Inflammation-induced epigenetic erosion drives stem cell ferroptosis during aging

Aging is a complex process associated with multiple events that lead to the decline in stem cell number and function. However, the relationship between these events and their initiation in biological systems remains ambiguous. Here, we investigate the effects of sustained, low-grade systemic inflammation on muscle stem cells (MuSCs) during aging. We show that the slow rise in inflammation during aging causes long-lasting epigenetic remodeling in MuSCs, leading to premature exit of quiescence followed by rapid ferroptotic cell death. The elevation of circulating cytokines results in erosion of histone H4 lysine 20 methylation, fine-tuning of the MuSC transcriptome for future injury response that resembles the Galert state. Prolonged exposure to inflammatory signals during aging results in the loss of H4K20me1 maintenance by lysine methyltransferase 5a (Kmt5a), leading to a disruption of key transcriptional programs required to preserve MuSC quiescence and survival. Mechanistically, we established that Kmt5a genetic deletion prematurely activates MuSC through Notch signaling. Activated cells cannot cycle properly as they display aberrant iron metabolism and repressed Gpx4, resulting in the accumulation of reactive oxygen species, genomic instability, lipid peroxidation, and ultimately, cell death by ferroptosis. Notably, a lifelong reduction in inflammation restores the MuSC number and function and rejuvenates MuSC iron homeostasis. Our findings demonstrates that chronic systemic inflammatory signals reprogram the MuSC epigenome into a primed state, which drives premature cell cycle re-entry and ferroptosis during aging.