[IGF and insulin signaling pathways in longevity].
The role of the somatotropic hormone axis in mammalian longevity has been studied in diverse experimental models in vivo. This endocrine axis allows regulation of lifespan via metabolism modifications and oxidative stress defense mechanisms. Signaling can be altered at ligand, receptor or signal transduction molecule level through mutagenesis. Mutant mouse models affecting pituitary differentiation factors Prop-1 or Pit1, cognate receptors of GH, IGF or insulin, or receptor substrates IRS-1 or IRS-2 showed that regulation of the somatotropic endocrine axis is pivotal for maintaining an equilibrium between growth, metabolism, oxidative stress defense and longevity. Brain-specific gene inactivation of IGF-1R and IRS-2 resulted in similarly long-lived phenotypes indicating that control of longevity is possible by selectively targeting the brain. In addition to genetic modification, lifespan can be efficiently manipulated in mice by altering the environment, for instance by modifying caloric intake, or pharmacologically, as has been shown in a recent study about the effects of rapamycin on lifespan. Moreover, recent studies of the human genetics of aging revealed that mutations of IGF-1R and variants of FoxO3a are more frequent in certain centenarian cohorts. This suggested that these results are in principle transposable to humans.
Centre de Recherche Inserm, UMR 938, Université Pierre et Marie Curie, Paris 6, France.
Géraldine
G
Gontier
Martin
M
Holzenberger
D000375:Aging / Q000502:physiology*; D000818:Animals; D020868:Gene Silencing; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008017:Life Expectancy; D008136:Longevity; D051379:Mice; D023421:Models, Animal; D009473:Neuronal Plasticity; D018384:Oxidative Stress; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1