DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy.

Qiong Lin,Ian J Deary,Ivan G Costa,Riccardo E Marioni,Carola I Weidner,Wolfgang Wagner,Marcelo R P Ferreira

doi:10.18632/aging.100908

Abstract

DNA-methylation (DNAm) levels at age-associated CpG sites can be combined into epigenetic aging signatures to estimate donor age. It has been demonstrated that the difference between such epigenetic age-predictions and chronological age is indicative for of all-cause mortality in later life. In this study, we tested alternative epigenetic signatures and followed the hypothesis that even individual age-associated CpG sites might be indicative for life-expectancy. Using a 99-CpG aging model, a five-year higher age-prediction was associated with 11% greater mortality risk in DNAm profiles of the Lothian Birth Cohort 1921 study. However, models based on three CpGs, or even individual CpGs, generally revealed very high offsets in age-predictions if applied to independent microarray datasets. On the other hand, we demonstrate that DNAm levels at several individual age-associated CpGs seem to be associated with life expectancy - e.g., at CpGs associated with the genesPDE4C and CLCN6. Our results support the notion that small aging signatures should rather be analysed by more quantitative methods, such as site-specific pyrosequencing, as the precision of age-predictions is rather low on independent microarray datasets. Nevertheless, the results hold the perspective that simple epigenetic biomarkers, based on few or individual age-associated CpGs, could assist the estimation of biological age.

Highlights

Aging is associated with highly reproducible DNAmethylation (DNAm) changes at specific sites in the genome [1,2,3,4,5]
This follow-up study further substantiates the notion that epigenetic age-predictions are indicative for biological rather than chronological age [9,18]
We demonstrated that the error of age-predictions can be improved for the 3-CpG model by training on HumanMethylation450 BeadChip data

Summary

Introduction

Aging is associated with highly reproducible DNAmethylation (DNAm) changes at specific sites in the genome [1,2,3,4,5]. Various combinations of age-associated CpG dinucleotides have been used for age-estimation and the average absolute difference of DNAm-predicted and chronological age (∆age) can be less than five years [6,7,8]. While such epigenetic aging signatures are usually trained to be as precise as possible, the ∆age can partly be attributed to effects of biological aging. Using our previously described model based on three CpG sites (associated with genes ASPA, ITGA2B and PDE4C) [8] there was no clear correlation with chronological age and this 3-CpG model was not further considered [9]

Methods

Results

Conclusion