Physical fitness confers a great many benefits. Based on the broad evidence for reduced mortality and improved health, it is worth the effort required to maintain an above average level of fitness into later life. The research noted here is one of many studies to look at specific immunological differences between relatively fit and relatively unfit older individuals. It is well understood that greater fitness produces improved immune function, but the immune system is very complex and there is a great deal of room for further exploration of the fine details.
Aging is associated with immune dysfunction, but long-term endurance training may confer protective effects on immune cell function. This study investigates how natural killer (NK) cell phenotypes, functional markers, and metabolism differ between endurance-trained and untrained older adults. Ex vivo expanded NK cells from endurance-trained (63.6 ± 2.1 years) and untrained (64.3 ± 3.3 years) males were exposed to adrenergic blockade (propranolol; 0-200 ng/mL) or mTOR inhibition (rapamycin; 10-100 ng/mL), both with or without inflammatory stimulation induced by phorbol 12-myristate 13-acetate (PMA). Flow cytometry assessed NK subsets, activation (CD38, CD57, CD107a, NKG2D), senescence (KLRG1), and inhibitory markers (PD-1, LAG-3, TIM-3, NKG2A). Seahorse analysis measured mitochondrial metabolic parameters.
Trained participants displayed healthier immune profiles (lower neutrophil-to-lymphocyte ratio and Systemic Immune-Inflammation Index) and higher effector NK cells with lower cytotoxic subsets. Propranolol at 100 ng/mL blunted PMA-driven increases in CD57, CD107a, and NKG2D, while potentiating regulatory markers KLRG1, LAG-3, and PD-1 in the trained group, indicating stronger immunoregulation. With rapamycin, trained NK cells preserved NKG2D and CD107a at 10 ng/mL, maintaining cytotoxicity and degranulation. In contrast, at 100 ng/mL rapamycin plus PMA, trained NK cells shifted toward an effector phenotype with higher CD57 and CD107a, yet a blunted PMA-increased LAG-3 and TIM-3, suggesting resistance to exhaustion. PD-1 and KLRG1 remained elevated, reflecting balanced immune control.
Mitochondrial analysis revealed that trained NK cells exhibited higher basal and maximal oxygen consumption rate, greater spare respiratory capacity, and oxygen consumption rate to extracellular acidification rate ratio, reflecting superior metabolic fitness. These findings indicate that endurance-trained older adults have NK cells with greater functional adaptability, reduced senescence, and enhanced metabolism under inflammatory and pharmacological stress.
Link: https://doi.org/10.1038/s41598-025-06057-y
View the full article at FightAging
