Senescent CD8+ T cells accumulate in ulcerative colitis (UC) mucosa through a discrete metabolic cascade: NAD+ depletion triggers mitochondrial dysfunction, causing cytosolic leakage of mitochondrial DNA, which activates the cGAS-STING innate immune sensing pathway and locks CD8+ T cells into a senescent, pro-inflammatory state. Spatial transcriptomics confirmed these senescent cells congregate specifically within NAD+-depleted mucosal niches. Critically, this senescent-metabolic signature predicted non-response to biologic therapies in UC patients, and systemic senolytic treatment significantly reduced colitis severity in experimental models.
This finding reframes UC pathogenesis beyond conventional adaptive immune dysregulation, implicating immunosenescence—typically studied in aging and cancer—as a direct disease driver in inflammatory bowel disease. The NAD+-cGAS-STING connection is particularly compelling: it bridges metabolic decline, innate immune activation, and T cell aging into a single mechanistic axis, each node of which already has pharmacological tools in development or clinical use. NAD+ precursors (NMN, NR) are widely available; cGAS-STING inhibitors are in early trials; senolytics like dasatinib plus quercetin have human safety data. The practical implication—that a patient's mucosal NAD+ metabolic profile might predict biologic non-response—could meaningfully improve treatment stratification in a disease where roughly 30-40% of patients fail first-line biologics. Limitations include the absence of a randomized human senolytic trial and reliance on correlative spatial transcriptomics for the clinical claims. Still, this is a paradigm-shifting mechanistic contribution that opens credible therapeutic avenues.