Research Article: Methylation of the ribosomal RNA gene promoter is associated with aging and age‐related decline

Date Published: June 17, 2017

Publisher: John Wiley and Sons Inc.

Author(s): Patrizia D’Aquila, Alberto Montesanto, Maurizio Mandalà, Sabrina Garasto, Vincenzo Mari, Andrea Corsonello, Dina Bellizzi, Giuseppe Passarino.


The transcription of ribosomal RNA genes (rDNA) is subject to epigenetic regulation, as it is abrogated by the methylation of CpG dinucleotides within their promoter region. Here, we investigated, through Sequenom platform, the age‐related methylation status of the CpG island falling into the rDNA promoter in 472 blood samples from 20‐ to 105‐year‐old humans and in different tissues (blood, heart, liver, kidney, and testis) of 15 rats 3–96 weeks old. In humans, we did not find a consistently significant correlation between CpG site methylation and chronological age. Furthermore, the methylation levels of one of the analyzed CpG sites were negatively associated with both cognitive performance and survival chance measured in a 9‐year follow‐up study. We consistently confirmed such result in a replication sample. In rats, the analysis of the homologous region in the tissues revealed the existence of increased methylation in old rats. rRNA expression data, in both humans and rats, were consistent with observed methylation patterns, with a lower expression of rRNA in highly methylated samples. As chronological and biological ages in rats of a given strain are likely to be much closer to each other than in humans, these results seem to provide the first evidence that epigenetic modifications of rDNA change over time according to the aging decline. Thus, the methylation profile of rDNA may represent a potential biomarker of aging.

Partial Text

The transcription of nuclear ribosomal RNA (rRNA) genes is a key control point highly regulated in ribosome biogenesis which is crucial for cellular adaptation, stress response, cellular growth, and proliferation as well as to energetic requirements of cells (Russell & Zomerdijk, 2005; Grummt & Voit, 2010). In higher eukaryotes, a single transcription unit (~13 kb) contains the sequence for both the small (5.8S) and large (18S and 28S) rRNA molecules. Each unit is repeated in tandem and clusters of units are dispersed within nucleolar organizer regions and separated from each other by a nontranscribed spacer (~30 Kb) (Gonzalez & Sylvester, 1995). The mammalian rRNA gene promoter is composed by a core element spanning from −45 to +20 relative to the start site (+1), that is essential for accurate transcription initiation, and an upstream control element (UCE), from −180 to −107, displaying a regulatory role. Spacing between the two sequences and their relative orientation were demonstrated to be crucial for a correct functioning of the transcriptional apparatus (Paule & White, 2000). The promoter contains a number of short direct and inverted repeats and palindromes. By comparison of the regions in three mammalian species (human, mouse, and rat), several conserved sequences were found upstream and downstream the transcription starting point (Financsek et al., 1982).

Alteration of the ribosome biogenesis and an overall protein synthesis rate decline have been observed to characterize aging process in many organisms, including humans (Syntichaki et al., 2007; Tavernarakis, 2008; Charmpilas et al., 2015). This decline could be an effect of the progressive deterioration in most cellular functions usually associated with aging, or it could be a concurrent factor in the process. If to date a general reduction of protein synthesis has been attributed to the decreased frequency of mRNA translation, current studies, reporting an involvement of epigenetic mechanisms in silencing a large fraction of the rRNA genes, with a consequent impairment of rDNA function, could lead to a new understanding of the phenomenon (Syntichaki et al., 2007; Hands et al., 2009).

This work was supported by the European Union’s Seventh Framework Programme (FP7/2007‐2011, IDEAL Project, grant number 259679) and by Programma Operativo Nazionale (01_00937)—MIUR ‘Modelli sperimentali biotecnologici integrati per lo sviluppo e la selezione di molecole di interesse per la salute dell’uomo’.

The authors declare no competing financial interests.

PDA, AM, DB, and GP designed the study; PDA performed the experiments; AM performed the statistical analysis; SG, VM, and AC provided the human blood samples belonging to RD1 and RD2; MM provided rat tissues; DB and GP wrote the initial draft; PDA, AM, MM, DB, and GP participated in critical revision and approved the final manuscript before submission.




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