Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity.
Document Type
Article
Publication Date
8-2017
JAX Source
Aging Cell 2017 Aug; 16(4):672-682.
Volume
16
Issue
4
First Page
672
Last Page
682
ISSN
1474-9726
PMID
28401650
DOI
https://doi.org/10.1111/acel.12595
Grant
AG038070, CA034196
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. Aging Cell 2017 Aug; 16(4):672-682.
Recommended Citation
Sutphin GL,
Backer G,
Sheehan S,
Bean S,
Corban C,
Liu T,
Peters M,
van Meurs J,
Murabito J,
Johnson A,
Korstanje R.
Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity. Aging Cell 2017 Aug; 16(4):672-682.