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; Jan Vijg

doi:10.1038/ncomms7790

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, Jan Vijg

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Article number	6790
Journal	Nature Communications [E]
Volume	6
DOIs	https://doi.org/10.1038/ncomms7790
Publication status	Published - 2015

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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.",

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year = "2015",

doi = "10.1038/ncomms7790",

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volume = "6",

journal = "Nature Communications [E]",

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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

PY - 2015

Y1 - 2015

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.

U2 - 10.1038/ncomms7790

DO - 10.1038/ncomms7790

M3 - Article

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SN - 2041-1723

VL - 6

JO - Nature Communications [E]

JF - Nature Communications [E]

M1 - 6790

ER -

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

Abstract

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