Continuous Aging of the Human DNA Methylome Throughout the Human Lifespan

Abstract

DNA methylation plays an important role in development of disease and the process of aging. In this study we examine DNA methylation at 476,366 sites throughout the genome of white blood cells from a population cohort (N = 421) ranging in age from 14 to 94 years old. Age affects DNA methylation at almost one third (29%) of the sites (Bonferroni adjusted P-value <0.05), of which 60.5% becomes hypomethylated and 39.5% hypermethylated with increasing age. DNA methylation sites that are located within CpG islands (CGIs) more often become hypermethylated compared to sites outside an island. CpG sites in promoters are more unaffected by age, whereas sites in enhancers more often becomes hypo- or hypermethylated. Hypermethylated sites are overrepresented among genes that are involved in DNA binding, transcription regulation, processes of anatomical structure and developmental process and cortex neuron differentiation (P-value down to P = 9.14*10(-67)). By contrast, hypomethylated sites are not strongly overrepresented among any biological function or process. Our results indicate that the 23% of the variation in DNA methylation is attributed chronological age, and that hypermethylation is more site-specific than hypomethylation. It appears that the change in DNA methylation partly overlap with regions that change histone modifications with age, indicating an interaction between the two major epigenetic mechanisms. Epigenetic modifications and change in gene expression over time most likely reflects the natural process of aging and variation between individuals might contribute to the development of age-related phenotypes and diseases such as type II diabetes, autoimmune and cardiovascular disease.

Figure 1. Distribution of A) Ages in the study cohort, B) DNA methylation levels for autosomal markers in males and females, C) DNA methylation level for autosomal markers in the youngest (age <18, N = 51) and oldest (age>71, N = 52) individuals of the study, and D) DNA methylation levels for X chromosomal markers in males and females.

Figure 2. Increase in DNA methylation level with age of one CpG site (cg16867657) in the promoter of the ELOVL2 gene and corresponding regression line.

Figure 3. Location of CpG site depending on correlation between DNA methylation level and chronological age.

Observations are ordered by the correlation coefficients and combined into 100 bins. The illustrations show the fraction of markers within each bin with a location in relation to, A) CGIs, island shores and islands shelves, B) Known promoter and enhancer regions, and C) Gene and transcription starting site.

Figure 4. Summary statistics for the CGIs depending on the correlation between DNA methylation level and chronological age.

Observations are ordered by the correlation coefficients and combined into 100 bins. The features of the CGIs within each bin is summarized as, A) Mean length of the CGIs, B) Mean percentage of CpGs in the islands, and C) Mean of observed to expected ration of CpGs in the islands.

Figure 5. Distribution of DNA methylation sites mapped to regions with different chromatin states as defined by Ernst et al

. DNA methylation marks are ordered by the correlation coefficient with age and combined into 100 bins.