Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs

Abstract

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.

Fig. 1

Increase in within-pair methylation discordance with age. Absolute within-pair difference in percent DNA methylation for global DNA methylation and for specific loci plotted for (A) Young MZ twins (below 30 years old; n = 66 pairs) vs. old MZ twins (above 74 years old; n = 67 pairs). (B) The full age range divided by the four stages of adult life; from left to right: up to 25 years of age (early adulthood, n = 30 pairs), 26 up to 50 years of age (early middle age, n = 78 pairs), 51 up to 75 years of age (late middle age, n = 56 pairs), and above 76 years of age (old age, n = 54 pairs). (C) 19 elderly MZ pairs (73–82 years old), after 10 years of follow-up (83–92 years old). The bars show the interquartile range, the thick line in the center of the bar shows the median, and the whiskers show the 5th (bottom whisker) and 95th (top whisker) percentiles.

Fig. 2

Contribution of familial and unique (individual) environmental factors to increasing methylation variation with age. Estimated changes in the variation in DNA methylation (y-axis, given as standard deviation in percent DNA methylation) plotted against the adult lifespan (x-axis, age in years). The changes in total variation of DNA methylation (area under the thick line) and the contributions of familial factors (shared environment and genotype, filled-in area between thick and dashed line) and unique factors (individual environment, blank area under the dashed line) were estimated in 219 MZ pairs ranging from 18 to 89 years of age. From top left to bottom right, global DNA methylation and the loci KCNQ1OT1, GNASAS, IGF2DMR, LEP, and CRH are investigated. Significance of the estimates of total, familial, and individual related increases in variation is given in Table S6 (Supporting information).