Accelerated immunosenescence in SLE: current evidence and clinical translation

Patients with systemic lupus erythematosus (SLE) often develop age-related adverse outcomes at a young age, raising the possibility that immune-aging processes may interact with chronic immune activation, treatment exposure, and accumulated damage in shaping long-term disease burden. Although immune-age acceleration has also been reported in rheumatoid arthritis and chronic viral infections (e.g., HIV/CMV), SLE is particularly well suited as a human model of inflammation-driven immune aging because of its typical onset in young women and the convergence of aging signatures across clinical, cellular, and molecular levels.

This review synthesizes evidence for accelerated immunosenescence in SLE across systemic manifestations, immune cell remodeling, and molecular senescence markers. Clinically, SLE is linked to premature cardiovascular disease, frailty, cognitive impairment, severe infections, and reduced vaccine responsiveness. Immunologically, senescent-like immune subsets (including terminally differentiated T cells, age-associated/double-negative B cells, dysfunctional NK cells, and senescence-like myeloid cells) expand prematurely. Molecular features include inflammaging-like cytokine patterns, telomere attrition, and epigenetic age acceleration. We also discuss a translational framework for quantifying immunosenescence using immunophenotyping, telomere/epigenetic clocks, and composite immune clocks, with potential applications in risk stratification, treatment decisions, and monitoring immune-reprogramming strategies.

Accelerated immunosenescence provides a biologically plausible and clinically relevant framework for understanding SLE heterogeneity across systemic, cellular, and molecular levels. However, immune-aging measures should currently be regarded as candidate research biomarkers rather than validated clinical decision tools. Prospective SLE-specific studies are needed to establish their predictive value, disease specificity, and clinical utility.