Aging is a multi-factorial process of the progressive gradual decline of cellular functions with the passage of time. It is clear that aging affects the mammalian epigenome, including hypomethylation of DNA. DNA methylation is a crucial biological process that controls maintenance of genomic integrity and an accurate expression of genetic information. The accurate status of DNA methylation is balanced in mature cells, but with age this balance is strongly shifted in favor of DNA demethylation. Therefore, DNA hypomethylation that occurs during normal aging appears to be a critical risk factor contributing to the development of chronic age-related human pathological states. This review describes the involvement of DNA hypomethylation in the pathogenesis of several major age-related human diseases, including cancer, atherosclerosis, Alzheimer’s disease, psychiatric disorders, and autoimmune pathologies.