Intermittent hypoxia induces reversible epigenetic age acceleration in old mice

Epigenetic mechanisms are considered adaptive regulators of gene expression, yet mechanisms driving aging-associated DNA methylation remain unclear. Prior work hinted that epigenetic aging might reflect a response to oxygen availability, with age‑differential methylation in immune cells enriched near binding sites for hypoxia‑responsive factors ARNT and REST. To test this hypothesis, we exposed adult (11 months) and old (23 months) mice to 1 month of intermittent hypoxia (IH) followed by normoxic recovery. IH induced epigenetic age acceleration in lungs, spleen, and heart in old mice only. This acceleration reversed upon return to normoxia. Reversible shifts were enriched at bivalent domains and PRC2 targets, indicating oxygen-sensitive chromatin remodeling. Human translational validation in young adults at high altitude (5260 m) confirmed rapid, conserved epigenetic aging. Our findings establish oxygen availability as a primary, conserved modulator of epigenetic aging across tissues and species, showing that oxygen fluctuations are a potent, reversible driver of epigenetic aging.