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Aging and the Mammalian Regulatory Triumvirate
C. David Rollo 1 ;
1 Department of Biology, McMaster University, Hamilton, Ontario, Canada ;
Figure 1. Insulin-like growth factor IGF-1 signaling relevant to the target of rapamycin TOR and forkhead transcription factors FOXO. Growth hormone GH upregulates IGF1 in early sleep both directly and by downregulating IGF-1 binding protein 1 IGFBP-1. IGF-1 activates two pathways PI3K-AKT and MAPKERK that both regulate protein
synthesis and growth processes. IGF-1 activity generates free radicals via membrane-bound NADPH oxidases. Oxidation of phosphatases disinhibits kinase signaling and both
IGF-1 signaling pathways. The toggle switch regulating TOR-FOXO antagonism is bifurcation of PI3K signaling according to the phosphorylation status of Protein Kinase B
PKBAKT. Activated PKBAKT inhibits FOXO and activates TOR via disinhibitory signaling to tuberous sclerosis factor 2 TSC2. Inhibition of TSC2 releases activity of Rheb Ras
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homolog enriched in brain
which in turn activates TOR. TOR signaling then activates eukaryotic initiation factor elF4E and S6 protein kinase S6K activity required for protein
synthesis. Stress, amino acid availability and energy supply strongly modulate TOR activity. REDD1 regulated in development and DNA damage-1 signals status of diverse
stressors and AMP activated protein kinase AMPK reflects energy associated with AMPATP status. S6K is also a sensor of amino acids and energy and is implicated in insulin
resistance via impacts on the insulin receptor substrate. Lack of insulin and IGF-1 signaling, termination of oxidase activity, activation of phosphatases PTEN and PP2A and
unphosphorylated PKBAkt inhibits TOR and releases FOXO nuclear localization and activation in late sleep. Modified after Rollo [ 20 ].