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

Abstract

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.