Understanding how physical exercise generates molecules that directly benefit the aging brain began 25 years ago with the publication of a pair of papers by Henriette van Praag, a postdoc at the Salk Institute for Biological Studies in California. Those papers examined the brains of adult mice that spent time on a treadmill versus those that didn’t. The data showed for the first time in mammals that exercise induced the birth of new neurons, or neurogenesis, in the brain of adult mice. Those changes were accompanied by improvements in spatial memory and learning

How does physical exercise benefit the brain?

Van Praag, now an associate professor at Florida Atlantic University’s Stiles-Nicholson Brain Institute, says the discovery was a bit of a fluke. In a previous study, the researchers had seen evidence that some component of an enriched environment — where mice had access to various stimuli, such as places to hide or toys — generated new neurons. So he set out to find the critical factor. “Running was actually one of the controls in my study,” he laughs.

“Van Praag’s work is critical in linking running to neurogenesis and improved brain function, and is important not only to the neurobiology community, but also in paving the way for exercise and muscle researchers to study the interaction between training, muscles and the brain”, Handschin elaborates.

In 2002, Bruce Spiegelman, a cell biologist at the Dana-Farber Cancer Institute and Harvard Medical School, was studying a protein called PCG1-alpha that regulates the body’s metabolism by turning genes on and off. He found that increasing the amount of this protein in mice made their muscles stronger, redder, and had more blood vessels; it was as if the animals had been training hard in the gym without ever setting foot on a treadmill.

Around this time, scientists began to realize that moving muscles produced hormones and other molecules (called myokines) that were released into the bloodstream and provided benefits to distant organs. So the discovery of PGC1-alpha led Spiegelman to ask the following questions: if that protein makes the muscle look like it’s been exercised, then “maybe it also prompts the muscle to secrete things that are produced during exercise”. It could then use protein to help you find the molecules responsible for the valuable changes in metabolism and immune function that exercise promotes.

The search culminated in 2012 when Spiegelman and colleagues discovered irisin, a myokine released by exercising muscle. They discovered that irisin transforms white fat into beige fat. Since beige fat burns calories (unlike white fat, which stores them), Spiegelman thought that Irisin May Hold Key to How Exercise Fights Obesity and Diabetes.

More pieces of the puzzle fell into place the following year, when Christiane Wrann, then a postdoctoral researcher working with Spiegelman, showed that the muscle “talked” to the brain during exercise. When muscle cells produce irisin, it increases levels of another protein called brain-derived neurotrophic factor (BDNF) in the hippocampus, one of the first brain regions to change in neurodegenerative diseases. There, BDNF supports the health and growth of synapses and neurons, helping them mature and enhancing synaptic plasticity.

Last year, Wrann, now a neuroscientist at Massachusetts General Hospital and Harvard Medical School, tested irisin’s role in exercise and cognitive function. His team compared mice genetically engineered to lack irisin with control mice that could still produce the molecule. After exercise, control mice performed better on a task that relies on spatial memory and learning. Irisin-deficient mice did not show this same improvement, suggesting that irisin is what promotes these cognitive abilities.

When Wrann’s team examined the brains of the mice, they found that both groups of mice produced neurons in response to exercise, but the new neurons from the irisin-deficient mice were abnormal, affecting their ability to form connections. When the gene that produces irisin was added back to the brains of mice that lacked the protein, they were better able to distinguish between two similar patterns, a skill that humans find useful for locating a car in a parking lot, for example. .

physical Exercise and neurodegenerative disease
Wrann’s team also discovered that irisin appeared to play a role in protecting against neurodegeneration. The researchers bred mice that lacked irisin and had Alzheimer’s-like symptoms. These doubly affected mice experienced symptoms more quickly physical than mice with Alzheimer’s disease alone, and showed cognitive improvements when irisin production was restored.

Wrann suspects that one of the ways irisin helps is because it dampens inflammation caused by the brain’s immune system malfunctioning. This system is mainly made up of cells called microglia and astrocytes, which are normally responsible for reducing brain infection and cleaning up debris after injury. However, as mammals age, these cells can remain active after the acute danger has passed and interfere with neuronal function, first destroying the connections between neurons and then killing the cells themselves.

This activity causes chronic brain inflammation that has been linked to many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. But the irisin-treated lab mice had less inflammation in their hippocampi, and their physical microglia and astrocytes were reduced, suggesting that irisin helped curb the unhinged immune response.

Are these results applicable to humans? Perhaps, based on preliminary work done in Wrann’s lab and by other teams. Irisin has an identical physical molecular structure in mice and humans physical , he says, suggesting that it serves similar functions in both species.

The results have interesting implications for the neurological benefits of physical exercise, as studies show elevated levels of irisin in people’s blood after a workout. On the other hand, postmortem analyzes of the brains of Alzheimer’s patients reveal a 70 percent reduction in the precursor molecule irisin compared to age-matched controls, suggesting that irisin may be neuroprotective.

From a therapeutic point of view, “irisin certainly shows promise,” says Handschin, “especially given the data on its effect on the brain.” But he cautions that irisin has not yet passed the tests that are being done for drug development. “Whether this works in human patients remains to be seen.”

Depression, anxiety and mood disorders
Handschin is interested in the interactions between muscles, exercise, mood, and motivation. In unpublished work, his group examined the effect that certain molecules produced by exercised muscle have on the willingness of mice to run on a treadmill. Animals that lack these factors are able to run but choose not to, an atypical behavior for mice, which typically run almost 10 kilometers a day.

“There must be something in the muscle that sends signals to the brain and somehow reduces this urge to run for running,” Handschin infers.

The promise of this field for the treatment of mood disorders (particularly major depression) also interests Spiegelman, who calls it one of medicine’s great unmet needs. “Major depression is the leading cause of suicide, and it’s especially common in young people,” he says. He and his colleagues are currently evaluating the impact of irisin on anxiety-induced depression in experimental mouse models.

Y the brain’s conversation during exercise is not limited to the muscles. Its interaction with molecules (mainly proteins) secreted by the liver, fat and bone remodels the brain to sharpen our thinking, avoid depression, etc.

With viable drug candidates like irisin and others on the horizon, Rodriguez, of the University of Alabama, believes “we are on the cusp of a great era of discovery that is finally going to translate to the clinic.”

But the explosion of research on muscle-brain crosstalk offers both rewards and challenges, says Karina Alviña, associate professor of neuroscience at the University of Florida School of Medicine. The most prominent molecules affect multiple systems in multiple ways, which means their potential reach is huge, but untangling their various dependencies can be a headachephysical . Designing a drug that doesn’t have unintended consequences will be a big challenge, she says.

Still, Alviña finds a measure of hope in the research she and others are conducting, as it suggests that “environment and our lifestyle choices can have a big effect on how we age,” Alviña says. . That means it’s up to us to age healthier and maintain a higher quality of life for longer.

“So if I had to say one thing, it would be: stay active, even if it’s just walking a few minutes a day. If you can, do it.”

Source: codelist