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.
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Acknowledgements
The authors acknowledge Prof. John Sedivy (Department of Molecular Biology, Brown University, Providence, RI, USA) for providing DNA of fetal lung fibroblasts; Antonino Romeo (Radiotherapy Unit, IRST-IRCCS Meldola, Forlì) for their technical assistance for gamma radiation exposure experiments; Michela Cortesi and Sara Pignatta (Bioscience Laboratory, IRST-IRCCS Meldola, Forlì) for their technical assistance in comet assay and cytofluorimetric analysis experiments. A particular acknowledge to Michele Guescini (University of Urbino) for his technical assistance on EV isolation and characterization and to Cristina Fabbri (University of Bologna) for primary fibroblasts cultures. This work has been supported by (1) the EU-FP7 Projects under the grant agreements no. 613979 “MyNewGut”; no. 602757 “HUMAN” to CF; (2) by the EU-H2020 Project under the grant agreement no. 634821 “Propag-ageing” to CF; (3) by Roberto and Cornelia Pallotti Legacy for Cancer Research (University of Bologna) to MB and SS; (4) by Bologna AIL (Italian Association against Leukemia, Lymphoma and Myeloma.
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Storci, G., De Carolis, S., Papi, A. et al. Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians. Cell Death Differ 26, 1845–1858 (2019). https://doi.org/10.1038/s41418-018-0255-8
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DOI: https://doi.org/10.1038/s41418-018-0255-8
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