A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

Abstract

SummaryCaloric 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.

Gene expression‐based drug repurposing to target aging

“…For instance, the Connectivity Map (CMap), a database of drug‐induced gene expression profiles, has been used to identify DR mimetics and found 11 drugs that induced expression profiles significantly similar to those induced by DR in rats and rhesus monkeys (Calvert et al, 2016). Another study generated a combined score reflecting both the aging relevance of drugs based on the GenAge database and GO annotations as well as the likely efficacy of the drugs in model organisms, using structural analyses and other criteria such as solubility (Ziehm et al, 2017).…”

A Biomedical Investigation of the Hepatoprotective Effect of Radix salviae miltiorrhizae and Network Pharmacology-Based Prediction of the Active Compounds and Molecular Targets

“…Secondly, previous researchers explored and provided only a small number of hepatoprotective target genes. Last but not least, stringently assessing the relationships between compounds and corresponding targets and obtaining accurate action modes such as activated drug–target interactions or inhibited drug–target interactions are still a challenge for the present network pharmacology study [46,47]. To resolve these problems, herbal compound libraries should be established and further enriched to better correlate compound functions with structures.…”

“…The integrative efficacy of the ingredients in Danshen was determined by analyzing the compounds and targets interactions obtained from the Search Tool for Interactions of Chemicals and Proteins (STITCH) database(Available online: ) [44], HIT (Herbal Ingredients’ Targets) Database (Available online: ) [45] and omics-based Ligand-Target Chemogenomic model (LTC) [46], respectively. Then, for better defining the role of Danshen in hepatoprotective potentials, these targets were mapped to the Therapeutic Target Database (TTD, Available online: ) [47], PharmGKB (Available online: ) [48], and the Comparative Toxicogenomics Database (CTD, Available online: ) [49] to eliminate the unrelated target protein and provide a more complete and accuracy view on compound-hepatoprotective target associations.…”

High throughput small molecule screening reveals NRF2-dependent and - independent pathways of cellular stress resistance

“…Other screens have revealed the ability of anticonvulsants 16 , angiotensin converting enzyme antagonists 17 , and modulators of other signaling pathways to increase worm lifespan 18, 19 . Recent studies have employed in silico strategies to prioritize compounds for direct lifespan testing in nematodes and other organisms [20][21][22] .…”

“…Cells were then aliquoted into 384-well plates (Greiner cat# 781080) and incubated overnight at 37 o C in a 10% humified CO 2 incubator. On day 2, 0.2 μ l of test compounds (plate columns[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] or DMSO (plate columns 1-2 and 23-24) were added, for an initial compoundconcentration of 16 μ M and initial DMSO concentration of 0.8%. Plates were then incubated overnight.…”