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

George L Sutphin,Teresa Liu,Susan Sheehan,Joyce B J Van Meurs,Joanne M Murabito,Caroline Corban,Shannon Bean,Ron Korstanje,Andrew D Johnson,Marjolein J Peters,Grant Backer

doi:10.1111/acel.12595

Abstract

SummaryWe report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity‐correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu‐1), a neuronal leucine‐rich repeat protein (iglr‐1), a tetraspanin (tsp‐3), a regulator of calcineurin (rcan‐1), and a voltage‐gated calcium channel subunit (unc‐36). Knockdown of each gene extended healthspan without impairing reproduction. kynu‐1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu‐1, tsp‐3, and rcan‐1 are of particular interest for immediate follow‐up. kynu‐1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp‐3 is a novel modulator of hypoxic signaling and rcan‐1 is a context‐specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age‐associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow‐up.

Highlights

Understanding which molecular processes contribute to aging is critical to developing interventions capable of extending healthy human lifespan and delaying onset of age-associated diseases
Our initial goal was to determine which genes were capable of directly influencing lifespan in C. elegans
We identified C. elegans orthologs for each human gene using the WORMHOLE ortholog prediction tool (Sutphin et al, 2016), yielding 88 C. elegans orthologs corresponding to 61 of the 125 human candidate genes (Tables 1 and S2, Supporting information)

Summary

Introduction

Understanding which molecular processes contribute to aging is critical to developing interventions capable of extending healthy human lifespan and delaying onset of age-associated diseases. A key step in this process is building a comprehensive model encompassing the range of genetic and environmental factors that influence lifespan and describing the complex interaction between these factors in an aging organism. Genetic screens in the nematode, Caenorhabditis elegans, have identified hundreds of genes capable of influencing lifespan (Yanos et al, 2012; Sutphin & Korstanje, 2016). Pharmacological agents identified as prolongevity using invertebrate models – rapamycin, metformin, resveratrol – are in clinical trials for treatment of age-associated disease in humans (Kennedy & Pennypacker, 2015)

Results

Discussion

Conclusion