Abstract
In general, it is known that the oxidative stress is a principle cause of ageing. In C.elegans, mutant of the gene daf-2, which encodes an insulin/IGF-1 receptor, significantly enhances the resistance for oxidative stress and extremely extends lifespan. However, it is unclear that whether insulin signaling controls the tolerance of oxidative stress and the extension of lifespan in mammals. In order to investigate the relevant biological significance of the mutation that was found in daf-2 longevity mutant of C. elegans, we generated the analogous mouse model for longevity mutant, in which Pro-1195 of insulin receptor (IR) was replaced by Leu. In order to investigate whether IR mutant mice are resistant to oxidative stress, the mice were exposed to 80% oxygen in airtight chamber. The result indicated that IR mutant mice survived longer than wild type mice in oxidative conditions. We demonstrated that the expression and activity of MnSOD were up-regulated in IR mutant mice. Interestingly, we found the gender difference in the tolerance for oxidative stress and the up-regulation of MnSOD in IR mutant mice, suggesting the possibility that one of downstream signals triggered by insulin may be influenced by sex hormones. To investigate the influence of sex hormones, we performed ovariectomy in female mice and administered estrogen in male mice. We demonstrated that the antioxidant system induced by insulin signaling was conserved between C.elegans and mouse. Furthermore, the antioxidant system in mammals was modulated by estrogen and dietary restriction. [Jpn J Physiol 55 Suppl:S33 (2005)]
