Physical exercise can ‘train’ the immune system

In an article published in the journal Scientific Reports, an international team of researchers describes how the defense cells of older adults with a history of endurance training are more effective against inflammation.

By Maria Fernanda Ziegler  |  Agência FAPESP – In addition to strengthening the muscles, lungs, and heart, regular physical exercise also strengthens the immune system. This finding came from a study of older adults with a history of endurance training, which involves prolonged physical activity such as long-distance running, cycling, swimming, rowing, and walking. An international team of researchers analyzed the defense cells of these individuals and found that “natural killer” cells, which patrol the body against viruses and diseased cells, were more adaptable, less inflammatory, and metabolically more efficient.

The research, which was supported by FAPESP and published in the journal Scientific Reports, investigated natural killer (NK) cells. NK cells are a type of white blood cell (lymphocyte) that can destroy infected and diseased cells, including cancer cells. They are at the forefront of the immune system because they detect and fight viruses and other pathogens. The researchers analyzed the cells of nine individuals with an average age of 64, divided into two groups: untrained and trained in endurance exercise.

“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.

The study is the result of Minuzzi’s postdoctoral research and is part of a larger research project led by São Paulo State University (UNESP) researchers in Brazil and supported by FAPESP.

According to the study’s findings, regular endurance training modulates the inflammatory response 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 points out that the immune system can be influenced by several factors, such as sleep quality, diet, and vaccination, as well as stress, a sedentary lifestyle, and the use of immunosuppressive drugs, which reduce the activity of defense cells. “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

In addition to analyzing the phenotype, function, and mitochondrial metabolism of NK cells in response to inflammatory stimuli, the researchers exposed expanded NK cells from trained and untrained older adults to different pharmacological blockers, such as propranolol and rapamycin.

“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 drug that blocks the adrenergic pathway, the neural and endocrine circuit that releases neurotransmitters such as adrenaline and noradrenaline. It was used to isolate the role of this activation/mobilization pathway in NK cells. Rapamycin, on the other hand, inhibits the mTORC1 signaling pathway, which is related to the control of cell growth and proliferation. In the study, rapamycin altered the phenotype of NK cells and decreased their expansion in vitro at high doses (100 ng/mL).

“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.

The article “Natural killer cells from endurance-trained older adults show improved functional and metabolic responses to adrenergic blockade and mTOR inhibition” can be read at www.nature.com/articles/s41598-025-06057-y.

The article “Differential inflammatory responses to acute exercise and ex vivo immune challenge in young and master athletes” can be read at www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1601405/full.

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