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1.  Dietary restriction attenuates the accelerated aging phenotype of Sod1−/− mice 
Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the anti-aging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1−/− mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage. We found that dietary restriction increased the life span of Sod1−/− mice 30%, returning it to that of wild type, control mice fed ad libitum. Oxidative damage in Sod1−/− mice was markedly reduced by dietary restriction, as indicated by a reduction in liver and brain F2-isoprostanes, a marker of lipid peroxidation. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1−/− mice fed the dietary restricted-diet compared to Sod1−/− mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver specific pathology, the burden and severity of both neoplastic and non-neoplastic lesions was also significantly reduced in the Sod1−/− mice fed the dietary restricted-diet. These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1−/− mice that arises from increased oxidative stress/damage.
PMCID: PMC3696984  PMID: 23459073
dietary restriction; aging oxidative stress; CuZnSOD
2.  Does Reduced IGF-1R Signaling in Igf1r+/− Mice Alter Aging? 
PLoS ONE  2011;6(11):e26891.
Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo- insufficiency of the IGF-1 receptor (Igf1r+/−) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r+/− mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r+/− mice show reduced IGF-1 signaling. Aged male, but not female Igf1r+/− mice were glucose intolerant, and both genders developed insulin resistance as they aged. Female, but not male Igf1r+/− mice survived longer than wild type mice after lethal paraquat and diquat exposure, and female Igf1r+/− mice also exhibited less diquat-induced liver damage. However, no significant difference between the lifespans of the male Igf1r+/− and wild type mice was observed; and the mean lifespan of the Igf1r+/− females was increased only slightly (less than 5%) compared to wild type mice. A comprehensive pathological analysis showed no significant difference in end-of-life pathological lesions between the Igf1r+/− and wild type mice. These data show that the Igf1r+/− mouse is not a model of increased longevity and delayed aging as predicted by invertebrate models with mutations in the insulin/IGF-1 signaling pathway.
PMCID: PMC3223158  PMID: 22132081

Results 1-2 (2)