Hallmarks of aging in systemic sclerosis: implications for pathogenesis, multimorbidity, and therapeutic development

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterised by marked clinical variability and a substantial burden of comorbidities, which may reflect underlying biological aging processes. Although chronological age influences disease presentation and prognosis, growing evidence suggests that biological aging processes may contribute directly to disease pathogenesis. Hallmarks of aging, including chronic low-grade inflammation and immunosenescence, have been identified across tissues affected by SSc and may drive persistent immune activation, vascular injury, defective tissue repair, and progressive fibrosis. Aging is increasingly recognised as a tissue-specific and multidimensional process rather than a uniform consequence of chronological time. Differential aging trajectories across organs may influence susceptibility to SSc-related damage, shaping heterogeneous clinical phenotypes. Aging-related mechanisms may also affect disease presentation, severity, comorbidities, and outcomes across the life course and contribute to therapeutic challenges in routine care. In this review, we examine current evidences linking molecular and cellular mechanism of aging to the pathogenesis, clinical manifestations, and outcomes of SSc. We discuss the implications for comorbidity burden and treatment decision-making. A deeper understanding of aging-related mechanisms may provide a unifying framework for disease heterogeneity and support the development of more individualised management strategies and therapeutic approaches in SSc.