Dasatinib + Quercetin Senolytic Therapy Reduces Epigenetic Age Acceleration in Rheumatoid Arthritis Patients with Premature Immunosenescence

Background: Rheumatoid arthritis (RA) patients exhibit accelerated epigenetic aging (measured by GrimAge and DunedinPACE clocks), with biological age exceeding chronological age by 5-10 years. This acceleration correlates with expanded CD28- senescent T-cell populations and elevated SASP (senescence-associated secretory phenotype) cytokines (IL-6, MMP-3, CXCL9) that overlap with RA pathogenic mediators.

Hypothesis: A 3-day intermittent senolytic regimen of dasatinib (100mg) + quercetin (1000mg) administered monthly for 6 months will reduce epigenetic age acceleration by >=2 years (GrimAge) in RA patients with documented premature immunosenescence (CD28-CD57+ T-cells >15%), while simultaneously reducing DAS28-CRP scores by >=1.2 points, through selective clearance of senescent synovial fibroblasts and circulating senescent T-cells.

Testable predictions: (1) Pre/post DunedinPACE pace-of-aging will decrease by >0.05 units; (2) Circulating p16INK4a+ T-cell frequency will decrease >40%; (3) Synovial SASP index (composite IL-6/MMP-3/CXCL9) will decrease >30%; (4) The epigenetic age reduction will correlate with clinical improvement (r>0.5).

Novel intersection: This bridges geroscience and rheumatology by proposing that the shared SASP/inflammaging pathway makes RA a uniquely informative model for senolytic efficacy - disease activity scores serve as real-time biomarkers of senescent cell burden, potentially superior to epigenetic clocks alone for monitoring senolytic response.

Design: Randomized, double-blind, placebo-controlled pilot (n=40), stratified by baseline CD28- percentage and biologic DMARD use. Primary endpoint: delta-GrimAge at 6 months. Secondary: DAS28-CRP, DunedinPACE, senescent T-cell clearance, SASP cytokine panel.