title: Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing.
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.
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Ryan R
authors: RR
authors: White
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Brandon
authors: B
authors: Milholland
authors: Faculty of Veterinary Medicine, Department of Pathobiology, Dutch Molecular Pathology Center, Utrecht University, Yalelaan1, 3584 CL Utrecht, The Netherlands.
authors: Alain
authors: A
authors: de Bruin
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA.
authors: Samuel
authors: S
authors: Curran
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA.
authors: Remi-Martin
authors: RM
authors: Laberge
authors: National Institute of Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, MA 3721 Bilthoven, The Netherlands.
authors: Harry
authors: H
authors: van Steeg
authors: 1] Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA [2] Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors: Judith
authors: J
authors: Campisi
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Alexander Y
authors: AY
authors: Maslov
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA.
authors: Jan
authors: J
authors: Vijg
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors; D008099:Liver / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013752:Tetracycline / Q000494:pharmacology; D019076:Transgenes
chemical_list: D015415:Biomarkers; D004247:DNA; C024408:endodeoxyribonuclease SacI; D015252:Deoxyribonucleases, Type II Site-Specific; D013752:Tetracycline