TY - JOUR
T1 - Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
AU - White, Ryan R.
AU - Milholland, Brandon
AU - De Bruin, Alain
AU - Curran, Samuel
AU - Laberge, Remi Martin
AU - Van Steeg, Harry
AU - Campisi, Judith
AU - Maslov, Alexander Y.
AU - Vijg, Jan
N1 - Funding Information:
This work was supported by the National Institutes of Health grant AG17242, the Ellison Medical Foundation, the Glenn Foundation, the Sue Golding Graduate Division of the Albert Einstein College of Medicine, and by the Albert Einstein College of Medicine Human Genome Program Pilot project grant (AYM) and the Einstein-Nathan Shock Center of Excellence Pilot and feasibility grant 5P30AG038072–05 (AYM). We thank Dr Rani Sellers and the Histopathology Core, Dr Shahina Maqbool and the Epigenomics Core, Dr Cristina Montagna and the Molecular Cytogenetics Core and the Analytical Imaging Facility of the Albert Einstein College of Medicine for their help and suggestions. We are also grateful to Dr Sameh Youssef of the Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, for performing the lipofuscin analysis. We also thank Brent Calder for his assistance with the analysis of the RNA-seq results and Dr Tao Wang for assistance and recommendations in biostatistics.
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/4/10
Y1 - 2015/4/10
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms7790
DO - 10.1038/ncomms7790
M3 - Article
C2 - 25858675
AN - SCOPUS:84927630671
SN - 2041-1723
VL - 6
JO - Nature communications
JF - Nature communications
M1 - 6790
ER -