Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians

Gianluca Storci, Sabrina De Carolis, Alessio Papi, Maria Giulia Bacalini, Noémie Gensous, Elena Marasco, Anna Tesei, Francesco Fabbri, Chiara Arienti, Michele Zanoni, Anna Sarnelli, Spartaco Santi, Fabiola Olivieri, Emanuela Mensà, Silvia Latini, Manuela Ferracin, Stefano Salvioli, Paolo Garagnani, Claudio Franceschi, Massimiliano Bonafè

Research output: Contribution to journalArticle

Abstract

Current literature agrees on the notion that efficient DNA repair favors longevity across evolution. The DNA damage response machinery activates inflammation and type I interferon signaling. Both pathways play an acknowledged role in the pathogenesis of a variety of age-related diseases and are expected to be detrimental for human longevity. Here, we report on the anti-inflammatory molecular make-up of centenarian's fibroblasts (low levels of IL-6, type 1 interferon beta, and pro-inflammatory microRNAs), which is coupled with low level of DNA damage (measured by comet assay and histone-2AX activation) and preserved telomere length. In the same cells, high levels of the RNAseH2C enzyme subunit and low amounts of RNAseH2 substrates, i.e. cytoplasmic RNA:DNA hybrids are present. Moreover, RNAseH2C locus is hypo-methylated and RNAseH2C knock-down up-regulates IL-6 and type 1 interferon beta in centenarian's fibroblasts. Interestingly, RNAseH2C locus is hyper-methylated in vitro senescent cells and in tissues from atherosclerotic plaques and breast tumors. Finally, extracellular vesicles from centenarian's cells up-regulate RNAseH2C expression and dampen the pro-inflammatory phenotype of fibroblasts, myeloid, and cancer cells. These data suggest that centenarians are endowed with restrained DNA damage-induced inflammatory response, that may facilitate their escape from the deleterious effects of age-related chronic inflammation.

Original languageEnglish
Pages (from-to)1845-1858
Number of pages14
JournalCell Death and Differentiation
Volume26
Issue number9
DOIs
Publication statusPublished - Sep 2019

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Storci, G., De Carolis, S., Papi, A., Bacalini, M. G., Gensous, N., Marasco, E., Tesei, A., Fabbri, F., Arienti, C., Zanoni, M., Sarnelli, A., Santi, S., Olivieri, F., Mensà, E., Latini, S., Ferracin, M., Salvioli, S., Garagnani, P., Franceschi, C., & Bonafè, M. (2019). Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians. Cell Death and Differentiation, 26(9), 1845-1858. https://doi.org/10.1038/s41418-018-0255-8