Autoimmune diseases (AIDs) are a group of disorders in which the immune system mistakenly attacks the body's own tissues, characterized by the loss of tolerance to self-antigens and the production of autoantibodies. Aging is a natural process of physiological decline that also triggers significant alterations in immune system, a condition known as immunosenescence. This study aims to delineate the mechanisms by which immunosenescence facilitates the loss of self-tolerance and to explore the bidirectional causal relationship between the aging process and the pathogenesis of autoimmunity.

This review synthesizes fundamental research and clinical evidence to evaluate the mechanistic pathways through which immunosenescence influences autoimmunity. Our analysis is structured around two pivotal themes: first, the remodeling of self-antigen properties precipitated by systemic aging and “inflammaging”， specifically the accumulation of apoptotic debris resulting from impaired clearance and oxidative stress-induced post-translational modifications, such as citrullination and carbamylation. Second, the review delineates cellular-level evolution, encompassing the contraction of T-cell receptor repertoire diversity secondary to thymic involution, premature telomere attrition, and the pathological expansion of age-associated B cells and CD4+CD28- pro-inflammatory T-cell subsets. Furthermore, we elucidate the critical contributions of mitochondrial dysfunction, cGAS-STING pathway activation, and the senescence-associated secretory phenotype (SASP) to the persistence of chronic inflammation within the tissue microenvironments of AIDs.

Significant correlations exist between immunosenescence and the pathogenesis of AIDs. From an antigenic perspective, the “dual imbalance” precipitated by immunosenescence compromises the fidelity of immune responses, fostering the accumulation of long-lived proteins and the subsequent emergence of neo-antigenic determinants. These alterations are accompanied by widespread “premature immunosenescence” across various AIDs, as evidenced by the reduced thymic output and accelerated telomere attrition observed in patients with rheumatoid arthritis and juvenile idiopathic arthritis. Notably, the aberrant expansion of age-associated B cells in systemic lupus erythematosus intrinsically links to the secretion of pathogenic autoantibodies and elevated Disease Activity Index scores. Concurrently, the SASP releases potent pro-inflammatory cytokines, such as IL-6 and IL-1β, which not only amplify Th17-mediated responses but also drive organ-specific pathologies, including synovial destruction, renal inflammation, and vascular remodeling. Ultimately, metabolic profiling reveals that mitochondrial-derived reactive oxygen species and the leakage of cytosolic mtDNA serve as the primary upstream triggers driving this cascade of senescent phenotypes.

Systemic aging drives progressive immune dysfunction and loss of homeostasis, while premature immunosenescence serves as a hallmark across various AIDs. The interplay between these processes is bidirectional and mutually reinforcing, creating a pathological cycle that complicates the distinction between cause and consequence. Current senotherapeutic strategies have shown preliminary efficacy in preclinical models. Although these targeted interventions offer a promising frontier for resetting immune aging, further investigation into their specificity and clinical safety is imperative.