title: Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity.
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.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: George L
authors.identifier: 0000-0002-3659-4678
authors.initials: GL
authors.lastname: Sutphin
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Backer
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Sheehan
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Bean
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Corban
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Peters
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Joyce B J
authors.initials: JBJ
authors.lastname: van Meurs
authors.affiliation: Section of General Internal Medicine, Boston University School of Medicine, 801 Massachusetts Ave, Crosstown Center, Boston, MA, 02118, USA.|The National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Suite 2, Framingham, MA, 01702-5827, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Suite 2, Framingham, MA, 01702-5827, USA.|Population Sciences Branch, National Heart, Lung, and Blood Institute, Building 31, Room 5A52, 31 Center Drive MSC 2486, Bethesda, MD, 20892, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Korstanje
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D063990:Gene Ontology; D016678:Genome; D055106:Genome-Wide Association Study; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090263:Leucine-Rich Repeat Proteins; D008136:Longevity / Q000235:genetics*; D058977:Molecular Sequence Annotation; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D059470:Tetraspanins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D015220:Calcium Channels; D000090263:Leucine-Rich Repeat Proteins; D009124:Muscle Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D059470:Tetraspanins; C585116:UNC-36 protein, C elegans; D006867:Hydrolases; C021480:kynureninase
keywords: 
  Caenorhabditis elegans
  ; 
  Homo sapiens
  ; aging; comparative genetics; lifespan; transcriptomics