This study investigates the impact of aging and environmental exposures on tissue-specific DNA methylation patterns in 217 non-pathologic human tissues from 10 autosomal sites. The researchers used methylation profiling to analyze 1,413 autosomal CpG loci associated with 773 genes. They found that methylation profiles were significantly associated with age and tissue origin, with CpG island-containing loci gaining methylation and non-CpG island loci losing methylation with age. The study also revealed significant correlations between methylation and exposure to environmental factors such as tobacco smoking. These findings highlight the dynamic nature of epigenomes and the role of aging and environmental factors in altering tissue-specific methylation patterns, which may contribute to disease susceptibility. The work provides insights into the mechanisms of epigenetic dysregulation and has implications for the construction of reference epigenomes and the interpretation of disease-related alterations.This study investigates the impact of aging and environmental exposures on tissue-specific DNA methylation patterns in 217 non-pathologic human tissues from 10 autosomal sites. The researchers used methylation profiling to analyze 1,413 autosomal CpG loci associated with 773 genes. They found that methylation profiles were significantly associated with age and tissue origin, with CpG island-containing loci gaining methylation and non-CpG island loci losing methylation with age. The study also revealed significant correlations between methylation and exposure to environmental factors such as tobacco smoking. These findings highlight the dynamic nature of epigenomes and the role of aging and environmental factors in altering tissue-specific methylation patterns, which may contribute to disease susceptibility. The work provides insights into the mechanisms of epigenetic dysregulation and has implications for the construction of reference epigenomes and the interpretation of disease-related alterations.