Immunosenescence: Molecular Mechanisms, Diseases, and Therapeutic Innovations

Immunosenescence denotes progressive deterioration of immune system during physiological aging, initially recognized by the observation of heightened susceptibility to diverse pathologies in elder population. Beyond exhibiting canonical cellular senescence features, senescent immune cells manifest multidimensional dysfunction characterized by impaired secretory capacity and functional disorders. This process further triggers systemic epigenetic dysregulation and failure in damage repair, which collectively remodel metabolic and inflammatory microenvironments to attenuate immune responses and elevate risks of diverse degenerative diseases or multiple types of cancer. Critically, senescence-associated secretory phenotype (SASP) factors secreted by senescent cells display profound disease-associated content and spatial-temporal heterogeneity, engaging in bidirectional crosstalk with pathological progression through interconnected signaling axes. Reciprocally, both pathogenic evolution and therapeutic pressures are confirmed to exacerbate immunosenescence, driving impaired replenishment of immune cells and pathological accumulation of immunosuppressive factors that impact disease progression and poor outcomes. As indicated by clinical evidence, senotherapies designed to eliminate senescent cells or block SASP signaling have emerged as promising interventions to ameliorate age-related pathologies. In this review, we systematically combed and delineated disease-specific immunosenescent hallmarks, dissect disease-immunosenescence interplay patterns, and evaluated the translational value of immunosenescence-targeting strategies.