Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in <i>C. elegans</i>

Greer, Eric Lieberman; Brunet, Anne-Christine

doi:10.1111/j.1474-9726.2009.00459.x

Cited by 528 publications

(532 citation statements)

References 86 publications

(217 reference statements)

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“…However, although fmo‐2 is induced by some DR feeding regimens (Leiser et al., 2015), it is not upregulated in eat‐2 mutants, and nhr‐49 is dispensable for the increased longevity of this mutant (Heestand et al., 2013). These studies suggest that NHR‐62 and NHR‐49 may act in parallel pro‐longevity pathways that are both regulated by nutrient availability and provide further evidence that different fasting/DR regimes evoke different pro‐longevity transcriptional responses involving different transcriptional regulators to extend lifespan (Greer & Brunet, 2009). …”

Section: Discussionmentioning

confidence: 77%

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

et al. 2018

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SummaryEndogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator‐activated receptor α (PPARα), Caenorhabditis elegans NHR‐49 is a well‐established regulator of lipid metabolism. Here, we reveal that NHR‐49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro‐longevity gene fmo‐2/flavin‐containing monooxygenase. These NHR‐49‐dependent, stress‐responsive genes are also upregulated in long‐lived glp‐1/notch receptor mutants, with two of them making critical contributions to the oxidative stress resistance of wild‐type and long‐lived glp‐1 mutants worms. Similar to its role in lipid metabolism, NHR‐49 requires the mediator subunit mdt‐15 to promote stress‐induced gene expression. However, NHR‐49 acts independently from the transcription factor hlh‐30/TFEB that also promotes fmo‐2 expression. We show that activation of the p38 MAPK, PMK‐1, which is important for adaptation to a variety of stresses, is also important for peroxide‐induced expression of a subset of NHR‐49‐dependent genes that includes fmo‐2. However, organic peroxide increases NHR‐49 protein levels, by a posttranscriptional mechanism that does not require PMK‐1 activation. Together, these findings establish a new role for the HNF4/PPARα‐related NHR‐49 as a stress‐activated regulator of cytoprotective gene expression.

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Section: Discussionmentioning

confidence: 77%

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

et al. 2018

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“…4,5 In contrast, worms grown in liquid culture with lower bacteria concentrations are not more resistant to paraquat and H 2 O 2 , 6 and eat-2 mutant worms do not have increased thermotolerance. 7 Indeed, skn-1 and pha-4, but not daf-16, are required for the longevity response induced by these 2 methods of DR [4] . It is interesting to note that wwp-1 is essential for lifespan extension mediated by all 3 methods described above, 1 suggesting that these different DR regimens evoke at least 2 distinct genetic pathways involving WWP-1.…”

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confidence: 95%

“…5 Here, the FOXO TF daf-16 is essential for the increased longevity induced by this method; however, there is no requirement for skn-1 and pha-4. 4,5 In contrast, worms grown in liquid culture with lower bacteria concentrations are not more resistant to paraquat and H 2 O 2 , 6 and eat-2 mutant worms do not have increased thermotolerance. 7 Indeed, skn-1 and pha-4, but not daf-16, are required for the longevity …”

mentioning

confidence: 97%

“…Furthermore, the distinct methods used to manipulate the worm diet to extend lifespan have different effects on stress responses in worms. 4 For instance, worms grown on agar plates with lower bacteria concentrations have increased resistance to the oxidative-damaging agent paraquat. 5 Here, the FOXO TF daf-16 is essential for the increased longevity induced by this method; however, there is no requirement for skn-1 and pha-4.…”

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confidence: 99%

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Fitting wwp-1 in the dietary restriction network

