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 Maslov, Jan Vijg

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Article number6790
JournalNature Communications
Volume6
DOIs
StatePublished - Apr 10 2015

Fingerprint

Double-Stranded DNA Breaks
liver
Liver
strands
mice
induction
deoxyribonucleic acid
Aging of materials
Tissue
Adenoviridae
DNA Damage
DNA
adenoviruses
Phenotype
phenotype
Poisons
Cellular Structures
Tetracycline
Transcriptome
Mitochondria

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing. / White, Ryan R.; Milholland, Brandon; De Bruin, Alain; Curran, Samuel; Laberge, Remi Martin; Van Steeg, Harry; Campisi, Judith; Maslov, Alexander; Vijg, Jan.

In: Nature Communications, Vol. 6, 6790, 10.04.2015.

Research output: Contribution to journalArticle

White, Ryan R. ; Milholland, Brandon ; De Bruin, Alain ; Curran, Samuel ; Laberge, Remi Martin ; Van Steeg, Harry ; Campisi, Judith ; Maslov, Alexander ; Vijg, Jan. / Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing. In: Nature Communications. 2015 ; Vol. 6.
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