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

Aging Cell. 2017 Aug;16(4):672-682. doi: 10.1111/acel.12595. Epub 2017 Apr 12.

Abstract

We 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.

Keywords: Caenorhabditis elegans; Homo sapiens; aging; comparative genetics; lifespan; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Gene Expression Regulation, Developmental*
  • Gene Ontology
  • Genome*
  • Genome-Wide Association Study
  • Humans
  • Hydrolases / antagonists & inhibitors
  • Hydrolases / genetics
  • Hydrolases / metabolism
  • Longevity / genetics*
  • Molecular Sequence Annotation
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Proteins / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Tetraspanins / antagonists & inhibitors
  • Tetraspanins / genetics
  • Tetraspanins / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Calcium Channels
  • Muscle Proteins
  • Proteins
  • RNA, Small Interfering
  • Tetraspanins
  • UNC-36 protein, C elegans
  • leucine-rich repeat proteins
  • Hydrolases
  • kynureninase