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. 2011 Nov 23;2:75. doi: 10.3389/fendo.2011.00075

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Copyright © 2011 Allard and Duan.

This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

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Endocrine signaling pathways affecting longevity. (A) Role of the conserved IIS signaling pathway in longevity regulation. Insulin-like peptides bind to an insulin/IGF receptor on the plasma membrane. Ligand binding causes dimerization of the receptor, activating the intracellular tyrosine kinase domain. Phosphorylation by the receptor kinase domain activates the PI3 Kinase (PI3K). The signaling activity of PI3K, antagonized by the PTEN phosphatase, activates the Akt kinase. Akt phosphorylates FOXO/DAF-16 which is then sequestered in the cytosol. In the absence of IIS signaling, FOXO translocates to the nucleus and activates transcription of longevity promoting genes. AKT signaling also opposes longevity by activating the TOR pathway, which inhibits autophagy, a pro-longevity process. (B) Endocrine signaling in the C. elegans germline longevity pathway. The germ line stem cells send an unknown signal that allows other tissues to detect that they are present. When the germ line stem cells are ablated, the somatic gonad releases the steroid dafachronic acid that binds to the nuclear hormone receptor DAF-12. It is unclear exactly where DAF-12 acts to receive this signal but the intestine is a possible location. As a result of signaling via DAF-12, DAF-16/FOXO activity increases in the nuclei of intestinal cells. This in turn leads to signaling from the intestine to the other tissues that informs them about status of the DAF-16/FOXO in the intestine. INS-7 promotes IIS signaling which suppresses DAF-16/FOXO activity but DAF-16/FOXO in the intestine can down regulate the expression of INS-7 and this may be one mechanism by which intestinal DAF-16/FOXO controls other tissues. (C) Regulation of longevity by 20-hydroxyecdysone (20E) and juvenile hormone (JH) in insects. JH suppresses reproductive diapause which promotes longevity. JH may also negatively affect longevity in other ways. The receptor(s) to which JH binds is unknown. 20E activates the ecdysone receptor which may reduce longevity. IIS engages in cross talk with both JH and 20E and also reduces longevity via other signaling pathways.