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. Here we show that the ISC aging phenotype can be propagated from old to young mice utilizing heterochronic parabiosis, and implicate a role for inflammation in these effects, as anti-inflammatory drugs, including TNF antibodies, restored function. Parabiotic rescue experiments demonstrate that TNFR1 knockout protected young ISCs from the old environment. In young organoids, TNF downregulated crypt budding, while impairing mitochondrial pathways and fatty acid oxidation (FAO). However, aged ISC function was enhanced by boosting mitochondrial fusion, whereas FAO in aged crypts was improved by countering inflammation with salicylate treatment. Thus, these data identify the old environment through the progeronic factor TNF, as a driver of ISC aging phenotypes through intestinal epithelial cell TNF receptor 1 signaling to downregulate FAO, proliferation and regenerative capacity in these cells.