Distinct DNA methylomes of newborns and centenarians

TLDR

Human aging cannot be fully explained by genetics alone, and epigenetic drift is proposed as an alternative mechanism for age‑associated changes. The study compared whole‑genome bisulfite sequencing of newborn and centenarian genomes to investigate age‑related methylation differences. Centenarian genomes exhibit globally lower DNA methylation, reduced CpG correlation, and widespread hypomethylation across all genomic compartments—especially at CpG‑poor promoters—while CpG island promoters remain more methylated; these patterns were confirmed in a larger cohort and positioned intermediate methylomes in middle‑aged individuals, providing a unique single‑nucleotide resolution comparison of human life extremes.

Abstract

Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes. The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status of neighboring cytosine--phosphate--guanine (CpGs) throughout the genome in comparison with the more homogeneously methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions, the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of more hypomethylated DNA sequences in the advanced age group. WGBS and 450,000 analyses of middle-age individuals demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups. Our study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level.