Decline in genomic DNA methylation through aging in a cohort of elderly subjects

Abstract

Loss of genomic DNA methylation has been found in a variety of common human age-related diseases. Whether DNA methylation decreases over time as individuals age is unresolved. We measured DNA methylation in 1097 blood DNA samples from 718 elderly subjects between 55 and 92 years of age (1-3 samples/subjects), who have been repeatedly evaluated over an 8-year time span in the Boston area Normative Aging Study. DNA methylation was measured using quantitative PCR-Pyrosequencing analysis in Alu and LINE-1 repetitive elements, heavily methylated sequences with high representation throughout the human genome. Age at the visit was negatively associated with Alu element methylation (beta=-0.12 %5mC/year, p=0.0005). A weaker association was observed with LINE-1 elements (beta=-0.06 %5mC/year, p=0.049). We observed a significant decrease in average Alu methylation over time, with a -0.2 %5mC change (p=0.012) compared to blood samples collected up to 8 years earlier. The longitudinal decline in Alu methylation was linear and highly correlated with time since the first measurement (beta=-0.089 %5mC/year, p<0.0001). In contrast, average LINE-1 methylation did not vary over time [p=0.51]. Our results demonstrate a progressive loss of DNA methylation in repetitive elements dispersed throughout the genome.

Figures

Figure 1

Association between Age and Methylation in Alu (A) and LINE-1 (B) repetitive elements. The graphs show the decrease of methylation (change in % 5Methyl-cytosine [%5mC]/year) in relation to the subject’s age at time of visit. Regression lines and data points represent the unadjusted values. Adjusted and unadjusted Regression coefficients (β) and p-values shown are obtained from unadjusted models and from models adjusted for body mass index, systolic and diastolic blood pressure, fasting blood glucose, percent lymphocytes and neutrophils in blood count, statin use, season of the visit.

Figure 2

Correlation between the first and the second measurement of Alu (A) and LINE-1 (B) repetitive element methylation taken 2–8 years apart on the same subjects.