We know that regular exercise is good for us. It strengthens the heart, helps maintain a healthy weight, lifts mood, and reduces the risk of dozens of chronic diseases. But a new study published in Scientific Reports adds a remarkable dimension to that picture: long-term endurance training doesn’t just keep older adults physically fitter, it fundamentally transforms the behavior, resilience, and energy metabolism of their immune cells.
The cells in question are natural killer (NK) cells, which are among the immune system’s most important first responders. Understanding how exercise affects them offers a compelling biological explanation for why physically active older adults seem to age better and suggests that keeping up with cardio into your 60s and 70s might genuinely help keep your immune system younger.
What are natural killer cells, and why do they matter?
Natural killer cells are a type of white blood cell that patrols your body looking for threats, particularly virus-infected cells and cancer cells. Unlike other immune cells that need to learn to recognize specific threats, NK cells can identify and destroy abnormal cells quickly, even without prior exposure. They are, as the name suggests, fast-acting killers.
With age, NK cells tend to become less effective. They accumulate markers of “senescence, ” a kind of cellular old age in which they’re still present but no longer functioning properly. They also become more susceptible to exhaustion, more prone to inflammation, and less metabolically flexible. This age-related decline in immune function, sometimes called immunosenescence, is one reason older adults are more vulnerable to infections, respond less well to vaccines, and face higher cancer risk.
The central question this study asked was simple but important: Does a lifetime of endurance training protect NK cells from this decline? The answer, based on detailed laboratory analysis, appears to be yes.
What the researchers did
Scientists recruited older men in their early to mid-sixties who were long-term endurance-trained athletes (with a VO₂max of around 43 mL/kg/min, indicating excellent cardiovascular fitness) and four untrained men of the same age (with a VO₂max of around 25 mL/kg/min, which is average for sedentary older adults). Blood was drawn from all participants, and NK cells were isolated and expanded in the laboratory.
The team then subjected these cells to a range of challenges, including the beta-blocker propranolol (which blocks adrenergic or adrenaline-related signaling) and rapamycin (a drug that inhibits the mTOR pathway, a key cellular energy-sensing and growth-regulating system). They also exposed cells to an inflammatory stimulus to mimic the immune challenge the body might encounter during infection. The goal was to determine how NK cells from trained and untrained individuals responded to these stresses at the molecular level.
The trained immune cells were fundamentally different.
Even before any drugs or stressors were applied, striking differences were evident. Trained participants had lower levels of inflammatory markers in their blood, a lower overall neutrophil-to-lymphocyte ratio, and a lower systemic immune-inflammation index, all of which are indicators of chronic low-grade inflammation. Their NK cells showed lower KLRG1 levels, a marker of cellular senescence, suggesting that their immune cells were biologically younger than those of the untrained men, despite being the same chronological age.
38% Lymphocyte percentage in the trained group vs. 30% in the untrained group, indicating a healthier immune balance
Higher Effector NK cell frequency in the trained group at baseline and under stress
Lower Levels of the Senescence marker KLRG1 in trained NK cells indicate less cellular “old age.”
2× Greater spare respiratory capacity in NK cells from trained individuals
When the going got tough, trained NK cells held up better.
When propranolol was administered at moderate doses, it blunted NK cell inflammatory responses, reducing key activation markers, including CD57 and CD107a (a marker of degranulation, the process by which NK cells deliver their cytotoxic payload), in both groups. But the trained group’s NK cells maintained these functions at higher levels throughout, suggesting greater resilience to adrenergic disruption.
What was particularly interesting was the pattern of “regulatory” immune markers. Trained NK cells showed higher expression of molecules like LAG-3 and PD-1, which are sometimes called “checkpoint” molecules. These markers put the brakes on immune activity to prevent excessive inflammation and collateral damage. The fact that trained individuals showed more, not less, activation of these regulators suggests their immune cells have achieved a more sophisticated balance: capable of fighting hard when needed, but also of switching off when appropriate.
Untrained NK cells
- Higher senescence (KLRG1)
- Lower effector cell frequency
- Less degranulation (CD107a)
- More susceptible to drug-induced decline
- Less metabolic flexibility
Trained NK cells
- Lower senescence markers
- Higher effector cell frequency
- Better preserved cytotoxicity
- More resistant to stress
- Superior mitochondrial function
The rapamycin experiments revealed an important aspect of flexibility.
