InsulinIGF1 Signaling

Among the most extensively studied mouse models of delayed aging are the Ames and Snell dwarf mice, which harbor mutations in transcription factors that regulate pituitary development. Such mice are among the longest lived of all the delayed-aging mouse models, showing life span increases of 50% to 70% and postponement of all major age-related pathologies. Both models are deficient from birth in several hormones, but the most important deficiency is growth hormone, because very similar effects are achieved by germline disruption in the growth hormone receptor (161). In turn, the most important consequence of growth hormone deficiency for life-span extension is the marked reduction in IGF-1 production (158). These mice also show a reduction in insulin levels (158). Moreover, cells from these animals are resistant to multiple exogenous stresses, although it is not known whether this stress resistance is due to reduced senescence or reduced apoptosis (162).

Mice that are constitutively deficient in growth hormones and IGF-1 suffer from dwarfism, compromised fertility, and other problems (163). However, mouse models in which there is a more modest reduction in IGF-1 signaling, for example, mice in which only one copy of the IGF-1 receptor was genetically inactivated, are phenotypically normal yet long lived (164). In this case, however, life span extension was also modest (16-33%). Likewise, genetic manipulations that selectively eliminate the insulin receptor in adipose tissue increase longevity, but again only modestly (<20%) (165). Thus, blunting the insulin/IGF-1 pathway increases longevity in mice, as it does in simpler organisms, although to a significantly lesser extent.

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