DNA damage in normally and prematurely aged mice

Aging Cell

Alexander Y. Maslov⁴  Shireen Ganapathi⁴  Maaike Westerhof⁴  Wilber Quispe-Tintaya⁴  Ryan R. White⁴  Bennett Van Houten²  Erwin Reiling⁵  Martijn E. T. Dollé⁵  Harry van Steeg⁵  Paul Hasty¹  Jan H. J. Hoeijmakers³ 

[1] Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, TX, USA;Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;MGC Department of Genetics, CBG Cancer Genomics Center, Erasmus Medical Center, Rotterdam, The Netherlands;Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA;National Institute of Public Health and the Environment, Bilthoven, The Netherlands

关键词: aging;    DNA damage;    Ercc1;    Ku80;    long‐distance PCR;    premature aging;   

DOI  :  10.1111/acel.12071

来源: Wiley

【 摘 要 】

Summary

Steady-state levels of spontaneous DNA damage, the by-product of normal metabolism and environmental exposure, are controlled by DNA repair pathways. Incomplete repair or an age-related increase in damage production and/or decline in repair could lead to an accumulation of DNA damage, increasing mutation rate, affecting transcription, and/or activating programmed cell death or senescence. These consequences of DNA damage metabolism are highly conserved, and the accumulation of lesions in the DNA of the genome could therefore provide a universal cause of aging. An important corollary of this hypothesis is that defects in DNA repair cause both premature aging and accelerated DNA damage accumulation. While the former has been well-documented, the reliable quantification of the various lesions thought to accumulate in DNA during aging has been a challenge. Here, we quantified inhibition of long-distance PCR as a measure of DNA damage in liver and brain of both normal and prematurely aging, DNA repair defective mice. The results indicate a marginal, but statistically significant, increase in spontaneous DNA damage with age in normal mouse liver but not in brain. Increased levels of DNA damage were not observed in the DNA repair defective mice. We also show that oxidative lesions do not increase with age. These results indicate that neither normal nor premature aging is accompanied by a dramatic increase in DNA damage. This suggests that factors other than DNA damage per se, for example, cellular responses to DNA damage, are responsible for the aging phenotype in mice.

【 授权许可】

Unknown   
© 2013 John Wiley & Sons Ltd and the Anatomical Society