PLoS Biol., published online 10 April 2012, doi:10.1371/journal.pbio.1001305

In Caenorhabditis elegans, bile acid–like steroids called dafachronic acids (DAs) serve as ligands for the nuclear hormone receptor DAF12, which regulates developmental progression and lifespan. DAs are synthesized from dietary cholesterol in a pathway for which several key biosynthetic enzymes and intermediates remain unknown. Now, Wollam et al. apply a genome-wide RNAi screen to identify DHS-16, a conserved short-chain dehydrogenase/reductase, as a new component of the DA biosynthetic pathway. The phenotype of dhs-16 mutants is characteristic of DA deficiency—gonadal migration defects and constitutive dauer formation. Lipid extracts from dhs-16 mutants had less lathosterone and Δ7-DA, its downstream product, than extracts from wild-type animals. Supplementation of the mutants with sterol intermediates pointed to a specific role for DHS-16 in the production of the 3-ketosteroid lathosterone from 3-alcohol sterols such as lathosterol. The authors provided further support for the enzymatic activity of DHS-16 by expressing the protein in HEK293 cells and detecting lathosterone in lipid extracts. It is established that germline-deficient worms live longer and that DAs mediate the lifespan extension. The authors showed that DHS-16 also functions in the gonadal longevity pathway, as it was necessary for the long lifespan of germline-less worms. Future studies will show whether similar small-molecule metabolites and the enzymes controlling their biosynthesis can influence mammalian lifespan.