Changes in DNA methylation during aging have implications for various age-related diseases. While the deleterious effects of age-dependent methylation changes after adulthood have attracted the attention of researchers, the relationship between those changes and changes that occur before adulthood have not been focused on. In this study, dozens of CpG sites whose methylation status changed after adulthood were identified in the mouse muscle, brain, and liver, by analysis of the methylation status of 316 CpG sites located within -7 to 3 kb of the transcription start sites (TSS-flanking regions) of 350 genes. Although the majority of the methylation changes were tissue-specific, two characteristics were observed in the methylation changes of each tissue. First, most DNA methylation changes after adulthood were preceded by prominent and same-direction DNA methylation changes before adulthood, and second, the expression levels of genes near progressively methylated and demethylated CpG sites were already significantly low and high, respectively, in young mice. The latter finding was also confirmed by analyzing recently published data of genome-wide age-dependent methylation changes. These results suggest that the DNA methylation status consistently move toward development/maturation throughout lifespan, and the tissue-dependent epigenetic or transcriptional status underlies the methylation changes. (C) 2010 Elsevier Ireland Ltd. All rights reserved.