A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans
Version of Record online: 16 DEC 2015
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 15, Issue 2, pages 256–266, April 2016
How to Cite
Calvert, S., Tacutu, R., Sharifi, S., Teixeira, R., Ghosh, P. and de Magalhães, J. P. (2016), A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans. Aging Cell, 15: 256–266. doi: 10.1111/acel.12432
- Issue online: 8 MAR 2016
- Version of Record online: 16 DEC 2015
- Manuscript Accepted: 8 NOV 2015
- Royal Society. Grant Number: RG120543
- BBSRC DTP studentship. Grant Number: BB/J014516/1
- Marie Curie FP7-PEOPLE-IEF Fellowship within the 7th European Community Framework Programme
- NIH Office of Research Infrastructure Programs. Grant Number: P40 OD010440
- Caenorhabditis elegans ;
- drug repositioning;
Caloric restriction (CR), a reduction in calorie intake without malnutrition, retards aging in several animal models from worms to mammals. Developing CR mimetics, compounds that reproduce the longevity benefits of CR without its side effects, is of widespread interest. Here, we employed the Connectivity Map to identify drugs with overlapping gene expression profiles with CR. Eleven statistically significant compounds were predicted as CR mimetics using this bioinformatics approach. We then tested rapamycin, allantoin, trichostatin A, LY-294002 and geldanamycin in Caenorhabditis elegans. An increase in lifespan and healthspan was observed for all drugs except geldanamycin when fed to wild-type worms, but no lifespan effects were observed in eat-2 mutant worms, a genetic model of CR, suggesting that life-extending effects may be acting via CR-related mechanisms. We also treated daf-16 worms with rapamycin, allantoin or trichostatin A, and a lifespan extension was observed, suggesting that these drugs act via DAF-16-independent mechanisms, as would be expected from CR mimetics. Supporting this idea, an analysis of predictive targets of the drugs extending lifespan indicates various genes within CR and longevity networks. We also assessed the transcriptional profile of worms treated with either rapamycin or allantoin and found that both drugs use several specific pathways that do not overlap, indicating different modes of action for each compound. The current work validates the capabilities of this bioinformatic drug repositioning method in the context of longevity and reveals new putative CR mimetics that warrant further studies.