Aging is a major risk factor for individuals’ health problems. Moreover, environmental signals have a widespread influence on the aging process. Epigenetic modification, e.g. DNA methylation, represents a link between genetic and environmental signals via the regulation of gene transcription. An abundance of literature indicates that aberrant epigenetic change occurs throughout the aging process at both the cellular and the organismal level. In particular, DNA methylation presents globally decreasing and site-specific increasing in aging. In this review, we focus on the crucial roles of DNA methylation in aging and age-related disease and highlight the great potential of DNA methylation as a therapeutic target in preventing age-related diseases and promoting healthy longevity.