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24 reviewsHigh altitude presents a challenging environment for human settlement. DNA methylation is an essential epigenetic mechanismthat responds to environmental stimuli, but its roles in high-altitude short-term acclimatization (STA) and long-term adaptation(LTA) are poorly understood. Here, we conducted a methylome-wide association study involving 687 native highlanders and 299acclimatized newcomers in the Tibetan Plateau and 462 native lowlanders to identify differentially methylated sites (DMSs)associated with STA or LTA. We identified 93 and 4070 DMSs for STA and LTA, respectively, which had no overlap, showed oppositeasymmetric effect size patterns, and resided near genes enriched in distinct biological pathways/processes (e.g., cell cycle for STAand immune diseases and calcium signalling pathway for LTA). Epigenetic clock analysis revealed evidence of accelerated ageing in1234567890();,:the acclimatized newcomers compared to the native lowlanders. Our research provides novel insights into epigerelation to high altitude and intervention strategies for altitude-related ageing or illnesses.Cell Discovery;