Immunosenescence is classically characterized by a progressive decline in protective immunity, leading to increased susceptibility to infections and reduced vaccine efficacy. Paradoxically, aging is also associated with a higher incidence of autoimmune diseases, indicating a coexistence of immune deficiency and immune hyperactivation. The cellular and molecular mechanisms underlying this apparent contradiction remain incompletely understood, and existing models centered primarily on T cell dysfunction fail to fully account for the emergence and persistence of autoreactivity with age.

This review synthesizes recent advances from human cohort studies, murine models, and single-cell multi-omics analyses to redefine the developmental origin, functional properties, and pathogenic roles of age-associated B cells (ABCs). Mechanistic insights are integrated across key regulatory axes, including innate immune sensing, cytokine signaling, metabolic reprogramming, and epigenetic remodeling, to construct a unified framework of ABC function in aging and autoimmunity.

ABCs, characterized by a T-bet–driven transcriptional program and the convergence of B cell receptor and Toll-like receptor signaling, expand progressively with age and are prematurely enriched in multiple autoimmune conditions. Rather than representing passive byproducts of immune aging, ABCs actively contribute to inflammaging through the production of pro-inflammatory cytokines and enhanced antigen presentation. Simultaneously, they promote autoreactive immune responses by favoring extrafollicular B cell activation and autoantibody generation, thereby bypassing classical germinal center tolerance checkpoints. Emerging evidence further indicates that ABCs integrate diverse age-related signals—including endogenous nucleic acids, chronic inflammatory cytokines, metabolic stress, and epigenetic alterations—into sustained pathogenic outputs. These features position ABCs at the interface of immune decline and immune activation, providing a mechanistic explanation for their dual role in impaired host defense and enhanced autoimmunity.

ABCs represent a previously underappreciated immunological hub that bridges immunosenescence and autoimmunity. Targeting the upstream signals and intrinsic regulatory programs that govern ABC expansion and function may offer novel opportunities for precision immunomodulation, with the potential to simultaneously alleviate age-related autoimmune pathology and restore immune competence in aging populations.