Steinkraus, K. A. et al. Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 7, 394-404

Department of Pathology, University of Washington, Seattle, WA 98195, USA.
Aging cell (Impact Factor: 6.34). 07/2008; 7(3):394-404. DOI: 10.1111/j.1474-9726.2008.00385.x
Source: PubMed


Dietary restriction increases lifespan and slows the onset of age-associated disease in organisms from yeast to mammals. In humans, several age-related diseases are associated with aberrant protein folding or aggregation, including neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. We report here that dietary restriction dramatically suppresses age-associated paralysis in three nematode models of proteotoxicity. Similar to its longevity-enhancing properties, dietary restriction protects against proteotoxicity by a mechanism distinct from reduced insulin/IGF-1-like signaling. Instead, the heat shock transcription factor, hsf-1, is required for enhanced thermotolerance, suppression of proteotoxicity, and lifespan extension by dietary restriction. These findings demonstrate that dietary restriction confers a general protective effect against proteotoxicity and promotes longevity by a mechanism involving hsf-1.


Available from: George L Sutphin, Mar 17, 2014
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    • "Using BDR and the eat-2 mutant, Bishop and Guarente (2007) showed that the transcription factor SKN-1 in the ASI neurons is indispensable and other transcriptional regulators, such as PHA-4, HIF-1, HSF-1 and CBP-1 were identified as important players mediating the DR effect (Chen et al., 2009; Panowski et al., 2007; Steinkraus et al., 2008; Zhang et al., 2009). Furthermore, other genes, including the energy sensor aak-2 (Greer et al., 2007) and two downstream targets of SKN-1, cup-4 and nlp-7 (Park et al., 2010) are involved in the lifespanextending effect of DR. "
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    ABSTRACT: In Caenorhabditis elegans, there are several ways to impose dietary restriction (DR) all of which extend lifespan to a different degree. Until recently, the molecular mechanisms underlying the DR-mediated lifespan extension were completely unknown but extensive efforts led to the identification of several key players in this process. Culture in sterile axenic medium is a method of DR (ADR), leading to an impressive doubling of lifespan. Earlier, we established that ADR-mediated longevity is independent of ins/IGF signaling and eat-2. The only gene reported to be indispensable for the ADR lifespan effect is cbp-1 (Zhang et al., 2009) which was confirmed in this study. In an attempt to identify more genes involved in ADR-mediated longevity, we tested several candidate genes known to regulate lifespan extension in other DR regimens. We found that cup-4 is equally important as cbp-1 in ADR-mediated longevity and we identified some genes that may contribute to ADR-induced longevity, but are not required for the full lifespan effect.
    Experimental Gerontology 07/2014; 58. DOI:10.1016/j.exger.2014.07.015 · 3.49 Impact Factor
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    • "unc-54::human Aβ Paralyzed daf-2(e1370) protected against Aβ toxicity via DAF-16-16 and HSF-1 (Cohen et al., 2006). unc-54::human Aβ Paralyzed Dietary restriction protected against Aβ toxicity via HSF- 1 (Steinkraus et al., 2008). unc-54::human Aβ Paralyzed AIP-1 was protective against Aβ toxicity via regulation of proteasome (Hassan et al., 2009). "
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    ABSTRACT: Neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and others are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons is the hallmark of these diseases. Despite the research progress in identification of several disease-related genes, the mechanisms underlying the neurodegeneration in these diseases remain unclear. Given the molecular conservation in neuronal signaling between Caenorhabditis elegans and vertebrates, increasing number of research scientists has used the nematode to study this group of diseases. This review paper will focus on the model system that has been established in Caenorhabditis elegans to investigate the pathogenetic roles of those reported disease-related genes in AD, PD, ALS, HD and others. The progress in Caenorhabditis elegans provides useful information of the genetic interactions and molecular pathways that are critical in the disease process, and may help our better understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.
    Experimental Neurology 10/2013; 250. DOI:10.1016/j.expneurol.2013.09.024 · 4.70 Impact Factor
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    • "What will be the functional significance of up-regulation of HSF-1 activity by reduced TOR signaling? A previous report showed that dietary restriction increases lifespan and enhances resistance to polyglutamine aggregation in an hsf-1-dependent manner (Steinkraus et al., 2008). As dietary restriction reduces TOR signaling (Kaeberlein & Kennedy, 2011), it seems likely that dietary restriction promotes longevity and stress resistance via inhibiting TOR signaling and subsequently increasing HSF-1 activity. "
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    ABSTRACT: Target of rapamycin (TOR) signaling is an evolutionarily well-conserved pathway that regulates various physiological processes, including aging and metabolism. One of the key downstream components of TOR signaling is ribosomal protein S6 kinase (S6K) whose inhibition extends the lifespan of yeast, Caenorhabditis elegans, Drosophila, and mice. Here, we demonstrate that the activation of heat shock factor 1 (HSF-1), a crucial longevity transcription factor known to act downstream of the insulin/IGF-1 signaling (IIS) pathway, mediates the prolonged lifespan conferred by mutations in C. elegans S6K (rsks-1). We found that hsf-1 is required for the longevity caused by down-regulation of components in TOR signaling pathways, including TOR and S6K. The induction of a small heat shock protein hsp-16, a transcriptional target of HSF-1, mediates the long lifespan of rsks-1 mutants. Moreover, we show that synergistic activation of HSF-1 is required for the further enhanced longevity caused by simultaneous down-regulation of TOR and IIS pathways. Our findings suggest that HSF-1 acts as an essential longevity factor that intersects both IIS and TOR signaling pathways. This article is protected by copyright. All rights reserved.
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