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

Ryan R. White (), Brandon Milholland, Alain de Bruin, Samuel Curran, Remi-Martin Laberge, Harry van Steeg, Judith Campisi, Alexander Y. Maslov and Jan Vijg ()
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Ryan R. White: Albert Einstein College of Medicine
Brandon Milholland: Albert Einstein College of Medicine
Alain de Bruin: Faculty of Veterinary Medicine, Dutch Molecular Pathology Center, Utrecht University
Samuel Curran: Buck Institute for Research on Aging
Remi-Martin Laberge: Buck Institute for Research on Aging
Harry van Steeg: National Institute of Public Health and the Environment (RIVM)
Judith Campisi: Buck Institute for Research on Aging
Alexander Y. Maslov: Albert Einstein College of Medicine
Jan Vijg: Albert Einstein College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract DNA 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.

Date: 2015
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DOI: 10.1038/ncomms7790

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