Widely available supplement may explain brain boost from exercise

2022-02-03

A good workout doesn’t just boost your mood—it also boosts the brain’s ability to create new neurons. But exactly how this happens has puzzled researchers for years. “It’s been a bit of a black box,” says Tara Walker, a neuroscientist at the University of Queensland’s Brain Institute.

Now, Walker and her colleagues think they have found a key: the chemical element selenium. During exercise, mice produce a protein containing selenium that helps their brains grow new neurons, the team reports today. Scientists may also be able to harness the element to help reverse cognitive decline due to old age and brain injury, the authors say.

It’s a “fantastic” study, says Bárbara Cardoso, a nutritional biochemist at Monash University’s Victorian Heart Institute. Her own research has shown selenium—which is found in Brazil nuts, grains, and some legumes—improves verbal fluency and the ability to copy drawings correctly in older adults. “We could start thinking about selenium as a strategy” to treat or prevent cognitive decline in those who cannot exercise or are more vulnerable to selenium deficiency, she says, such as older adults, and stroke and Alzheimer’s disease patients.

In 1999, researchers reported that running stimulates the brain to make new neurons in the hippocampus, a region involved in learning and memory. But which molecules were released into the bloodstream to spark this “neurogenesis” remained unclear.

So 7 years ago, Walker and her colleagues screened the blood plasma of mice that had exercised on a running wheel in their cages for 4 days, versus mice that had no wheel. The team identified 38 proteins whose levels increased after the workout.

One in particular caught Walker’s eye: selenoprotein P (SEPP1). This protein, which transports selenium to the brain and has antioxidant properties, more than doubled after the rodents worked out.

In the new study, Walker’s team, which was not funded by the supplement industry, added either of two forms of selenium—sodium selenite (found as a salt in water and soil) or selenomethionine (found as an amino acid in the diet)—to a dish filled with cells that give rise to new neurons. In just 14 days, the number of these “neural precursor cells” doubled. When the researchers injected sodium selenite directly into the mice’s brains for 7 days, the number of neural precursor cells in the hippocampus tripled, they report in Cell Metabolism.

“I’ve been working on neurogenesis for almost 20 years … and we’ve never seen anything like that before,” Walker says.

Mice genetically engineered to lack SEPP1 or its receptor got no boost in neural precursor cells with exercise, the team found, confirming SEPP1 was key to making the new neurons.

“It’s the first time a substance that is usually in the diet has been found to have such a relevant and clear effect in neurogenesis,” says Juan Encinas, a neurobiologist at the Achucarro Basque Center for Neuroscience. But he says other blood proteins boosted by exercise may also be at play.

To find out whether selenium can help the aging brain, Walker’s team added selenomethionine to the drinking water of 18-month-old mice (the equivalent of 60-year-old humans). After nearly 1 month, the number of new neurons in the rodents’ hippocampi had doubled.

The selenium-treated mice also performed better than controls in two memory tasks that rely on this brain region. In the first one, the treated mice learned to avoid a place where they got a mild electric shock better than controls. In the second, the team placed the mice in a brightly lit table with 32 holes, one of which allowed the animals to escape to a dark chamber. (Mice instinctively avoid bright, open spaces.) Using markings on the table as cues, the treated mice learned to escape about twice as fast as controls.

Finally, the researchers investigated whether selenium could help reverse the cognitive deficits that result from brain injury. They injected a molecule into the mice’s hippocampus to cause a strokelike lesion that destroys neurons and hurts memory. The lesioned but treated mice performed just as well as normal mice on a suite of memory tasks. The untreated lesioned mice, on the other hand, failed to recognize objects as new, and they had a hard time remembering locations where they had received a shock the day before.

The recovery effects seemed dependent on the neurogenesis boost: In a mouse model where the scientists could “delete” newly formed neurons, the beneficial effects of selenium disappeared.

The new results are “another piece of the puzzle” of how exercise impacts neurogenesis and cognition, says Sandrine Thuret, a neuroscientist at King’s College London who was not involved with the work. She notes that a recent study showed clusterin, a molecule that also activates SEPP1’s receptor—LRP8—is also elevated in blood after physical activity in mice and humans, and boosts memory. “That makes this [new] paper even more exciting.”

Selenium is a cheap and widely available supplement. But Cardoso cautions that the chemical is toxic in high doses, and people who have normal selenium levels are less likely to benefit from supplementation. Still, she says, these preliminary results open avenues for testing selenium compounds to treat stroke patients. “I’m keen to see future studies in humans to see if they find the same thing.”

Science, 3 February 2022
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