this treatment produced dramatic improvements in learning and memory in the older mice, similar to that seen in the mice who had exercised regularly. When they examined the animals’ brains, they found evidence of enhanced production of new neurons in the hippocampus, a well-documented proxy for the rejuvenating benefits of exercise.
To discover what specific biological factors in the blood might be behind these effects, Horowitz, Fan, and colleagues measured the amounts of different soluble proteins in the blood of active versus sedentary mice. They identified 30 candidate proteins, 19 of which, to their surprise, were predominantly derived from the liver and many of which had previously been linked to functions in controlling the body’s metabolism. Two of these proteins, Gpld1 and Pon1m stood out as particularly important for metabolic processes, and the researchers chose to study Gpld1 in more detail because few previous studies had investigated its function. “We figured that if the protein had already been investigated thoroughly, someone would have stumbled upon this effect,” Villeda said. “I like to say—if you’re going to take a risk by exploring something new, you might as well go big!”
The team found that Gpld1 increased in the blood circulation of mice following exercise, and that levels of the protein correlated closely with improvements in the animals’ cognitive performance. Analysis of human data collected as part of the UCSF Memory and Aging Center’s Hillblom Aging Network study also found elevated blood levels in healthy, active elderly adults, compared with levels in less active elders. “These data identify Gpld1 as an exercise-induced circulating blood factor in aged mice and humans with potential relevance to cognitive function in mice,” they wrote.
To test whether Gpld1 itself could drive the observed benefits of exercise, the researchers then engineered mice to overexpress Gpld1 in the liver, and evaluated the animals’ performance in multiple tests that measure various aspects of cognition and memory. To their amazement, three weeks of the treatment produced effects similar to six weeks of regular exercise, and also generated dramatic increases in new neuron growth in the hippocampus. “Together, these data indicate that selectively increasing liver-derived systemic concentrations of Gpld1 is sufficient to improve adult neurogenesis and cognitive function in the aged hippocampus,” the scientists stated.
“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,” Villeda noted. “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.” Further laboratory experiments have shown that Gpld1 produced by the liver does not pass through the blood-brain barrier. Instead, the protein appears to exert its effects on the brain via pathways that reduce inflammation and blood coagulation throughout the body. Both blood coagulation and inflammation are known to be elevated with age and have been linked to dementia and age-related cognitive decline.
“This is a remarkable example of liver-to-brain communication that, to the best of our knowledge, no one knew existed,” Villeda continued. “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 findings could have more broad-ranging implications, the authors suggested. “Cumulatively, our data show that beneficial effects of exercise on the aged brain can be transferred through administration of blood components … Given that transfer of young blood simultaneously elicits central and peripheral enhancements in regenerative capacity in aged mice, our data raise the possibility that the beneficial effects of exercise could be promoted broadly across tissues through circulating blood factors.”
The Villeda lab is now working to better understand precisely how Gpld1 interacts with other biochemical signaling systems to produce its brain-boosting effects. The hope is to identify specific targets for therapeutics that could one day confer many of the protective benefits of exercise for the aging brain.