Fig. 1.

Insulin/IGF1 signaling affects the lifespan. This pathway involves a cascade of phosphorylation events that ultimately regulate the translocation and activity of FOXO proteins, leading to a change in lifespan. In response to exogenous stimulation (e.g., diet) or growth hormone, the islet cells of the pancreas secrete insulin into the plasma, and liver cells produce IGF-1. Insulin/IGF-1 binds to the receptors, and activates a downstream signaling pathway containing IRS1 (insulin receptor substrate protein 1), PI3K, IP3, PDK1, and AKT. AKT is a kinase that can phosphorylate and inactivate FOXO transcription factors. Both the chronic dietary restriction and decreased concentration of growth hormone could downregulate the activity of these molecules involved in this signaling pathway, and lead to an up-regulated expression of FOXO proteins, resulting in transcriptional regulation and a prolonged lifespan.