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

Abstract

Longevity is tightly linked across evolution to the maintenance of genomic stability. Centenarians are long-living subjects who reach the extreme limits of human lifespan, while escaping the inflammatory age-related diseases. Current literature underpins that genomic damage elicits inflammation by engaging cytoplasmic sensors via the misplacement of nucleic acids (including RNA:DNA hybrids) outside the nucleus. Here, we report that high genomic stability (i.e. preserved telomere length) and blunted DNA-damage-induced inflammation characterize centenarian's fibroblasts. This molecular make-up is associated with reduced amounts of cytoplasmic RNA:DNA hybrids. These cells convey high levels of the RNA:DNA degrading enzyme subunit RNAseH2C, whose knock-down up-regulates inflammatory mediators. The RNAseH2C locus is hypomethylated in centenarian's cells, hyper-methylated in senescent cells, and in atherosclerotic plaques and cancer tissues. Noteworthy, RNAseH2C expression and anti-inflammatory phenotype can be elicited in different cell types exposed to Extracellular Vesicles isolated from centenarian's cell cultures. These data provide evidence on the molecular mechanisms that allow centenarians to escape the deleterious effects of inflamm-aging and to avoid inflammatory age-related diseases.Running title: RNAseH2-driven genomic stability in centenarians

Mitochondria, immunosenescence and inflammaging: a role for mitokines?

“…Many other anti-inflammatory molecules are known, including resolvins, maresins, adiponectin, IL-10, TGF-β, etc. Some of them are particularly elevated in centenarians [125][126][127][128], suggesting that these exceptional people owe their longevity, among others, to a successful balancing between pro-and anti-inflammatory mediators. Now, the discovery that other molecules endowed with anti-inflammatory and immunomodulatory activity increase with age not only in centenarians but also in elderly people suggests that a large, comprehensive anti-inflammaging network is physiologically put in place likely as a general attempt of the ageing organism to cope with the progressive increase of chronic inflammation (inflammaging) and its deleterious effects.…”

Novel RNASEH2C mutation in multiple members of a large family: insights into phenotypic spectrum of Aicardi-Goutières Syndrome

“…Mutations involving RNASEH2C gene are associated with impaired ribonucleotide excision repair and accumulation of embedded ribonucleotides 11. In addition, a recent report has highlighted that RNASEH2C knock-down up-regulates interleukin (IL)-6 and type 1 interferon beta suggesting the role of the gene in inflammation 12. The pathogenesis of AGS is immune mediated and inflammatory.…”

Inflamm-Aging: Why Older Men Are the Most Susceptible to SARS-Cov-2 Complicated Outcomes

“…Inflamm-aging is regarded as a major risk factor for the common ARDs, in line with the mounting evidence that an inflammatory pathogenesis is shared by most common ARDs (Franceschi et al, 2000). The situation is different in centenarians, who are characterized by specific prolongevity traits and anti-inflammatory markers that delay ARD onset, which seem to protected them against the adverse outcomes of sustained inflammation (Franceschi, 2007;Storci et al, 2019). In older men with ARDs, who have the highest rate of inflamm-aging, the inflammatory response induced by SARS-CoV2 infection seems to favor a poorer outcome.…”

“…The rate of biological aging (including inflamm-aging) varies among subjects as a result of interactions among genetic make-up, epigenetic modulation, environment, and random factors and can be traced and measured by biomarkers such as TL, circulating nucleic acids, epigenetic changes involving extracellular vesicles, and the expression of inflammatory cytokines such as IL-6 (Ferrucci et al, 2020;Jylhava et al, 2017;Maggio et al, 2006;Mensà et al, 2020;Mensà et al, 2019;Sabbatinelli et al, 2019;Storci et al, 2019). The ability to measure "real" biological age would help determine a person's aging rate.…”