Methylation of Ribosomal RNA Genes Correlates with Aspects of Aging

This paper is an example of the further explorations of DNA methylation and aging presently taking place in the research community. DNA methylation is one of the epigenetic decorations to DNA that alter gene expression, and thus the pace at which specific proteins are generated in the cell. A few different epigenetic clocks have been discovered in recent years, patterns of change in DNA methylation levels that correlate well with biological age, in that people of a given chronological age who are more damaged and impacted by aging than their peers tend to have distinctively different DNA methylation patterns. Moving beyond the existing epigenetic clocks, researchers are now searching for more and better correlations, as well as specific mechanistic links with other cellular processes already known to change with age.

Alteration of the ribosome biogenesis and an overall protein synthesis rate decline have been observed to characterize aging process in many organisms, including humans. 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 ribosomal RNA (rRNA) genes, with a consequent impairment of ribosomal DNA (rDNA) function, could lead to a new understanding of the phenomenon.

On the basis of this evidence, we investigated whether changes in the DNA methylation patterns of the rRNA gene promoter take place during the lifetime. DNA samples were extracted from whole blood collected from differently aged human individuals displaying different phenotypes according to cognitive, functional, and psychological parameters. We did not find a consistent statistically significant association between the methylation levels of the analyzed CpG sites with the age of the donor. On the other hand, although it is not associated with chronological aging, in middle/advanced-aged subjects the variability of CpG_5 methylation was found to be significantly correlated with both cognitive performances and survival in the 9-year follow-up period. This last result, which held multiple test correction, was further confirmed in the replication sample.

Our results seem to be particularly attractive, because they show a fine remodeling of the methylation profile associated with the biological aging rather than to the chronological age. The effects at molecular levels of the above association have to be clarified, but it is plausible to hypothesize that the decrease in the rRNA levels we observed late in life may be determined by the methylation of the CpG_5 site that in turn might be driven by multiple factors, including genetic variations, diet, environment, and the interindividual variation of the structure of rDNA cluster itself.

How could the methylation changes of peculiar CpG sites be functionally involved in the functional decline characterizing the aging process? If the epigenetic modification of functional sites may hamper ribosomal biogenesis, this may drastically reduce the cellular protein synthesis, being ultimately responsible of those multisystem deficits occurring over the lifetime. Thus, an interdependence seems to exist between rDNA promoter methylation and the aging process, and in particular with the aging associated decay, and these sites may represent an potential evolutionary conserved biomarker of the rate of the aging process.




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