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

Caenorhabditis Elegans Orthologs of Human Genes Differentially Expressed With Age Are Enriched for Determinants of Longevity

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Free PMC article

Caenorhabditis Elegans Orthologs of Human Genes Differentially Expressed With Age Are Enriched for Determinants of Longevity

George L Sutphin et al. Aging Cell. .
Free PMC article

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.

Figures

Figure 1
Figure 1
RNAi knockdown of 36 of 82 genes in CHARGE gene set increases lifespan at 25 °C. Bars indicate percent change in mean lifespan for RNAi targeting CHARGE genes relative to experiment‐matched EV(RNAi) when experiments were pooled. Error bars are standard error. Blue bars indicate RNAi clones that increased lifespan by our significance criteria. For each Caenorhabditis elegans gene, the table to the left indicates the corresponding human ortholog, the ortholog confidence category (high‐confidence ortholog, HCO; related protein, RP), the life stage at which RNAi was started, and the direction of change in expression of each human gene with age in specified tissues [lymphoblastoid cell line, LCL; peripheral blood mononuclear cell, PBMC; assembled from Peters et al. (2015)].
Figure 2
Figure 2
CHARGE gene set is enriched for longevity determinants at 25 °C. Worms fed RNAi targeting CHARGE genes lived significantly longer than worms fed RNAi targeting Random genes at 25 °C (P < 0.0001) (A), but not at 15 °C (P = 0.927, linear mixed‐effects model) (B). Lines represent mean percent lifespan extension for candidate RNAi relative to experiment‐matched EV(RNAi). RNAi are rank‐ordered by mean lifespan extension (left to right). (C) Lifespan extension at 15 and 25 °C is significantly correlated for Random, but not CHARGE genes (R = Pearson correlation coefficient).
Figure 3
Figure 3
RNAi knockdown of selected genes differentially affects lifespan, reproduction, and healthspan. (A) RNAi knockdown of kynu‐1, iglr‐1, tsp‐3, rcan‐1, or unc‐36 extends lifespan at 25 °C. kynu‐1(RNAi) alone (B) extends lifespan at 15 °C and (C) increases total brood size at 25 °C. (D) RNAi knockdown of kynu‐1, iglr‐1, tsp‐3, or rcan‐1, but not unc‐36 delays decline in motivated speed with age (top), while unmotivated speed is largely unaffected (middle). RNAi knockdown of kynu‐1, iglr‐1, rcan‐1, or unc‐36, but not tsp‐3, increases thrashing rate in liquid early in life (bottom). *P < 0.05 vs. age‐matched EV(RNAi). For box and whisker plots, center line indicates median, boxes indicate 25th and 75th percentiles, and whiskers indicate 5th and 95th percentiles.
Figure 4
Figure 4
Each candidate aging gene interacts with known aging pathways in a distinct manner. (A) Summary of lifespan interaction between kynu‐1, iglr‐1, tsp‐3, rcan‐1, or unc‐36 and aging pathway mutants: insulin signaling (daf‐16), hypoxic response (hif‐1), DR (eat‐2), mTOR signaling (rsks‐1), and sirtuins (sir‐2.1). Each point represents the mean lifespan for an RNAi (x‐axis) applied to a specific strain (line color) for pooled data. Error bars are standard error. *P < 0.05 vs. EV(RNAi) (Wilcoxon rank sum test with Bonferroni multiple test correction). (B) Survival curves for tsp‐3(RNAi) in hif‐1 (left) or daf‐16 (right) mutants. (C) Survival curves for rcan‐1(RNAi) in eat‐2 (top) or rsks‐1 (bottom) mutants. (D) Survival curves for unc‐36(RNAi) in eat‐2 (top) or rsks‐1 (bottom) mutants.
Figure 5
Figure 5
RNAi knockdown of kynu‐1 and tdo‐2 produces distinct aging phenotypes. (A) kynu‐1(RNAi) or tdo‐2(RNAi) robustly extends lifespan at 15 and 25 °C and (B) delays pathology in worms expressing amyloid‐beta (Aβ; modeling Alzheimer's disease) or a 35‐unit polyglutamine repeat (Q35; modeling Huntington's disease) in body wall muscle at 15 °C. (C) Neither kynu‐1(RNAi) nor tdo‐2(RNAi) affects the number of Q35::YFP aggregates that accumulate with age (top). tdo‐2(RNAi) significantly reduces total Q35::YFP volume per worm at all ages, while kynu‐1(RNAi) only does so in middle‐aged worms. *P < 0.05 vs. EV(RNAi) (Student's t‐test). (D) tdo‐2(RNAi) significantly reduces brood size at 15 °C, while kynu‐1(RNAi) significantly increases brood size at 25 °C. *P < 0.05 vs. EV(RNAi) (Student's t‐test). kynu‐1(RNAi), but not tdo‐2(RNAi), extends lifespan of (E) daf‐16 mutants at 25 °C, (F) eat‐2 mutants at 15 °C, and (G) rsks‐1 mutants at 15 °C. For box and whisker plots, center line indicates median, boxes indicate 25th and 75th percentiles, and whiskers indicate 5th and 95th percentiles.

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References

    1. Avery L (1993) The genetics of feeding in Caenorhabditis elegans . Genetics 133, 897–917. - PMC - PubMed
    1. Bell R, Hubbard A, Chettier R, Chen D, Miller JP, Kapahi P, Tarnopolsky M, Sahasrabuhde S, Melov S, Hughes RE (2009) A human protein interaction network shows conservation of aging processes between human and invertebrate species. PLoS Genet. 5, e1000414. - PMC - PubMed
    1. Bennett CF, Vander Wende H, Simko M, Klum S, Barfield S, Choi H, Pineda VV, Kaeberlein M (2014) Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans . Nat. Commun. 5, 3483. - PMC - PubMed
    1. de Castro E, Hegi de Castro S, Johnson TE (2004) Isolation of long‐lived mutants in Caenorhabditis elegans using selection for resistance to juglone. Free Radic. Biol. Med. 37, 139–145. - PubMed
    1. Chen D, Pan KZ, Palter JE, Kapahi P (2007) Longevity determined by developmental arrest genes in Caenorhabditis elegans . Aging Cell 6, 525–533. - PMC - PubMed

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