Prediction of C. elegans Longevity Genes by Human and Worm Longevity Networks

Abstract

Intricate and interconnected pathways modulate longevity, but screens to identify the components of these pathways have not been saturating. Because biological processes are often executed by protein complexes and fine-tuned by regulatory factors, the first-order protein-protein interactors of known longevity genes are likely to participate in the regulation of longevity. Data-rich maps of protein interactions have been established for many cardinal organisms such as yeast, worms, and humans. We propose that these interaction maps could be mined for the identification of new putative regulators of longevity. For this purpose, we have constructed longevity networks in both humans and worms. We reasoned that the essential first-order interactors of known longevity-associated genes in these networks are more likely to have longevity phenotypes than randomly chosen genes. We have used C. elegans to determine whether post-developmental inactivation of these essential genes modulates lifespan. Our results suggest that the worm and human longevity networks are functionally relevant and possess a high predictive power for identifying new longevity regulators.

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

“…This worm longevity network was successfully used to predict new longevity regulators, and we have shown that the first‐order interactors of known worm LAGs are also likely to participate in the regulation of lifespan (Tacutu et al ., 2012). As such, it is interesting to know how many more non‐LAG targets belong to the worm longevity network (Fig.…”

Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity

“…Gene dosage may have played a role too, for example, some genes previously reported to influence lifespan [e.g., Cdk5 in flies (Connell‐Crowley et al., 2007) and Clock (ortholog of Clk ) in mice (Dubrovsky, Samsa & Kondratov, 2010)] did not show the same effect upon shRNA knockdown. The longevity effects we observed for Gdi and rab5 were consistent in both genders and agree with the prior findings in worms (Samuelson, Carr & Ruvkun, 2007; Tacutu et al., 2012). Also, tkv and PH4alphaEFB emerged as two candidates for lifespan extension in female flies (Figure 4).…”

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

“…Tacutu et al . (2012) found that knockdown of 27% of C. elegans orthologs of genes found in human or worm longevity protein–protein interaction networks increased lifespan. While differences in strain, environment, and criteria for identifying long‐lived candidates make comparison between screens necessarily qualitative, it is remarkable that preselection of C. elegans orthologs of human genes differentially expressed with age resulted in a similar enrichment for longevity determinants as preselection based on secondary phenotypes known to correlate with C. elegans longevity.…”