Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.
Bibliographical noteFunding Information:
We thank Oliver Hobert, Esther Serrano-Saiz, Derek Seiburth, Jason Chan, Peter Chisnell, Cynthia Kenyon, Pankaj Kapahi, Simon Melov, and Noelle L'Etoile for reagents and/or technical assistance. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We are grateful to Georgia Woods, Vincent O' Connor, and members of the Lithgow, Holden-Dye, Kapahi, and Melov laboratories for useful discussion and comments on the manuscript. M.L. was supported by National Institutes of Health (NIH) Training Grant T32 AG000266 and an Ellison Medical Foundation/American Federation of Aging Research Post-Doctoral Fellowship. F.C. was funded by grant BB/L02439X/1. This work was supported by a Larry L. Hillblom Foundation grant, as well as National Institutes of Health grants; RL1 GM084432 to R.E.H; AG036992 to M.S.G.; UL1024917, supporting the Interdisciplinary Research Consortium on Geroscience, and 1R01AG029631-01A1 to G.J.L.
© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
- Drug Discovery
- dietary restriction