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

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 reduces 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 E. 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/6 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.

Starvation Based Differential Chemotherapy: A Novel Approach for Cancer Treatment

“…20 In the same way IGF-1 signaling deficiency may reduce the probability of spontaneous mutations and tumors in the kidneys and small intestine of DR mice. 37 In individuals with GH-receptor deficiency diabetes and cancer are very rare, but they don't reach older ages. 38 Hormonal changes, as a result of dietary restriction, may include increased adiponectin, and reduced triiodothyronine, testosterone, insulin, cholesterol, C-reactive protein, blood pressure and intima media thickness of carotid arteries, which are risk factors for cardiovascular diseases and cancer.…”

DNA damage and ageing: new-age ideas for an age-old problem

“…When dietary restriction and pituitary dwarfism are combined, an additive extension of lifespan is observed 57 . Thus, suppression of the GH/IGF1 axis is associated with delayed age-related morbidity and longevity, profound metabolic changes (including low serum glucose and insulin), enhanced antioxidant defences and stress resistance, and reduced frequency of somatic mutations 48,58,59 . Conversely, overexpression of GH causes pathology and markedly shortens lifespan 60 .…”

Pleiotropic effects of growth hormone signaling in aging

“…Involvement of other mechanisms in mediating the effects of reduced GH signaling on aging and longevity is suggested by the recent reports that GH-deficient, long-lived Ames dwarf mice differ from normal animals by reduced mutation rate (47), altered expression of multiple microRNA species (48) and genes related to purine metabolism (48), and reductions in the content of extra-cellular collagen in the heart (49) and in the size of cardiomyocytes (49). Reduced cell size likely reflects reduced levels of translation due to diminished levels and activation of mTOR in these animals (21).…”