Abstract
BackgroundDNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age.ResultsHere we test whether differences between people’s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43.ConclusionsDNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0584-6) contains supplementary material, which is available to authorized users.
Highlights
The association between Δage (DNA methylation-predicted age minus chronological age) and mortality was examined in four cohorts: Lothian Birth Cohort 1921 (LBC1921) (N = 446, ndeaths = 292), Lothian Birth Cohort 1936 (LBC1936) (N = 920, ndeaths = 106), the Framingham Heart Study (FHS) (N = 2,635, ndeaths = 238), and the Normative Aging Study (NAS) (N = 657, ndeaths = 226)
The Horvath predicted values were lower than the chronological ages in LBC1921 and LBC1936 participants by 4 to 5 years (SD approximately 6 years) but very similar to chronological age in the FHS (−0.60 years; SD 5.2) and the NAS (0.6 years; SD 5.8)
A third predictor, based on the Weidner predictor was examined, it had a low correlation with chronological age (LBC1921: Pearson R = 0.02; LBC1936: Pearson R = −0.03; FHS: Pearson R = 0.25; NAS: Pearson R = 0.43) and very large absolute median differences (LBC1921: 29.9 years, LBC1936: 19.8 years, FHS: 12.6 years, NAS: 18.4 years) so was not examined further
Summary
DNA sequence variants and epigenetic marks that are associated with changes in gene expression contribute to interindividual variation in complex phenotypes Epigenetic mechanisms such as DNA methylation, characterized by the addition of a methyl group to a cytosine nucleotide primarily at cytosine-phosphate-guanine (CpG) sites, play essential roles during development, acting through the regulation of gene expression [1]. Unlike genomic variants, such as single nucleotide polymorphisms (SNPs), levels of DNA methylation vary across. Weidner et al [12]
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