Spermidine disrupts mitochondrial respiration and redox homeostasis in aged CD44+ CD49d− CD8+ T cells

Spermidine (SPD) is a polyamine metabolite with anti-aging and immunomodulatory properties. We previously reported that SPD enhances mitochondrial respiration in CD44- CD8+ naïve T cells through the upregulation of fatty acid oxidation (FAO). However, the effects of SPD on CD44+ CD8+ effector T cells remain unknown. We found that SPD suppressed mitochondrial oxygen consumption rate (OCR) in CD44+ CD8+ T cells from aged mice, in contrast to its effects on those from young mice. This FAO-dependent reduction in respiration was associated with mitochondrial oxidative stress and accompanied by reduced IFN-γ production and proliferative capacity. Notably, within the aged CD44+ CD8+ T cell compartment, senescence-like CD44+ CD49d- subset (CD49d- cells)-predominantly accumulated with age-exhibited a marked decrease in OCR following SPD treatment, whereas CD44+ CD49d+ CD8+ T cells (CD49d+ cells) were unaffected. In CD49d- cells, SPD treatment disrupted redox balance as evidenced by reduced intracellular reduced-thiol levels with unchanged mitochondrial reactive oxygen species (ROS) levels, suggesting consumption of antioxidant reserves. SPD also induced structural remodeling of mitochondria in CD49d- cells, characterized by a shift toward shorter, more fragmented mitochondria with wider cristae spacing than in CD49d+ cells. In summary, our findings reveal that SPD paradoxically compromises mitochondrial respiration in a specific subset of aged CD8+ T cells by perturbing fatty acid metabolism and redox homeostasis.