Longevity & AgingMetformin Slows Expansion of Mutant Blood Stem Cells Linked to Cancer Risk
Clonal haematopoiesis occurs when mutant blood stem cells outcompete normal ones, raising risks of blood cancers and inflammatory disease. The most common driver mutation, DNMT3A R882, was studied in a mouse model carrying the equivalent Dnmt3a R878H mutation. Researchers found these mutant stem cells rely on elevated mitochondrial respiration (OXPHOS) for their competitive edge. Metformin, a diabetes drug that inhibits mitochondrial complex I, reduced this advantage both in vitro and in vivo over seven months. Multi-omics analysis revealed metformin restores methylation potential and reverses aberrant DNA and histone methylation patterns in mutant cells. The effect was also demonstrated in human DNMT3A R882H stem cells generated by prime editing, providing strong preclinical support for investigating metformin as a preventive therapy against clonal haematopoiesis.
