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Comparative Study
. 2008 Sep;129(9):528-33.
doi: 10.1016/j.mad.2008.04.013. Epub 2008 May 13.

Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues

Ana Maria Garcia  1 , Rita A Busuttil, R Brent Calder, Martijn E T Dollé, Vivian Diaz, C Alex McMahan, Andrzej Bartke, James Nelson, Robert Reddick, Jan Vijg
Affiliations
Comparative Study

Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues

Ana Maria Garcia et al. Mech Ageing Dev. 2008 Sep.

Abstract

Genetic instability has been implicated as a causal factor in cancer and aging. Caloric restriction (CR) and suppression of the somatotroph axis significantly increase life span in the mouse and reduce multiple symptoms of aging, including cancer. To test if in vivo spontaneous mutation frequency is reduced by such mechanisms, we crossed long-lived Ames dwarf mice with a C57BL/6J line harboring multiple copies of the lacZ mutation reporter gene as part of a plasmid that can be recovered from tissues and organs into Escherichia coli to measure mutant frequencies. Four cohorts were studied: (1) ad lib wild-type; (2) CR wild-type; (3) ad lib dwarf; and (4) CR dwarf. While both CR wild-type and ad lib dwarf mice lived significantly longer than the ad lib wild-type mice, under CR conditions dwarf mice did not live any longer than ad lib wild-type mice. While this may be due to an as yet unknown adverse effect of the C57BL/6J background, it did not prevent an effect on spontaneous mutation frequencies at the lacZ locus, which were assessed in liver, kidney and small intestine of 7- and 15-month-old mice of all four cohorts. A lower mutant frequency in the ad lib dwarf background was observed in liver and kidney at 7 and 15 months of age and in small intestine at 15 months of age as compared to the ad lib wild-type. CR also significantly reduced spontaneous mutant frequency in kidney and small intestine, but not in liver. In a separate cohort of lacZ-C57BL/6J mice CR was also found to significantly reduce spontaneous mutant frequency in liver and small intestine, across three age levels. These results indicate that two major pro-longevity interventions in the mouse are associated with a reduced mutation frequency. This could be responsible, at least in part, for the enhanced longevity associated with Ames dwarfism and CR.

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Figures

Figure 1
Figure 1
Breeding scheme. Homozygous C57BL/6J lacZ-plasmid transgenic mice (Prop1+/Prop1+, lacZA/A,B/B), carrying two integration sites, one on chromosome 3 (A) and one on chromosome 4 (B) were crossed to heterozygous Ames dwarf (Prop1df/Prop1+, lacZ−/−,−/−) mice. The heterozygous Ames dwarf F1 (Prop1df/Prop1+, lacZA/−,B/−) were backcrossed with homozygous C57BL/6J lacZ-plasmid transgenic mice (Prop1+/Prop1+, lacZA/A,B/B) up to F5 generation. The F5 heterozygous Ames were backcrossed to the original Ames background and the offspring were used in the experiment. Both homozygous dwarf (DF; Prop1df/Prop1df, lacZA/−,B/−) and wild-type (WT; Prop1+/Prop1+, lacZA/−,B/−) animals were ad lib (AL) fed or calorie-restricted (CR).
Figure 2
Figure 2
Survival plots of Ames dwarf (DF) and wild-type (WT) mice fed ad lib (AL) or calorie restricted (CR).
Figure 3
Figure 3
Mutant frequency at the lacZ reporter locus of Ames dwarf mice and their wild-type littermate controls at 7-month old (white bars) and 15-month old (black bars) animals after caloric restriction or fed ad lib. Error bars represent 95% confidence intervals.
Figure 4
Figure 4
Mutant frequency at the lacZ reporter locus of C57BL/6J mice at 7-, 15- and 25-months of age after caloric restriction (white bars) or fed ad lib (black bars). Error bars represent 95% confidence intervals.
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