Exercise might be the key to a younger, sharper immune system

The research, funded by FAPESP and published in Scientific Reports, focused on natural killer (NK) cells, a type of white blood cell (lymphocyte) that targets infected or damaged cells, including cancer cells. As key players in the body's first line of defense, NK cells detect and neutralize invading pathogens. The team analyzed samples from nine participants with an average age of 64, dividing them into two groups: one untrained and the other composed of individuals who had engaged in endurance exercise for years.

"In a previous study, we found that obesity and a sedentary lifestyle can trigger a process of premature aging of defense cells. This made us want to investigate the other side of the story, that is, whether an older adult who has been practicing endurance exercises for more than 20 years may have a better-prepared immune system. And that's indeed what we found. In these individuals, NK cells functioned better in the face of an inflammatory challenge, in addition to using energy more efficiently. Therefore, it's as if exercise also trains the immune system," says Luciele Minuzzi, a visiting researcher at Justus Liebig University Giessen (JLU) in Germany.

Minuzzi's work forms part of her postdoctoral research and contributes to a broader project led by São Paulo State University (UNESP) in Brazil, also supported by FAPESP.

The findings indicate that consistent endurance training helps regulate inflammation over time. "When we compared the cells of trained older adults with those of non-athletes of the same age, we found that those with a history of endurance exercise had fewer inflammatory markers and more anti-inflammatory markers. This means that, compared to non-athletic older adults, they had much better control of inflammation," says Fábio Lira, a professor at the Faculty of Science and Technology (FCT-UNESP), Presidente Prudente campus, and project coordinator.

Lira notes that the immune system is affected by many lifestyle factors, including sleep quality, nutrition, vaccination, stress, inactivity, and certain medications that suppress immune activity. "Physical exercise is one of these factors that can benefit the immune system, and in this research project, we're investigating how it can modulate the immune response over time," he says.

Changes in the cell

The team also examined how NK cells functioned and metabolized energy in response to inflammation. They exposed these cells from both trained and untrained older adults to pharmacological agents such as propranolol and rapamycin to observe their effects.

"Trained older individuals demonstrate more efficient and adaptable immunity, with greater metabolic control and less propensity for cellular exhaustion. Regular physical exercise appears to positively modulate both adrenergic sensitivity and cellular energy sensors, promoting a more balanced and less inflammatory response to external stimuli," says Minuzzi.

Propranolol is a medication that blocks the adrenergic pathway -- a network of neural and hormonal signals that release neurotransmitters like adrenaline and noradrenaline -- and was used to study this pathway's role in NK cell activity. Rapamycin, by contrast, inhibits the mTORC1 signaling pathway, which governs cell growth and replication. In the experiment, high doses of rapamycin (100 ng/mL) altered NK cell characteristics and reduced their growth in laboratory conditions.

"In both cases, even with the blocking of signaling pathways, the NK cells of the trained older adults were able to maintain their immune function, while the cells of the untrained individuals showed cellular exhaustion or failure in the inflammatory response. This means that long-term endurance training is associated with protective 'immunometabolic' adaptations in NK cells in older adults. In other words, the cells become more mature and effective, less senescent, and metabolically better prepared to respond to inflammatory or pharmacological stressors," says the researcher.

Inflammatory response

In another study, the same group of researchers compared the immune response of young and master athletes before and after an acute exercise session. To do this, they analyzed whole blood and PBMC (the mononuclear fraction of blood formed by lymphocytes and monocytes, which includes NK cells) data from 12 master athletes (with an average age of 52 and more than 20 years of continuous training) and compared it with data from young athletes (with an average age of 22 and more than 4 years dedicated to training).

The results showed that the master athletes had a more controlled inflammatory response than the younger athletes. When their blood cells were stimulated with a pathogen (LPS), both groups produced more IL-6, a cytokine that signals inflammation. However, the increase was more pronounced in young people. "Another important inflammatory cytokine, TNF-α, was only increased in the younger group," says the researcher.

The young athletes showed a more intense inflammatory response, while the older athletes showed a more regulated and controlled profile. According to the researchers, this suggests that lifelong training can promote beneficial, balanced immune adaptation.

"Because they train regularly, their bodies are accustomed to dealing with inflammatory episodes, which requires more intense stimuli to generate significant long-term inflammatory responses. It's this type of 'training' that, over time, adapts the immune system, making it stronger," she explains.

Minuzzi points out that research on immune cells in athletes with a long training history has once again shown that decades of physical activity seem to "train" the regulation of inflammation. "The system doesn't stop responding, but it avoids exaggeration. This is particularly interesting for a greater understanding of healthy aging since disordered inflammatory responses are linked to several chronic diseases," she concludes.