Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by loss of immune tolerance and multi-organ inflammation. Although its pathogenesis involves multiple factors, the peak incidence of SLE in individuals over 48 years of age points to immunosenescence as a key driver of the disease.Even in younger patients, SLE frequently often presents as premature aging of the immune system. This review synthesizes recent advances in understanding how immunosenescence drives pathogenesis through immune dysregulation across major lymphocyte and myeloid subsets. Within the chronic inflammatory microenvironment, replicative exhaustion of T cells leads to accelerated telomere attrition, persistent activation of the DNA damage response, and telomerase dysfunction. This cascade culminates in the accumulation of senescent T cells displaying a characteristic CD28-CD57+KLRG1+ phenotype, accompanied by a pro-inflammatory state defined by enhanced cytotoxicity and impaired regulatory function. These characteristics correlated directly with disease activity and cumulative organ damage. The process arises from the interplay of metabolic reprogramming and epigenetic remodeling. In parallel, age-associated B cells (ABCs) accumulate, producing high-affinity anti-dsDNA and other autoantibodies, and potentiating inflammation via enhanced antigen presentation. Meanwhile, an aged bone-marrow microenvironment together with clonal hematopoiesis skews monocyte and macrophage polarization toward a pro-inflammatory (M1) profile. These cells show reduced phagocytic capacity and heightened secretion of senescence-associated secretory phenotype (SASP)-like mediators, further driving inflammaging. This review synthesizes current insights into the relationship between SLE risk and immunosenescence. We discuss the mechanisms through which immune aging instigates autoimmunity and explore emerging therapeutic strategies aimed at mitigating immunosenescence.
