Regulation of T Cell Senescence in Health and Diseases

Aging is accompanied by a progressive decline in immune function, a process termed immunosenescence, which affects both innate and adaptive immune compartments. Among these, the adaptive immune system-and particularly T cells-undergoes the most profound functional and phenotypic alterations, critically impairing host defense against infections, cancer, and vaccination responses. The age-associated decline of adaptive immunity is shaped by the divergent senescence pathways of CD4⁺ helper and CD8⁺ cytotoxic T cells. While both lineages enter a state of cell-cycle arrest, their distinct immunological roles dictate fundamentally different molecular triggers, metabolic adaptations, and functional outcomes. This review synthesizes these subset-specific differences, highlighting how DNA damage-dependent mechanisms and DNA damage-independent processes drive distinct senescence phenotypes. Furthermore, we discuss how these differences contribute to immune system remodeling during aging and explore emerging therapeutic strategies targeting metabolic and signaling pathways to mitigate T cell senescence.