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

doi:10.1073/pnas.0700847104

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

*Max-Planck-Institut fuer Molekulare Genetik, Ihnestrasse 73, 14195 Berlin, Germany;
^†Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, Room M320, One Baylor Plaza, Houston, TX 77030; and
^‡Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Room ND9.124A, 6001 Forest Park, Dallas, TX 75390

Communicated by Keith R. Yamamoto, University of California, San Francisco, CA, January 30, 2007 (received for review November 7, 2006)

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.

Footnotes

^§To whom correspondence should be addressed. E-mail: aantebi{at}bcm.edu
Author contributions: B.G. and V.R. contributed equally to this work; B.G., V.R., H.L., and A.A. designed research; B.G., V.R., D.L., and A.A. performed research; D.L.M., C.L.C., and D.J.M. contributed new reagents/analytic tools; B.G. and V.R. analyzed data; and B.G., V.R., and A.A. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0700847104/DC1.
Freely available online through the PNAS open access option.