Longevity & AgingInflammation Erases a Key Histone Mark, Triggering Iron-Driven Death in Aging Muscle Stem Cells
Researchers discovered that systemic age-related inflammation (inflammaging) drives muscle stem cell (MuSC) loss through an epigenetic mechanism. Inflammatory signals, particularly via CCR2 signaling, suppress the histone methyltransferase KMT5A, causing erosion of the histone mark H4K20me1. Loss of this mark silences genes that protect against ferroptosis—an iron-dependent form of cell death—leading to iron accumulation, reactive oxygen species, and lipid peroxidation in aged MuSCs. Crucially, long-term suppression of systemic inflammation starting at 12 months of age preserved H4K20me1 levels, prevented ferroptosis, maintained MuSC numbers, and improved muscle regeneration and functional recovery in aged mice. This work identifies a druggable epigenetic switch linking chronic inflammation to stem cell aging.
