Longevity & AgingGut Bacteria Metabolite Fuels Pre-Leukemic Cell Growth via ALPK1 Receptor
Researchers discovered that ADP-heptose, a metabolite produced exclusively by Gram-negative gut bacteria, accumulates in the bloodstream of older individuals due to age-related intestinal barrier dysfunction. This circulating molecule binds the intracellular receptor ALPK1 in DNMT3A-mutant hematopoietic stem cells, triggering NF-κB activation and transcriptional reprogramming that gives pre-leukemic cells a competitive proliferative advantage. Using mouse models with intestinal injury, fecal microbiota transplants from aged donors, and human blood samples, the team demonstrated that blocking the ADP-heptose–ALPK1 axis reduces clonal expansion. The findings establish a direct mechanistic link between gut aging and clonal hematopoiesis of indeterminate potential (CHIP), suggesting this pathway is a promising drug target for preventing progression to leukemia and inflammatory cardiovascular disease.
