期刊
AGING-US
卷 7, 期 2, 页码 110-122出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100723
关键词
Aging; dermal fibroblasts; alkaline DNA unwinding; DNA double strand break repair; chromosome abnormalities; non-homologous end-joining
资金
- Deutsche Forschungsgemeinschaft [SFB 728, GK 1033]
- German Ministry of Research and Education [Network Gerontosys, Stromal Ageing]
- Cetics Healthcare GmbH, Esslingen, Germany
Dermal fibroblasts provide a paradigmatic model of cellular adaptation to long-term exogenous stress and ageing processes driven thereby. Here we addressed whether fibroblast ageing analysed ex vivo entails genome instability. Dermal fibroblasts from human female donors aged 20-67 years were studied in primary culture at low population doubling. Under these conditions, the incidence of replicative senescence and rates of age-correlated telomere shortening were insignificant. Genome-wide gene expression analysis revealed age-related impairment of mitosis, telomere and chromosome maintenance and induction of genes associated with DNA repair and non-homologous end-joining, most notably XRCC4 and ligase 4. We observed an age-correlated drop in proliferative capacity and age-correlated increases in heterochromatin marks, structural chromosome abnormalities (deletions, translocations and chromatid breaks), DNA strand breaks and histone H2AX-phosphorylation. In a third of the cells from old and middle-aged donors repair of X-ray induced DNA strand breaks was impaired despite up-regulation of DNA repair genes. The distinct phenotype of genome instability, increased heterochromatinisation and (in 30% of the cases futile) up-regulation of DNA repair genes was stably maintained over several cell passages indicating that it represents a feature of geroconversion that is distinct from cellular senescence, as it does not encompass a block of proliferation.
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