A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling

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.