Estrogen, Insulin, and Dietary Signals Cooperatively Regulate Longevity Signals to Enhance Resistance to Oxidative Stress in Mice

Abstract

To investigate the biological significance of a longevity mutation found in daf-2 of Caenorhabditis elegans, we generated a homologous murine model by replacing Pro-1195 of insulin receptors with Leu using a targeted knock-in strategy. Homozygous mice died in the neonatal stage from diabetic ketoacidosis, whereas heterozygous mice showed the suppressed kinase activity of the insulin receptor but grew normally without spontaneously developing diabetes during adulthood. We examined heterozygous insulin receptor mutant mice for longevity phenotypes. Under 80% oxygen, mutant female mice survived 33.3% longer than wild-type female mice, whereas mutant male mice survived 18.2% longer than wild-type male mice. These results suggested that mutant mice acquired more resistance to oxidative stress, but the benefit of the longevity mutation was more pronounced in females than males. Manganese superoxide dismutase activity in mutant mice was significantly upregulated, suggesting that the suppressed insulin signaling leads to an enhanced antioxidant defense. To analyze the molecular basis of the gender difference, we administered estrogen to mutant mice. It was found that the survival of mice under 80% oxygen was extended when they were administered estradiol. In contrast, mutant and wild-type female mice showed shortened survivals when their ovaries were removed. The influence of estrogen is remarkable in mutant mice compared with wild-type mice, suggesting that estrogen modulates insulin signaling in mutant mice. Furthermore, we showed additional extension of survival under oxidative conditions when their diet was restricted. Collectively, we show that three distinct signals; insulin, estrogen, and dietary signals work in independent and cooperative ways to enhance the resistance to oxidative stress in mice.

Evaluation of sex differences on mitochondrial bioenergetics and apoptosis in mice

“…When this transcription factor is activated, it is imported to the nucleus, where it stimulates transcription of MnSOD and GPx genes (Borras et al, 2005). Although, some reports show that female rats have higher antioxidant concentration and activity than male rats (Borras et al, 2003;Baba et al, 2005), others did not found such difference (Jang et al, 2004;Sverko et al, 2002Sverko et al, , 2004. This indicates that estrogen regulation may increase antioxidant defenses in some, but not in all strains.…”

The insulin signaling cascade from nematodes to mammals: Insights into innate immunity of Anopheles mosquitoes to malaria parasite infection

“…In a manner similar to the connections between the ISC and aging in other organisms, there is evidence for a role for IGF-I in the control of longevity in mammals. Specifically, mice heterozygous for an IGF receptor mutation exhibited a 33% increase in longevity and upregulated MnSOD activity [21]. In mice, as in fruit flies, overexpression of catalase targeted to the mitochondria lengthened lifespan and reduced oxidative tissue damage, including H 2 O 2 -induced aconitase inactivation and the development of mitochondrial deletions relative to control animals [22].…”

Mos1Mutagenesis Reveals a Diversity of Mechanisms Affecting Response ofCaenorhabditis elegansto the Bacterial PathogenMicrobacterium nematophilum

“…This pathway is also implicated in environmental stress response pathways and longevity in C. elegans as well as other organisms (Kenyon et al 1993;Tatar et al 2003;Baba et al 2005;Gami and Wolkow 2006). These studies have identified conserved host factors used against virulent pathogens with a generalized host range.…”