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Updated: May 31, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility
Daniel R McNeill1, Ping-Chang Lin, Marshall G Miller
1Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, IRP, Biomedical Research Center, Baltimore, MD 21224, USA.
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.
Insights
XRCC1 heterozygous mice show normal aging and lifespan but may have developmental issues and increased cancer risk when exposed to toxins. This highlights XRCC1
Area of Science:
- Genetics and Molecular Biology
- Aging Research
- DNA Repair Mechanisms
Background:
- Oxidative DNA damage contributes to aging and disease.
- XRCC1 (X-ray repair cross-complementing protein 1) is crucial for repairing oxidative DNA damage, especially single-strand breaks.
Purpose of the Study:
- To investigate the effects of XRCC1 haploinsufficiency on aging and disease susceptibility in mice.
- To evaluate the role of XRCC1 in chronological aging, biological aging markers, development, and response to genotoxic stress.
Main Methods:
- Assessment of chronological aging parameters (lifespan) in XRCC1 heterozygous (HZ) and wild-type (WT) mice.
- Evaluation of biological aging markers including weight, body composition, blood chemistry, organ health, behavior, brain function, and chromosomal integrity.
- Exposure of HZ and WT mice to the alkylating agent azoxymethane to assess genotoxicity and disease susceptibility.
Main Results:
- HZ and WT mice exhibited similar median lifespans (~26 months) and maximal life expectancies (~37 months).
- A subset of HZ mice displayed abdominal organ rupture, suggesting potential developmental abnormalities.
- Most evaluated aging parameters, including weight, body fat, blood chemistry, organ condition, behavior, brain metrics, and chromosome/telomere integrity, were normal in HZ mice.
- Azoxymethane treatment led to liver toxicity and increased precancerous colon lesions in HZ mice compared to WT.
Conclusions:
- XRCC1 haploinsufficiency has minimal impact on lifespan and general aging markers in mice without environmental challenges.
- XRCC1 haploinsufficiency may negatively affect normal development and increase susceptibility to genotoxic agents and associated diseases.
- These findings underscore the importance of XRCC1 in development and in mitigating risks from environmental genotoxic exposures.
