Isolation of long-lived mutants in Caenorhabditis elegans using selection for resistance to juglone

Castro, Edouard de; Castro, Sarah Hegi de; Johnson, Thomas E.

doi:10.1016/j.freeradbiomed.2004.04.021

Cited by 118 publications

(83 citation statements)

References 32 publications

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“…The percentage of candidate genes that directly affected lifespan at 25 °C (43.9%) was substantially higher than RNAi screens in C. elegans without a preselection criteria (<2%) (Lee et al ., 2003b; Hamilton et al ., 2005; Hansen et al ., 2005; Samuelson et al ., 2007) and within the range for screens that preselected candidates based on secondary C. elegans phenotypes, including developmental arrest (2–42%) (Chen et al ., 2007; Curran & Ruvkun, 2007), reproductive senescence (16%) (Wang et al ., 2014), thermal stress resistance (78%) (Munoz & Riddle, 2003), oxidative stress resistance (13–67%) (de Castro et al ., 2004; Kim & Sun, 2007), and activation of the mitochondrial unfolded‐protein response (53%) (Bennett et al ., 2014) (reviewed by Yanos et al ., 2012 and Sutphin & Korstanje, 2016). Tacutu et al .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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SummaryWe 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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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Our data provide further points of contrast between dwarf mice, and mice whose longevity reflects either a low-calorie or a methionine-restricted diet: the former show stress resistance in tests of skin cell fibroblasts, and the latter show resistance to APAP toxicity, but not vice versa. Work in worms and flies has suggested that resistance to multiple forms of stress is characteristic of mutants that confer extended life span (Larsen, 1993;Sorensen and Loeschcke, 2001;Arking, 2001;de Castro et al, 2004), leading to the plausible idea that stress resistance itself brings about the retardation of aging and postponement of death, at least in these invertebrate systems. We take, as our working hypothesis, the idea that stress resistance in one or more cell types may play a role in the anti-aging effects of dwarf, CR and Meth-R mice, but acknowledge that much more is still to be learned about the cells and tissues involved in each of these models, the ways in which stress resistance is induced by nutritional and hormonal deviations, and the pathways by which altered cellular properties delay or decelerate age-related injuries in critical tissues.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in nematodes (Caenorhabitis elegans) and fruit flies (Drosophila melanogaster) long-lived mutant strains are often significantly more resistant to multiple forms of stress (Larsen, 1993;Lithgow et al, 1995;Lin et al, 1998;Cheng et al, 2003;de Castro et al, 2004). Recent studies have shown similar phenomena in long-lived mice.…”

Section: Introductionmentioning

confidence: 99%

Stress resistance and aging: Influence of genes and nutrition

Harper

Salmon

Chang

et al. 2006

Mechanisms of Ageing and Development

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Previous studies have shown that dermal fibroblast cell lines derived from young adult mice of the long-lived Snell dwarf (dw/dw), Ames dwarf (df/df) and growth hormone receptor knockout (GHR-KO) mouse stocks are resistant, in vitro, to the cytotoxic effects of hydrogen peroxide, cadmium, ultraviolet light, paraquat, and heat. Here we show that, in contrast, fibroblasts from mice on low-calorie (CR) or low methionine (Meth-R) diets are not stress resistant in culture, despite the longevity induced by both dietary regimes. A second approach, involving induction of liver cell death in live animals using acetaminophen (APAP), documented hepatotoxin resistance in the CR and Meth-R mice, but dw/dw and GHR-KO mutant mice were not resistant to this agent, and were in fact more susceptible than littermate controls to the toxic effects of APAP. These data thus suggest that while resistance to stress is a common characteristic of experimental life span extension in mice, the cell types showing resistance may differ among the various models of delayed or decelerated aging.

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“…In life-span studies in a variety of organisms, it is frequently found that increased or decreased life span is associated with changes in the biology of reactive oxygen species (ROS) (Beckman and Ames 1998;Golden et al 2002;Droge 2003;Hekimi and Guarente 2003;Balaban et al 2005), and this is also true for a variety of C. elegans mutants (Vanfleteren and Braeckman 1999;Feng et al 2001;Senoo-Matsuda et al 2001;Hekimi and Guarente 2003;Shibata et al 2003;de Castro et al 2004;Kayser et al 2004;Sedensky and Morgan 2006) and wild-type animals treated by RNA interference (RNAi) (Dillin et al 2002;Lee et al 2003). However, although these studies, as well as many other studies that have investigated the biochemical and molecular changes that accompany altered patterns of aging, provide strong arguments for the importance of ROS in life-span determination, it remains difficult to prove or disprove the hypothesis that ROS cause aging by damaging macromolecules.…”

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confidence: 99%

A Measurable Increase in Oxidative Damage Due to Reduction in Superoxide Detoxification Fails to Shorten the Life Span of Long-Lived Mitochondrial Mutants of Caenorhabditis elegans

Yang¹,

Li²,

2007

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SOD-1 and SOD-2 detoxify superoxide in the cytoplasm and mitochondria. We find that, although several long-lived mutants of Caenorhabditis elegans have increased SOD levels, this phenomenon does not correlate with life span or growth rate. Furthermore, although disruption of sod-1 or -2 expression produces numerous phenotypes, including increased sensitivity to paraquat and increased oxidative damage to proteins (except in daf-2 mutants), this fails to shorten the life span of these long-lived mutants. In fact, sod-1(RNAi) increases the life span of daf-2 mutants and sod-2(RNAi) that of clk-1 mutants. Our results suggest that increased superoxide detoxification and low oxidative damage are not crucial for the longevity of the mutants examined, with the possible exception of daf-2, where our results are inconclusive. These results are surprising because several of the long-lived mutants that we examined specifically affect mitochondrial electron transport, a process whose involvement in life-span determination is believed to be related to superoxide generation. We discuss the significance of our findings in light of the oxidative stress theory of aging.

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Isolation of long-lived mutants in Caenorhabditis elegans using selection for resistance to juglone

Cited by 118 publications

References 32 publications

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

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

Stress resistance and aging: Influence of genes and nutrition

A Measurable Increase in Oxidative Damage Due to Reduction in Superoxide Detoxification Fails to Shorten the Life Span of Long-Lived Mitochondrial Mutants of Caenorhabditis elegans

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