This paper might be taken as an interesting sidebar to the large amount of research into the influence of insulin signaling on the pace of aging, a part of the way in which the operation of cellular metabolism determines natural variations in longevity. Many of the methods of slowing aging in laboratory species involve some form of impairment in insulin signaling, usually implemented globally in all tissues and throughout the entire life span via the use of genetic engineering to create an altered lineage of animals. Whether such alterations are global and when in life they occur matters, however. Further, most investigations have taken place in lower species such as flies and worms rather than in mammals. Here, researchers demonstrate that impaired insulin signaling achieved in adulthood and only in tissues other than the nervous system has no positive effect on mammalian life span.
Longevity is determined by a complex interaction between environmental and genetic factors. One of the most successful interventions to delay the onset of aging-associated diseases and increase life expectancy is the chronic reduction in food intake, that is calorie restriction (CR). One of the mechanisms through which CR may extend lifespan is through reduced activation of insulin/IGF1 signalling. Following food intake, insulin is released and acts via the insulin receptor (IR) to facilitate the metabolism of glucose. Altering glucose metabolism via the inhibition of glycolysis or the impairment of insulin/IGF1 signalling consistently extends lifespan in Caenorhabditis elegans and Drosophila melanogaster. However, the effect of insulin/IGF1 signalling cascade inhibition on longevity in mammals is less clear.
In mammals, prenatal complete ablation of the insulin receptor (IR) or IGF1 receptor (IGF1R) globally shortens lifespan, whereas ablation of the IR in some tissues such as the liver and pancreas induces a diabetic phenotype. The IR appears to play a central role in normal development, and central nervous system (CNS) IR expression in adulthood is required for the maintenance of glucose homeostasis. 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. Interestingly, deletion of the IR, which primarily targets adipose tissue but may also act on several other nervous system and peripheral tissues, as well as the disruption of the insulin/IGF1 signalling pathway downstream of the IR, is effective in prolonging lifespan in rodents. Furthermore, some genetic variations in the insulin/IGF1 pathway are associated with increased human lifespan expectancy. This is consistent with the requirement of the IR to facilitate metabolism of glucose in peripheral tissue and indicates that some degree of IR signalling is probably required during development and adulthood for normal life expectancy.
In all of these studies, however, the disruptions in insulin signalling were created using systems that were active from early developmental stages, so little is known about the effects of altered insulin signalling on longevity when the alteration is limited to adulthood. We have previously shown that partial disruption of the IR in mammalian cells causes adaptations, and similar adaptations extend the lifespan of C. elegans. In the present study, we determined the effect of partial or complete adult-induced peripheral tissue IR disruption on metabolism and lifespan of mice. 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 mice, their lifespan was reduced. By contrast, heterozygous disruption had no effect on lifespan. This was despite young male 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.