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A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans
Shaun Calvert1, Robi Tacutu1, Samim Sharifi1
1Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
Abstract:
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.
Insights
Researchers identified potential anti-aging drugs by analyzing gene expression data. Several compounds, including rapamycin and allantoin, extended lifespan and healthspan in worms, suggesting they mimic caloric restriction (CR) benefits.
Area of Science:
- Aging research
- Geroscience
- Pharmacology
Background:
- Caloric restriction (CR) extends lifespan in various animal models.
- Developing CR mimetics is crucial for translating CR benefits to humans without side effects.
Purpose of the Study:
- To identify novel compounds that mimic the longevity effects of caloric restriction (CR).
- To validate the use of bioinformatics, specifically the Connectivity Map, for discovering CR mimetics.
Main Methods:
- Utilized the Connectivity Map to identify drugs with gene expression profiles similar to CR.
- Tested predicted CR mimetics (rapamycin, allantoin, trichostatin A, LY-294002, geldanamycin) in Caenorhabditis elegans models.
- Assessed lifespan and healthspan effects in wild-type, eat-2 mutant (CR model), and daf-16 mutant worms.
Main Results:
- Five out of eleven predicted compounds, including rapamycin and allantoin, significantly increased lifespan and healthspan in wild-type worms.
- Observed no lifespan extension in eat-2 mutant worms, indicating CR-related mechanisms.
- Rapamycin, allantoin, and trichostatin A extended lifespan in daf-16 worms, suggesting DAF-16-independent action.
- Transcriptional profiling revealed distinct modes of action for rapamycin and allantoin.
Conclusions:
- The bioinformatics approach effectively identified potential CR mimetics.
- Rapamycin, allantoin, and trichostatin A are promising candidates for further investigation as CR mimetics.
- These findings support the use of drug repositioning for longevity research.
