Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity |
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| Authors: | George L Sutphin Grant Backer Susan Sheehan Shannon Bean Caroline Corban Teresa Liu Marjolein J Peters Joyce B J van Meurs Joanne M Murabito Andrew D Johnson Ron Korstanje the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Gene Expression Working Group |
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| Affiliation: | 1. The Jackson Laboratory, Bar Harbor, ME, USA;2. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands;3. Section 4. of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA;5. The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA;6. Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA |
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| 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. |
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