title: XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility.
abstract: Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of ~26 months and a nearly identical maximal life expectancy of ~37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated-weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity-HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure.
authors: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, IRP, Biomedical Research Center, Baltimore, MD 21224, USA.
authors: Daniel R
authors: DR
authors: McNeill
authors: Ping-Chang
authors: PC
authors: Lin
authors: Marshall G
authors: MG
authors: Miller
authors: Paul J
authors: PJ
authors: Pistell
authors: Nadja C
authors: NC
authors: de Souza-Pinto
authors: Kenneth W
authors: KW
authors: Fishbein
authors: Richard G
authors: RG
authors: Spencer
authors: Yie
authors: Y
authors: Liu
authors: Christina
authors: C
authors: Pettan-Brewer
authors: Warren C
authors: WC
authors: Ladiges
authors: David M
authors: DM
authors: Wilson
mesh_terms: D000375:Aging / Q000235:genetics*; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D001854:Bone Marrow Cells / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D042822:Genomic Instability; D057895:Haploinsufficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000633:toxicity; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D000477:Alkylating Agents; D004268:DNA-Binding Proteins; D009153:Mutagens; D000076105:X-ray Repair Cross Complementing Protein 1; C000619352:Xrcc1 protein, mouse