Exploring the Ribosomal DNA Epigenetic Clock as a Biological Age Estimator

Abstract

Biological age (BA) is a measure of overall health status that allows one to assess health risks in individuals of the same chronological age. To estimate BA, we need reliable biomarkers of aging (i.e. clocks). Various clocks have been developed with epigenetic clocks being the most widely used. They rely on the age-associated change in DNA methylation (DNAm) to estimate BA. However, they are not evolutionary or biologically grounded. To address this, Wang and Lemos (2019) proposed the ribosomal DNAm (rDNAm) clock, which estimates BA based exclusively on rDNAm. According to them, a biological clock should (1) be evolutionary conserved, (2) have a mechanistic relationship with age, (3) predict chronological age under control conditions and (4) respond to interventions that decrease or increase longevity. In order to explore the rDNAm clock in the light of these criteria, we designed four investigations with each dedicated to one of them. First, we used cohort studies on three vertebrate species to describe how the methylation of rDNA cytosines change with aging and found that only a limited number of them have a positive correlation. We interpret our results as being coherent with rDNAm of early life stages marked by lower methylation levels. Second, we investigated if rDNA is responsive to inflammation using a chicken inflammation trial. We found rDNAm patterns consistent with accelerated aging and, therefore, propose inflammaging as a biological mechanism underlying the rDNAm clock. Third, we tested if the rDNAm clock predicts chronological age in spermatogenic cells. We show that spermatozoa rDNAm is the result of the cumulative effects of mouse chronological aging and sperm development, both of which are captured by the rDNAm clock. Fourth, we demonstrate that exercise modulates rDNAm and that cardiovascular training reverses rDNAm aging. Altogether, we add evidence to the rDNAm clock being a biologically grounded, evolutionary conserved and cost-effective estimator of BA.