Physical Activity Modifies the Metabolic Profile of CD4 ⁺ and CD8 ⁺ T‐Cell Subtypes at Rest and Upon Activation in Older Adults

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T‐cell metabolism is a key regulator of immune function. Metabolic dysfunction in T cells from young mice results in an aged phenotype, accelerating immunosenescence. Physical activity (PA) maintains T‐cell function and delays immunosenescence in older adults, but the underlying mechanisms are poorly understood. We investigated the effects of PA on the metabolic and functional profiles at a single‐cell resolution of resting and stimulated T cells from young adults ( N = 9, 23 ± 3 years) and physically active older adults clustered between higher PA (HPA, N = 9, 75.5 ± 4.7 years) or lower PA levels (LPA, N = 10, 76.4 ± 2.1 years). Compared to young donors, HPA older adults had higher mitochondrial dependence (MD) and lower glucose dependence (GD) in unstimulated naïve, central memory (CM) and effector memory (EM) CD4 + and EM CD8 + T cells, while LPA older adults had higher overall protein synthesis in naïve and EM CD4 + and CD8 + . In response to PMA and Ionomycin stimulation, there was a similar increase in GD and a reduction in MD across groups for most T‐cell subsets. Although LPA and HPA underwent a higher increase in protein synthesis upon activation compared to the young subjects, HPA did not exhibit the excessive increase in the percentage of IL‐6 + T cells observed in the LPA group compared to young subjects. Taken together, our data provide evidence of a higher energy demand, impaired metabolic flexibility, and hyperinflammatory responses in aged T cells, and PA reduces metabolic demand in these cells, potentially through increased MD and improved metabolic flexibility.