Figure 2

Insulin/IGF-1 signaling network and its modulation by dietary restriction. Dietary restriction in the form of overall calorie restriction or specific restriction of carbohydrates or protein has specific effects on the insulin/IGF-1 system that transduces cellular signals through its insulin and IGF-1 tyrosine kinase receptors. This picture can only provide a partial overview of the complexity of this signaling network. The classical action of activated extracellular signal-regulated kinase (ERK)-1 and ERK-2 is their translocation into the nucleus where they activate mitogenic transcription factors. Similarly, mTORC1 targets transcription factors that increase proliferation and counteract apoptosis. Activation of mTORC1 via IR/IGF-1R−PI3K−AKT converges with its activation by amino acids at the lysosomal membrane. There, the guanosine triphosphatase (GTPase) Rheb (Ras homolog enriched in brain) stimulates mTOR activity, whereas a lack of growth signals activates the tumor suppressor tuberin (TSC2), which translocates to the lysosomal membrane and inhibits Rheb-stimulated mTORC1 activation.²¹⁴ High insulin levels activate AKT that phosphorylates and inactivates TSC2, whereas CR or glucose withdrawal induce energy stress, decrease the intracellular ATP/AMP ratio and activate TSC2 through liver kinase B1 (LKB1)—adenosine monophosphate-activated protein kinase (AMPK) signaling. AMPK can also directly inhibit mTORC1 by phosphorylating the regulatory-associated protein of mTOR (Raptor). AMPK has similar actions to the class III histone deacetylase SIRT1, which is a NAD⁺-dependent enzyme that is also activated under DR-induced energy stress through an increase in the NAD⁺/NADH ratio.³⁶ AMPK and SIRT1 amplify each other and both activate the peroxisome proliferator-activated receptor gamma 1α coactivator (PGC-1α) protein that cooperates with peroxisome proliferator-activated receptor α (PPARα) to induce major metabolic shifts under DR such as an upregulation of lipid oxidation and downregulation of glycolysis.³⁵ mTORC1 inhibits these actions, providing another link to insulin/IGF-1 signaling.