Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing

• DOI: 10.1038/ncomms7790
• Publication Date: 2015-04-10T11:07:25Z
• Authors: Ryan R. White; Brandon Milholland; Alain de Bruin; Samuel Curran; Remi-Martin Laberge; Harry van Steeg; Judith Campisi; Alexander Y. Maslov; Jan Vijg
• Keywords: Male; 0301 basic medicine; Aging; Mice, Inbred BALB C; 0303 health sciences; DNA Repair; Gene Expression Profiling; Genetic Vectors; DNA; Tetracycline; Article; Adenoviridae; 3. Good health; Mice; 03 medical and health sciences; Gene Expression Regulation; Liver; Animals; DNA Breaks, Double-Stranded; Transgenes; Deoxyribonucleases, Type II Site-Specific; Biomarkers

AbstractDNA damage has been implicated in ageing, but direct evidence for a causal relationship is lacking, owing to the difficulty of inducing defined DNA lesions in cells and tissues without simultaneously damaging other biomolecules and cellular structures. Here we directly test whether highly toxic DNA double-strand breaks (DSBs) alone can drive an ageing phenotype using an adenovirus-based system based on tetracycline-controlled expression of the SacI restriction enzyme. We deliver the adenovirus to mice and compare molecular and cellular end points in the liver with normally aged animals. Treated, 3-month-old mice display many, but not all signs of normal liver ageing as early as 1 month after treatment, including ageing pathologies, markers of senescence, fused mitochondria and alterations in gene expression profiles. These results, showing that DSBs alone can cause distinct ageing phenotypes in mouse liver, provide new insights in the role of DNA damage as a driver of tissue ageing.