Abstract
Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (ΔYO > 5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.Electronic supplementary materialThe online version of this article (doi:10.1007/s11357-014-9648-x) contains supplementary material, which is available to authorized users.
Highlights
The unavoidable and complex process of organismal aging is characterized by a progressive decline in structural and functional features of all organs in the body, resulting in increased morbidity and mortality
We have previously shown that activation of the PPARα nuclear receptor causes a pronounced change in gene expression in human peripheral blood mononucleated cells (PBMCs) (Bouwens et al 2008), but whether DNA methylation is involved in this process has not been determined yet
Aging-induced differential methylation identified by applying Infinium 450K BeadChip analysis
Summary
The unavoidable and complex process of organismal aging is characterized by a progressive decline in structural and functional features of all organs in the body, resulting in increased morbidity and mortality. Age-related changes in DNA methylation have been detected in wholeblood (Garagnani et al 2012; Hannum et al 2012; Horvath et al 2012; Rakyan et al 2010; Teschendorff et al 2010; Bell et al 2012) or in purified subsets of blood cells (Heyn et al 2012; Rakyan et al 2010), saliva (Bocklandt et al 2011), brain (Hernandez et al 2011; Horvath et al 2012; Numata et al 2012), or in various other cell and tissue types (Bork et al 2010; Koch et al 2011; Koch and Wagner 2011; Teschendorff et al 2010). Up until now, concomitant changes in gene expression have only marginally been explored on a genome-wide scale
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