Lifespan and Glucose Metabolism in Insulin Receptor Mutant Mice

Insulin/insulin-like growth factor type 1 signaling regulates lifespan and resistance to oxidative stress in worms, flies, and mammals. In a previous study, we revealed that insulin receptor (IR) mutant mice, which carry a homologous mutation found in the long-lived daf-2 mutant of Caenorhabditis elegans, showed enhanced resistance to oxidative stress cooperatively modulated by sex hormones and dietary signals (Baba et al., (2005)). We herein investigated the lifespan of IR mutant mice to evaluate the biological significance of insulin signaling in mice. Under normoxia, mutant male mice had a lifespan comparable to that of wild-type male mice. IR mutant female mice also showed a lifespan similar to that of wild-type female mice, in spite of the fact that the IR mutant female mice acquired more resistance to oxidative stress than IR mutant male mice. On the other hand, IR mutant male and female mice both showed insulin resistance with hyperinsulinemia, but they did not develop hyperglycemia throughout their entire lifespan. These data indicate that the IR mutation does not impact the lifespan in mice, thus suggesting that insulin signaling might have a limited effect on the lifespan of mice. 1. Introduction Accumulating evidence indicates that insulin/insulin-like growth factor type 1 (IGF-1) signaling regulates lifespan in worms, flies, and mammals [1, 2]. In Caenorhabditis elegans, a mutation of the daf-2 gene that encodes an insulin/IGF-1 receptor ortholog significantly extended the lifespan and enhanced the resistance of the worms to oxidative stress [3, 4]. The lifespan extension caused by daf-2 mutations required the activity of daf-16 [3], which encodes a FOXO family transcription factor [5, 6]. Insulin/IGF-1 receptor mutations can also increase the lifespan of Drosophila [7]. In addition, mutations in chico, a downstream insulin receptor (IR) substrate-like signaling protein, increased the lifespan of the flies [8]. In mice, long-lived hereditary dwarf mice have been described [9]. Low levels of circulating growth hormone (GH) and IGF-1 in the Ames and Snell dwarf mice, which have pituitary defects, were associated with an extension of their lifespan [9]. Mutations in upstream genes that regulate insulin and IGF-1 also extended lifespan. For example, Little mice harbor a mutation in the GH-releasing hormone receptor and display reduced GH, as well as prolactin secretion [10]. Little mice also show reduced IGF-1 in blood, and have an increased mean and maximal lifespan [9]. Furthermore, GH receptor (GHR) mutant mice showed reduced circulating