Impairment of insulin signalling in peripheral tissue fails to extend murine lifespan.

Troy L Merry,Doris Pöhlmann,Doreen Kuhlow,Beate Laube,Andreas F H Pfeiffer,C Ronald Kahn,Kim Zarse,Michael Ristow

doi:10.1111/acel.12610

Abstract

SummaryImpaired insulin/IGF1 signalling has been shown to extend lifespan in model organisms ranging from yeast to mammals. Here we sought to determine the effect of targeted disruption of the insulin receptor (IR) in non‐neuronal tissues of adult mice on the lifespan. We induced hemizygous (PerIRKO +/−) or homozygous (PerIRKO −/−) disruption of the IR in peripheral tissue of 15‐weeks‐old mice using a tamoxifen‐inducible Cre transgenic mouse with only peripheral tissue expression, and subsequently monitored glucose metabolism, insulin signalling and spontaneous death rates over 4 years. Complete peripheral IR disruption resulted in a diabetic phenotype with increased blood glucose and plasma insulin levels in young mice. Although blood glucose levels returned to normal, and fat mass was reduced in aged PerIRKO −/− mice, their lifespan was reduced. By contrast, heterozygous disruption had no effect on lifespan. This was despite young male PerIRKO +/− mice showing reduced fat mass and mild increase in hepatic insulin sensitivity. In conflict with findings in metazoans like Caenorhabditis elegans and Drosophila melanogaster, our results suggest that heterozygous impairment of the insulin signalling limited to peripheral tissues of adult mice fails to extend lifespan despite increased systemic insulin sensitivity, while homozygous impairment shortens lifespan.

Highlights

Longevity is determined by a complex interaction between environmental and genetic factors (Martin et al, 1996)
This was despite young male PerIRKO+/À mice showing reduced fat mass and mild increase in hepatic insulin sensitivity
In conflict with findings in metazoans like Caenorhabditis elegans and Drosophila melanogaster, our results suggest that heterozygous impairment of the insulin signalling limited to peripheral tissues of adult mice fails to extend lifespan despite increased systemic insulin sensitivity, while homozygous impairment shortens lifespan

Summary

Introduction

Longevity is determined by a complex interaction between environmental and genetic factors (Martin et al, 1996). Altering glucose metabolism via the inhibition of glycolysis or the impairment of insulin/IGF1 signalling consistently extends lifespan in C. elegans and D. melanogaster (Friedman & Johnson, 1988; Kenyon et al, 1993; Morris et al, 1996; Clancy et al, 2001; Tatar et al, 2001). The IR appears to play a central role in normal development (Accili et al, 1996; Okamoto et al, 2004), and central nervous system (CNS) IR expression in adulthood is required for the maintenance of glucose homeostasis (Bruning et al, 2000; Koch et al, 2008) This suggests that the absence of the IR in peripheral tissues during early development, and in the CNS during adulthood may contribute to reduced lifespan and diabetic phenotype seen in some prenatal IR knockout models

Results

Discussion

Conclusion