TNFR1 signaling connects inflammation to impaired fatty acid oxidation to drive intestinal stem cell aging

Aging is characterized by a decline in function of intestinal stem cells (ISCs), but the extent to which this is shaped by systemic factors is unclear. The study by Wang et al. aimed to elucidate the role of systemic inflammation in ISC aging. The authors utilized a novel approach of heterochronic parabiosis to transfer the aging phenotype from old to young mice, demonstrating that inflammation plays a crucial role in this process. Anti-inflammatory drugs, including TNF antibodies, restored function in aged ISCs, suggesting a potential therapeutic target for improving intestinal health. Parabiotic rescue experiments further supported the involvement of TNFR1 signaling, as TNF receptor 1 knockout protected young ISCs from the old environment. The study also revealed that TNF downregulated crypt budding, impaired mitochondrial pathways, and fatty acid oxidation (FAO) in young organoids. In contrast, boosting mitochondrial fusion in aged ISCs improved their function, while countering inflammation with salicylate treatment enhanced FAO in aged crypts. These findings identify TNFR1 signaling as a key driver of ISC aging phenotypes, mediated by inflammation and impaired FAO. The study highlights the importance of systemic inflammation in shaping ISC aging and suggests that targeting TNFR1 signaling may be a promising therapeutic strategy for improving intestinal health.