How does exercise keep your brain young?

Researchers are still sorting out what it is about physical activity that seems to lower the risk of dementia later in life. Even more uncertain is whether the effects of exercise can alter the course of diseases that cause dementia—chief among them, Alzheimer’s disease—once they’ve already taken root. A study published in Science offers some new clues. In mice that mimic a severe, genetic form of Alzheimer’s disease, a combination of treatments that prompt the growth of new brain cells and protect them from damage can mimic the beneficial effects of exercise in preventing memory decline. So, could we someday bottle the effects of exercise to treat Alzheimer’s? And if so, what exactly would we need to bottle? Here’s a rundown of what we know, and what’s still controversial.

What’s the link between exercise and brain aging?

Many large studies suggest staying active and fit throughout life lowers the risk of memory problems later on. For example, a recent project tracked more than 1000 Swedish women over 4 decades and found that for those judged to have “high” cardiovascular fitness on entering the study—as measured by the maximum workload they could handle on a stationary cycle machine before exhaustion—the onset of dementia was delayed, on average, by 9.5 years compared to those with “medium” fitness. But such studies can’t rule out all other confounding factors that might influence dementia risk—from genes to other aspects of a healthy lifestyle common in regular exercisers. And they don’t explain what exercise actually does to the brain.

Does exercise fight the effects of Alzheimer’s disease once someone has it?

Evidence for this is stronger in rodents than in humans. In one mouse model of Alzheimer’s, access to an “enriched” environment that included a running wheel reduced deposits of sticky brain plaques, made of the protein fragment ?-amyloid, thought to drive progression of the disease. And the study published on a different Alzheimer’s model found that diseased mice with access to a running wheel outperformed sedentary diseased mice on a series of memory tests—for example, a maze where mice had to learn and remember which areas contained a sunflower seed snack. But various studies that randomise elderly people with dementia—including those with Alzheimer’s dementia—to exercise or control groups have been contradictory: Only some have shown that exercise improves cognitive function. That raises questions about how much good exercise can do in the human brain once a neurodegenerative disease such as Alzheimer’s has already taken root.

What is it about exercise that might protect the brain?

A key benefit of exercise could be that it helps the brain make new neurons. In the hippocampus, a brain structure key to learning and memory, there are cells known as neural progenitors that can give rise to new brain cells. Recently, there’s been debate about whether humans make new neurons throughout life. But studies in rodents have shown that neurogenesis in adulthood helps keep certain cognitive skills sharp, including the ability to learn about the physical environment and remember how to navigate it. And some rodent studies have linked regular exercise to neurogenesis. For example, having mice run on a wheel seems to double the number of newborn hippocampal neurons that survive in their brains. In the new Science paper, the exercising mice that showed brain benefits in the memory tests also had markers of neurogenesis.

So, can neurogenesis in the absence of exercise help the brain?

The new study suggests neurogenesis alone might not be enough. The researchers gave the diseased mice a drug that protects neural progenitor cells in the hippocampus, plus a gene therapy that encourages these cells to proliferate. The mice made new brain cells, but that didn’t seem to help their memory. Only when they got an additional treatment—another gene to boost levels of a protein called brain-derived neurotrophic factor (BDNF)—did they outperform untreated control mice on the memory tests. BDNF, which encourages neural growth, also appeared to reduce inflammation in the diseased brain. The results suggest making new neurons early in life may protect memory later on, but that a brain already afflicted with Alzheimer’s is “a hostile playing environment,” says Rudolph Tanzi, a neurogeneticist at Harvard Medical School in Boston and co-author on the study. BDNF “cleans up the neighbourhood … so that the new neurons that are born can live.”

Could we treat Alzheimer’s in people with a similar strategy?

That approach has gotten less attention from drug companies than efforts to reduce amyloid plaques that surround and kill neurons. But some researchers think it deserves a closer look. There are still important caveats to such an approach, says Mark Mattson, a neuroscientist at the National Institute on Aging in Baltimore, Maryland. For one thing, progenitor cells in the hippocampus make a type of neuron key to spatial learning and memory, but this isn’t the same type of neuron that appears to degenerate and die in the hippocampi of people with Alzheimer’s. And even if making these new cells protects certain brain functions, there are lots of other brain regions outside the hippocampus affected by Alzheimer’s. Still, the approach is worth further study, he adds. “So far, it’s been kind of tunnel vision in focusing on amyloid,” he says. “The more approaches, in my mind, the better.”

Science, 6 September 2018 ;