NAD+ Metabolic Reprogramming Drives CD8+ T Cell Senescence and Exacerbates Ulcerative Colitis

While immunosenescence is increasingly recognized as a driver of chronic inflammatory disorders, its specific contribution to the pathogenesis of Ulcerative Colitis (UC) remains poorly understood. Here, we identify senescent CD8 T cells as a distinct pathogenic population that exacerbates colitis, demonstrating that their clearance via senolytic therapy significantly attenuates disease severity. Mechanistically, NAD metabolic dysregulation triggers mitochondrial dysfunction and cytosolic mitochondrial DNA (mtDNA) leakage, driving CD8 T cell senescence through the activation of the cGAS STING signaling pathway. Clinically, high senescent CD8 T cell infiltration and NAD dysregulation correlate with severe disease phenotypes and predict primary non-response to biologic therapies in UC patients. Collectively, our findings uncovere a critical NAD cGAS STING axis driving T cell senescence, establishing the clearance of senescent immune cells as a promising therapeutic strategy of UC.