Carrano¹,

Hunter²

2015

Cell Cycle

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One of the most universal environmental conditions that impacts longevity is dietary restriction (DR). DR is a reduction in caloric uptake without malnutrition; DR can increase health and life span in many organisms, from yeast to invertebrates and mammals. Studies in C. elegans have identified novel genetic regulators of DR, including transcription factors (TFs) and environmental sensors, such as pha-4, skn-1, ampk, and hsf-1. In addition, our group uncovered for the first time a role for the ubiquitin pathway in DR-mediated longevity by identifying the C. elegans wwp-1 HECT E3 ligase and its associated E2 ubiquitin conjugating enzyme, ubc-18, as positive regulators of lifespan in response to DR. 1 E2 and E3 enzymes facilitate the ubiquitylation of substrate proteins to alter their function in various ways. Therefore, the identification of targets of UBC-18/WWP-1 would yield an understanding of how this E2/E3 complex regulates the response to nutrient intake and longevity in worms.To identify substrates of WWP-1 that regulate DR-induced longevity, we performed a targeted RNAi screen by selecting worm orthologues of known ubiquitylated substrates of the mammalian WWP-1 orthologues-WWP1, WWP2, and ITCH. 2 None of the 12 genes we analyzed was able to extend lifespan in wild-type (WT) worms when knocked-down. However, we found that loss of one gene, the Kr€ uppel-like TF klf-1, was able to suppress the extended longevity of a DR genetic model (eat-2 mutant animals) while not affecting the lifespan of WT worms. Like wwp-1, we found that klf-1 was essential for the DR-longevity response, and that overexpression of klf-1 in the intestines, a site where longevity cues are expressed, led to lifespan extension dependent on wwp-1. Using biochemical approaches, we were able to demonstrate a direct physical interaction between WWP-1 and KLF-1 that results in the multi-monoubiquitylation of KLF-1 both in vitro and in vivo. 2 Together, our data support a model in which modulation of KLF-1 by WWP-1 regulates DR-mediated longevity. While the mechanism through which KLF-1 ubiquitylation drives lifespan extension is not known, it is reasonable to speculate that multi-monoubiquitylation modifies KLF-1 transcriptional output, possibly altering how nutrient stores are utilized in the worm. Given that wwp-1 is evolutionarily conserved and that mammalian WWP-1 orthologues target multiple KLFs, 3 we can speculate that a similar signaling pathway regulates DR-induced longevity in higher organisms.Many mutations or treatments that prolong lifespan in C. elegans also increase resistance to environmental stressors such as heat, UV, and oxidative conditions. Previously, we found that loss of wwp-1 decreased stress resistance in the adult worm. 1 To our surprise, reduced klf-1 expression did not affect the stress response in worms. Also in unpublished results, we found that loss of pha-4, which we had shown to be downstream of both wwp-1 and klf-1, 1,2 caused no change in stress resistance in worms, much like loss of klf-1. This would sugges...

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“…Both dietary restriction (DR) and mutations in insulin-IGF signalling (IIS) extend lifespan in Drosophila and many other species (Partridge et al 2005;Russell and Kahn 2007). Thus, it is likely that insights into aging mechanisms that are directly relevant to higher organisms will emerge from work conducted with this model (Grandison et al 2009;Greer and Brunet 2009). …”

Section: Introductionmentioning

confidence: 99%

Chemical changes in aging Drosophila melanogaster

Iqbal

Piper

Faragher

et al. 2009

AGE

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The "Green Theory" of aging proposes that organismal lifespan is limited by the failure to repair molecular damage generated by a broad range of metabolic processes. Two specific predictions arise from this: (1) that these processes will produce a wide variety of stable but dysfunctional compounds that increase in concentration with age, and (2) that organisms maintained under conditions that extend lifespan will display a reduced rate of accumulation of such "molecular rubbish". To test these predictions, novel analytical techniques were developed to investigate the accumulation of damaged compounds in Drosophila melanogaster. Simple preparative techniques were developed to produce digests of whole D.melanogaster for use in three-dimensional (3D) fluorimetry and 1 H NMR spectrometry. Cohorts of Drosophila maintained under normal conditions showed an age-related increase in signals consistent with damage whereas those maintained under conditions of low temperature and dietary restriction did not. 1 H NMR revealed distinct age-associated spectral changes that will facilitate the identification of novel compounds that both increase and decrease during aging in this species. These findings are consistent with the predictions of the "Green Theory".

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Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans

Cited by 528 publications

References 86 publications

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

Fitting wwp-1 in the dietary restriction network

Chemical changes in aging Drosophila melanogaster

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