Insulin/IGF-1 signaling and aging.

Insulin and IGF-1 have a high similarity in structure and play pivotal roles in regulation of aging and longevity. Insulin is bound to insulin receptor on cell surface, whereas IGF-1 is bound to IGF1R, but the molecules to transduce intracellular signals are almost identical, including Akt and FoxO. Akt is a kinase to regulate growth and metabolism in various tissues, and among the substrates, FoxO is one of the key transcription factors to regulate expression of a number or genes, including anti-oxidative enzymes. Akt phosphorylates FoxO and sup- presses its activity by promoting translocation to cytoplasm. In yeast, worms and flies, it is known that various mutations to impair insulin/IGF-1 signaling prolong longevity, potentially via activation of FoxO. In mice, however, longevity was prolonged in some models with disrup- tion of insulin/IGF-1 signaling-related genes, whereas it was shortened in others. Moreover, in many cases, prolonged longevity was accompanied by growth retardation or metabolic disorders, which means that they did not live a 'long and healthy' life. It is still controversial whether suppression of insulin/IGF-1 signaling is beneficial in terms of aging also in mammalians.