It's well-known that regular exercise comes with health benefits, but exactly how those benefits manifest at the cellular level isn't clear. Now, researchers have identified a series of changes in metabolism and the immune system that differentiate regular exercisers from people with sedentary lifestyles.

The findings, published Sept. 18 in the journal Science Advances, point to potential pathways for managing chronic diseases, such as diabetes, heart disease and cancer, the scientists say.

The team of researchers analyzed data from the Chinese Immune Multi-omics Atlas (CIMA), which includes data from 400 adults who gave blood samples and answered an in-depth questionnaire about their lifestyles.

To capture the biggest possible effects of exercise, the team included only data from participants who did the most or least exercise. One group worked out at least three times a week, racking up more than 150 minutes of moderate exercise or 75 minutes of high-intensity exercise in that timeframe. The sedentary group said they did not work out at all.

The researchers then analyzed their volunteers' blood samples for physiological markers, such as blood sugar and fat levels. They found that the participants who exercised more had signs of boosted sugar and fat metabolism, stronger muscle metabolism, and higher levels of antioxidant molecules, which combat cell-damaging processes.

Many of these systems and their links to exercise were already known, said Dr. Michael Siebers, a researcher at the University of Duisburg-Essen who wasn't involved with the study. The study's real step forward was its subsequent cellular analysis, he said.

"It's a really good paper, which is showing, for the first time, what is really happening when you're doing sports on the intercellular level," he said.

How exercise changes the immune system

This analysis used a multiomics approach, meaning it combined data from multiple biological sources. These included metabolites (the byproducts of metabolism), fats, proteins and RNA (a cousin of DNA that helps build proteins).

The team also studied a feature of DNA called chromatin accessibility. Our genes are wound onto DNA helices, creating structures that resemble tightly packaged spools of film. Higher chromatin accessibility means that the spool is less tightly wound, so the individual images on that film can be seen more easily. Ultimately, those genes are more easily switched on. In cells, this mechanism is essential for enabling genes to be transcribed and translated into the proteins that help the body function properly.

Together, these analyses enabled the research team to closely examine how cells in people who exercise regularly functioned differently from people with sedentary lifestyles. This deep dive showed multiple changes in immune cells.

The activity of exercisers' immune foot soldiers — including cytotoxic T cells and natural killer cells — was boosted compared with those of participants with sedentary lifestyles. Additionally, naive immune cells, which act as nonspecialized reservists that can be recruited to the immune infantry, had greater chromatin accessibility in genes needed to fight off threats. That meant they were more ready to enlist.

The team also noted changes in cells that are in charge of alerting the rest of the immune system to threats, called immune monocytes and B cells. In people who regularly exercised, these cells had increased expression of alarm-sounding genes.

The findings suggest that regular physical activity may make the immune system better prepared to fight potential threats, the researchers wrote in their study. It's already known that not exercising is a risk factor for chronic health conditions, including type 2 diabetes, and that working out reduces these risks. The study gives "a molecular perspective on [exercise's] systemic health benefits," the researchers wrote.

That said, there were limitations to the study. Siebers pointed out that, beyond the number of minutes participants worked out, the study didn't record what type of exercise they did and had little information about the participants' physical makeup.

The researchers also couldn't show that the regular exercise caused the immune improvements. It's possible that the reduced activation in sedentary participants' immune systems made them less able to exercise.

Despite the limitations, these types of deep dives into the cellular basis of exercise are important for furthering our understanding of why working out feels good, Siebers said. "This is really deep stuff."