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Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
Ryan R White1, Brandon Milholland1, Alain de Bruin2
1Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, New York 10461, USA.
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.
Insights
This study shows that DNA double-strand breaks (DSBs) alone can induce aging phenotypes in mouse liver. This provides direct evidence for DNA damage as a key driver of aging.
Area of Science:
- Molecular Biology
- Genetics
- Gerontology
Background:
- DNA damage is linked to aging, but direct causal evidence is limited.
- Inducing specific DNA lesions without collateral damage is challenging.
Purpose of the Study:
- To investigate if DNA double-strand breaks (DSBs) alone can cause aging phenotypes.
- To provide direct evidence for the role of DNA damage in aging.
Main Methods:
- Utilized an adenovirus system for tetracycline-controlled expression of the SacI restriction enzyme to induce DSBs in mouse liver.
- Compared molecular and cellular aging markers in treated mice with normally aged controls.
Main Results:
- Mice treated with DSBs exhibited signs of liver aging, including pathologies and senescence markers, within one month.
- Observed fused mitochondria and altered gene expression profiles consistent with aging.
- Not all signs of normal aging were present, suggesting DSBs are a significant but not sole factor.
Conclusions:
- DNA double-strand breaks (DSBs) are sufficient to induce distinct aging phenotypes in mouse liver.
- This research offers new insights into DNA damage as a driver of tissue aging.
- The findings support a causal link between DNA damage and the aging process.
