Age-dependent expression ofDNMT1andDNMT3Bin PBMCs from a large European population enrolled in the MARK-AGE study

Abstract

SummaryAging is associated with alterations in the content and patterns of DNA methylation virtually throughout the entire human lifespan. Reasons for these variations are not well understood. However, several lines of evidence suggest that the epigenetic instability in aging may be traced back to the alteration of the expression of DNA methyltransferases. Here, the association of the expression of DNA methyltransferases DNMT1 and DNMT3B with age has been analysed in the context of the MARK‐AGE study, a large‐scale cross‐sectional study of the European general population. Using peripheral blood mononuclear cells, we assessed the variation of DNMT1 and DNMT3B gene expression in more than two thousand age‐stratified women and men (35–75 years) recruited across eight European countries. Significant age‐related changes were detected for both transcripts. The level of DNMT1 gradually dropped with aging but this was only observed up to the age of 64 years. By contrast, the expression of DNMT3B decreased linearly with increasing age and this association was particularly evident in females. We next attempted to trace the age‐related changes of both transcripts to the influence of different variables that have an impact on changes of their expression in the population, including demographics, dietary and health habits, and clinical parameters. Our results indicate that age affects the expression of DNMT1 and DNMT3B as an almost independent variable in respect of all other variables evaluated.

Phenotypic characteristics of aged CD4+ CD28null T lymphocytes are determined by changes in the whole-genome DNA methylation pattern

“…Previous studies have observed global DNA demethylation with aging associated with a lower level of DNMT1 and DNMT3A/B expression. There is a linear decrease in DNMT3B expression with age, while the levels of DNMT1 only gradually decreased up to the age of 64 years (Ciccarone et al ., ). Moreover, Li et al .…”

“…Aging has been associated with gradual DNA methylation changes over the lifespan, marked by global hypomethylation and specific hypermethylation in promoter‐associated CpG islands (Martin, ; Heyn et al ., ). Some studies have linked these changes to alterations in the expression levels of DNMT1 and DNMT3B regardless of nutritional habits, lifestyle, or clinical parameters (Ciccarone et al ., ). In this way, age‐associated ‘epigenetic drift’ can potentially restrict the plasticity of T cells while supporting new phenotypes, such as exhausted or senescent T cells (Fraga et al ., ; Issa, ).…”

Epigenetics of T cell aging

“…[58][59][60][61] This loss may be attributed to a decline in DNMT1 expression with age. 18 It has been proposed that the loss of CpG methylation at repetitive sequences will heighten the risk of genomic instability due to retrotransposition events, although direct evidence in human aging is lacking. 34,51 In contrast to this general demethylation, DNA methylation arrays have also identified regions of hypermethylation.…”

“…DNMT1 (DNA methyltransferase 1) is the most abundant DNA methyltransferase in mammalian cells and adds methyl groups to hemimethylated CpG di‐nucleotides; its main function is to maintain the methylation during DNA replication. DNMT3A and DNMT3B can methylate hemimethylated and unmethylated CpG, which are critical in establishing methylation states . In humans, 70–80% of CpG cytosines are methylated.…”

Nutritional Factors Modulating Alu Methylation in an Italian Sample from The Mark-Age Study Including Offspring of Healthy Nonagenarians

“…Together with the known age-dependent expression changes of enzymes belonging to the DNA methylation/demethylation machinery [48,49], nutritional and dietary factors can affect Alu DNA methylation status in aging by changing the availability of the methyl donors and altering the activity of the DNMT enzymes [50,51].…”