When NK cells were exposed to rapamycin, a drug that suppresses the mTOR pathway, the differences between trained and untrained NK cells became even clearer. At low doses, trained NK cells preserved or even enhanced their killing function, maintaining cytotoxicity and degranulation capacity that untrained cells had lost. At higher doses that pushed cells toward exhaustion, trained NK cells showed higher expression of maturation markers while simultaneously keeping exhaustion-related markers such as LAG-3 and TIM-3 in check, a pattern the researchers describe as “resistance to exhaustion.”
This metabolic flexibility matters because the mTOR pathway is central to how immune cells decide whether to activate, proliferate, or conserve energy. An immune cell that can sense its environment, adapt its metabolism appropriately, and respond effectively under adverse conditions is better functioning. The trained NK cells showed all the hallmarks of this adaptability.
The mitochondria are the key.
Perhaps the most striking findings came from the metabolic analysis. Using a Seahorse analyzer, a tool that measures how cells consume oxygen and produce energy, the researchers found that NK cells from trained individuals had significantly higher basal and maximal oxygen consumption, as well as greater spare respiratory capacity. All of these measures point to mitochondria that are more numerous, more efficient, or both.
The OCR/ECAR ratio, which compares oxygen-based (aerobic) energy production to glycolysis (the less efficient, sugar-burning backup system), was significantly higher in the trained group. This means that trained NK cells preferentially use mitochondrial energy rather than glycolysis. Aerobic energy production is more efficient, more sustainable, and better suited to the sustained activation an NK cell needs to mount an effective immune response.
There was also no difference in “proton leak” between the groups, a sign of mitochondrial damage. This rules out the possibility that the trained cells were simply burning more energy because their mitochondria were dysfunctional. They were burning more energy because they were more capable.
Why does exercise do this?
The study’s authors offer a compelling mechanistic explanation rooted in what happens during each bout of exercise. When you exercise, your body releases adrenaline, which mobilizes NK cells from storage in the spleen and lymph nodes into the bloodstream. NK cell counts can rise up to fivefold during exercise. Exercise also triggers the release of IL-6 and IL-15, signaling molecules that activate NK cells and stimulate the mTOR pathway, which in turn drives metabolic reprogramming and enhances effector function.
Each exercise session trains the immune system, not just the muscles. Over years and decades, this repeated cycle of mobilization, activation, recovery, and adaptation appears to produce NK cells that are measurably more capable with better mitochondria, better functional resilience, and less age-related senescence.
Important caveats and limitations
The study is a pilot with a small sample size (9 men total), and NK cells were analyzed after in vitro expansion rather than directly from fresh blood, which can influence some measurements. The participants were all male, white, and in their early to mid-sixties, so the findings cannot be generalized immediately to women, other age groups, or more diverse populations. Larger, controlled trials are needed to confirm and extend these findings.
It’s also worth noting that the study compares people who have been active for many years with those who have not, so it can’t establish whether starting exercise later in life would produce the same benefits. The immune adaptations observed here may reflect decades of cumulative training rather than months.
The bottom line
This research adds to a growing body of evidence that the immune system is trainable, much like muscles and the cardiovascular system. Endurance exercise over a lifetime appears to produce NK cells that are biologically younger, more metabolically powerful, better at killing threats, and more resistant to the kinds of stress, inflammatory, pharmacological, and energetic challenges that immune cells encounter in an aging body.
We are still learning how to translate these findings into specific exercise prescriptions, and the sample size here warrants caution when drawing strong conclusions. But the direction of evidence is consistent and compelling: regular aerobic exercise, sustained over years, may be one of the most effective tools we have for keeping the immune system functional as we age. Not just keeping it going but keeping it young.
Reference
Minuzzi LG, Batatinha H, Weyh C, et al. Natural killer cells from endurance-trained older adults show improved functional and metabolic responses to adrenergic blockade and mTOR inhibition. Scientific Reports. 2025;15:25380. https://doi.org/10.1038/s41598-025-06057-y