Abstract
Aging is a complex biological process regulated by multiple cellular pathways and molecular mechanisms including epigenetics. Using genome-wide DNA methylation data measured in a large collection of Scottish old individuals, we performed discovery association analysis to identify age-methylated CpGs and replicated them in two independent Danish cohorts. The double-replicated CpGs were characterized by distribution over gene regions and location in relation to CpG islands. The replicated CpGs were further characterized by involvement in biological pathways to study their functional implications in aging. We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWER <0.05, 86% demethylated with increasing age. Double-replication resulted in 5,168 CpGs (39% age-methylated and 61% age-demethylated) which were characterized by high concentration of age-methylated CpGs at 1stExon and TSS200 and a dominant pattern of age-demethylated CpGs at other gene regions, and by overwhelming age-related methylation in CpG islands and demethylation at shore/shelf and open sea. The differential distribution patterns over gene regions for methylated and demethylated CpGs both relate to reduced gene activity during aging. Pathway analysis showed that age-dependent methylations were especially involved in cellular signalling activities while demethylations particularly linked to functions of the extracellular matrix, all implicated in the aging process and age-related disease risk.
Highlights
Aging is a complex biological process that involves numerous changes at various levels and in different organ systems from molecular modification to the functional regulation of systems through multiple biological mechanisms including epigenetics[7, 8]
The results show a predominant pattern of demethylation with increasing age in the significant CpGs
Among the CpGs replicated in the Danish longitudinal twin samples, 5,168 overlap with the 19,768 CpGs replicated in the cross-sectional samples, an overlapping rate of 70.4%
Summary
Aging is a complex biological process that involves numerous changes at various levels and in different organ systems from molecular modification to the functional regulation of systems through multiple biological mechanisms including epigenetics[7, 8]. As a reflection of this, most of the epigenetic association analyses of human aging have reported relatively large numbers of differentially regulated sites[4,5,6]. While the reported findings could reflect extensive involvement of epigenetic modification during the aging process, careful validation of the findings are www.nature.com/scientificreports/. Especially necessary both for reducing false discovery and for better characterizing the epigenetic changes accompanying human aging. The double-replicated CpGs were characterized by grouping across genomic regions and by investigating their functional pathways implicated in the dynamic patterns of age-related epigenetic modifications
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