Authors: Gerisch B; Rottiers V; Li D; Motola DL; Cummins CL; Lehrach H; Mangelsdorf DJ; Antebi A
Abstract: Broad aspects of Caenorhabditis elegans life history, including larval developmental timing, arrest at the dauer diapause, and longevity, are regulated by the nuclear receptor DAF-12. Endogenous DAF-12 ligands are 3-keto bile acid-like steroids, called dafachronic acids, which rescue larval defects of hormone-deficient mutants, such as daf-9/cytochrome P450 and daf-36/Rieske oxygenase, and activate DAF-12. Here we examined the effect of dafachronic acid on pathways controlling lifespan. Dafachronic acid supplementation shortened the lifespan of long-lived daf-9 mutants and abolished their stress resistance, indicating that the ligand is "proaging" in response to signals from the dauer pathways. However, the ligand extended the lifespan of germ-line ablated daf-9 and daf-36 mutants, showing that it is "antiaging" in the germ-line longevity pathway. Thus, dafachronic acid regulates C. elegans lifespan according to signaling state. These studies provide key evidence that bile acid-like steroids modulate aging in animals.
Keywords: Adaptation, Physiological/drug effects; Animals; Bile Acids and Salts/*pharmacology; Caenorhabditis elegans/*drug effects/*physiology; Caenorhabditis elegans Proteins/metabolism; Cell Nucleus/drug effects; Cytochrome P-450 Enzyme System/metabolism; Germ Cells/drug effects; Intestines/drug effects; Invertebrate Hormones/*pharmacology; Larva/drug effects; Ligands; Longevity/*drug effects; Receptors, Cytoplasmic and Nuclear/*metabolism; Recombinant Fusion Proteins/metabolism; Signal Transduction/*drug effects; Temperature|
Journal: Proceedings of the National Academy of Sciences of the United States of America Volume: 104 Issue: 12 Pages: 5014-9 Date: March 16, 2007 PMID: 17360327 |
Gerisch B, Rottiers V, Li D, Motola DL, Cummins CL, Lehrach H, Mangelsdorf DJ, Antebi A (2007) A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling. Proceedings of the National Academy of Sciences of the United States of America 104: 5014-9.
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