Date Published: August , 2012
Publisher: Blackwell Publishing Ltd
Author(s): Rudolf P Talens, Kaare Christensen, Hein Putter, Gonneke Willemsen, Lene Christiansen, Dennis Kremer, H Eka D Suchiman, P Eline Slagboom, Dorret I Boomsma, Bastiaan T Heijmans.
The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk of most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18–89 years, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass spectrometry, we investigated variation in global (LINE1) DNA methylation and in DNA methylation at INS, KCNQ1OT1, IGF2, GNASAS, ABCA1, LEP, and CRH, candidate loci for common diseases. Except for KCNQ1OT1, interindividual variation in locus-specific DNA methylation was larger in old individuals than in young individuals, ranging from 1.2-fold larger at ABCA1 (P = 0.010) to 1.6-fold larger at INS (P = 3.7 × 10−07). Similarly, there was more within-MZ-pair discordance in old as compared with young MZ pairs, except for GNASAS, ranging from an 8% increase in discordance each decade at CRH (P = 8.9 × 10−06) to a 16% increase each decade at LEP (P = 2.0 × 10−08). Still, old MZ pairs with strikingly similar DNA methylation were also observed at these loci. After 10-year follow-up in elderly twins, the variation in DNA methylation showed a similar pattern of change as observed cross-sectionally. The age-related increase in methylation variation was generally attributable to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ twins during aging.
The risk of most common diseases increases with age. A lifetime of accumulated epigenetic changes was proposed to contribute to the development of such diseases (Bjornsson et al., 2004). Epigenetic mechanisms determine the expression potential of genes without changing the DNA sequence (Jaenisch & Bird, 2003). The molecular basis includes the methylation of cytosines in CpG dinucleotides, which, together with histone modifications, noncoding RNAs, and localization, influence the accessibility of a genomic locus to the transcriptional machinery (Bernstein et al., 2007; Cedar & Bergman, 2009). DNA methylation can be measured on DNA samples that are commonly available in biobanks (Talens et al., 2010).
In this study, we report sustained age-related increases in variation of DNA methylation, in an analysis of 460 individuals, comprising 230 MZ pairs, aged from 18 to 89 years. Previously, this question was investigated using cross-sectional and longitudinal study designs on smaller sample sizes with narrower age ranges (Fraga et al., 2005; Feinberg et al., 2010; Gronniger et al., 2010; Talens et al., 2010). Our study extends their findings over the full adult lifespan, supporting the notion that a gradual accumulation of epigenetic changes, globally and at imprinted and nonimprinted loci, occurs up to very old ages. How such changes affect gene expression remains unclear, although some evidence suggests that small differences in DNA methylation may cause an amplified effect on gene expression (Lillycrop et al., 2008). The increase in epigenetic variation was mainly attributable to unique individual factors that cover both stochastic processes and environmental exposures, between which the design of our study cannot distinguish. This may lead to age-related epigenetic dysregulation and may contribute to the age dependency of common diseases (Jaenisch & Bird, 2003; Bjornsson et al., 2004). However, studies that can appropriately address the latter hypothesis will be complex in their design and execution because of the relatively small effect sizes involved and the tissue- and cell-specific nature of age-related changes (Heijmans & Mill, 2012).