Centenarians consistently present a younger epigenetic age than their chronological age with four epigenetic clocks based on a small number of CpG sites.

Aging is a progressive time-dependent biological process affecting differentially individuals, who can sometimes present exceptional longevity. Epigenetic alterations are one of the hallmarks of aging, which comprise the epigenetic drift and clock at DNA methylation level. In the present study, we estimated the DNA methylation-based age (DNAmage) using four epigenetic clocks based on a small number of CpGs in French centenarians and semi-supercentenarians (CSSC, n=214) as well as nonagenarians' and centenarians' offspring (NCO, n=143) compared to individuals from the French general population (CG, n=149). DNA methylation analysis of the nine CpGs included in the epigenetic clocks showed high correlation with chronological age (-0.66>R>0.54) and also the presence of an epigenetic drift for four CpGs that was only visible in CSSC. DNAmage analysis showed that CSSC and to a lesser extend NCO present a younger DNAmage than their chronological age (15-28.5 years for CSSC, 4.4-11.5 years for NCO and 4.2-8.2 years for CG), which were strongly significant in CSSC compared to CG (p-values<2.2e-16). These differences suggest that epigenetic aging and potentially biological aging are slowed in exceptionally long-lived individuals and that epigenetic clocks based on a small number of CpGs are sufficient to reveal alterations of the global epigenetic clock.