Insulin signaling and life span.
Hyperinsulinemia and metabolic diseases are known to be associated with a reduction in life span. In the presence of insulin resistance, insulin signaling is selectively impaired, contributing to longevity shortening. Insulin indeed activates a complex web of intracellular downstream pathways, which are involved in mechanisms regulating longevity, primarily affecting cellular proliferation and apoptosis. Insulin resistance promotes reactive oxygen species (ROS) formation and favors a pro-inflammatory milieu, both these conditions playing a critical role in the reduction of life span. Insulin resistance/hyperinsulinemia also influences longevity regulating other intracellular signaling downstream in a direct or indirect manner, such as the phosphoinositide 3-kinase pathway that appears selectively impaired by insulin resistance. Decreased NAD-dependent deacetylase sirtuin (Sirt) 1 activity may mediate the shortened life span in conditions of insulin resistance. Furthermore, insulin resistance and diabetes may also associate with the telomere shortening, another important regulator of life span. This review will focus on the main intracellular pathways and mediators regulated by insulin and altered by hyperinsulinemia/insulin resistance; it summarizes the underlying mechanisms and provides evidence of these observations in experimental animal models and in human, giving further insight on the hypothesis that insulin signaling may play an important role in life span.
Avogaro
Angelo
A
Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy. angelo.avogaro@unipd.it
de Kreutzenberg
Saula Vigili
SV
Fadini
Gian Paolo
GP
D000818:Animals; D031204:Caloric Restriction; D006801:Humans; D007249:Inflammation / Q000209:etiology; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D008017:Life Expectancy; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013234:Stem Cells / Q000502:physiology; D016615:Telomere / Q000502:physiology
D007328:Insulin; D017382:Reactive Oxygen Species; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D007334:Insulin-Like Growth Factor I; C447939:SIRT1 protein, human; D056564:Sirtuin 1