Longevity & AgingHow Premature Immune Aging Drives Rheumatoid Arthritis Onset and Severity
Rheumatoid arthritis (RA) peaks after age 65, implicating immune aging as a core disease driver rather than an overactive immune system. RA patients exhibit premature aging of CD4+ T cells—measurable as a 25-year left shift in telomere length—present even in healthy HLA-DRB1*04+ individuals before any joint inflammation. Defects in DNA repair enzymes (ATM, MRE11A, Pol β), mitochondrial dysfunction, lysosomal failure, and dysregulated mTORC signaling collectively reprogram T cells into hyperinflammatory, tissue-invasive effectors. Age-associated B cells amplify autoantibody production, while clonal hematopoiesis generates hypermetabolic macrophages that perpetuate inflammaging. Together, these findings reframe RA as a disease of immune aging rather than immune excess.
