Ageing-associated changes in DNA methylation in humans

Background: DNA methylation, a component of the epigenome that regulates both single genes and large sections of chromatin, is altered with ageing and is speculated to be one of the molecular mechanisms contributing to the ageing process. In our analysis, we sought to identify ageing-associated methylation changes at single- CpG-site resolution in blood leukocytes and to ensure that the observed changes were not due to differences in the proportions of leukocytes. The association of the methylation changes with gene expression levels was also investigated in the same individuals. Results: By applying Illumina 450K array technology and a two-step analysis process, we identified 8540 high-confidence ageing-associated CpG sites, 46% of which were hypermethylated in nonagenarians. The hypermethylation-associated genes belonged to a common category, and they were predicted to be regulated by a common group of transcription factors and were enriched in a related set of GO terms and canonical pathways. On the contrary, the hypomethylation-associated genes appeared to be a more random group, as only a limited set of GO terms and canonical pathways were identified in this group. Among the 8540 CpG sites associated with ageing, there was an association with gene expression levels in 377. The genes displaying methylation-regulated expression were enriched in GO terms and canonical pathways associated with immune system functions, particularly phagocytosis. Conclusions: According to our results, certain ageing-associated immune-system impairments may be mediated via changes in DNA methylation. The results also imply that ageing-associated hypo- and hypermethylation are distinct processes: hypermethylation could be caused by programmed changes, while hypomethylation could be the result of environmental and stochastic processes. Study population consisted of nonagenarians (n=122) and young controls (n=21, 19-30 years).