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

While immunosenescence is increasingly implicated in chronic inflammatory disorders, its precise pathogenic contribution to ulcerative colitis (UC) remains elusive. Here, we identify senescent CD8⁺ T cells as a distinct pathogenic population that exacerbates colitis, demonstrating that systemic senolytic treatment significantly attenuates disease severity. Mechanistically, nicotinamide adenine dinucleotide (NAD⁺) metabolic dysregulation triggers mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, promoting CD8⁺ T cell senescence through the activation of the cGAS-STING signaling pathway. Spatial transcriptomic mapping reveals that senescent CD8⁺ T cells are enriched within mucosal niches experiencing NAD⁺ metabolic dysregulation. Crucially, this senescent-metabolic signature correlates with severe disease phenotypes and predicts non-response to biologic therapies in UC patients. Collectively, our findings uncover a critical NAD⁺-cGAS-STING axis driving T cell senescence, establishing the clearance of senescent immune cells as a promising therapeutic strategy for UC.