Hsu A, Murphy C, Kenyon C.. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300: 1142-1145

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-2200, USA.
Science (Impact Factor: 33.61). 06/2003; 300(5622):1142-5. DOI: 10.1126/science.1083701
Source: PubMed

ABSTRACT The Caenorhabditis elegans transcription factor HSF-1, which regulates the heat-shock response, also influences aging. Reducing hsf-1 activity accelerates tissue aging and shortens life-span, and we show that hsf-1 overexpression extends lifespan. We find that HSF-1, like the transcription factor DAF-16, is required for daf-2-insulin/IGF-1 receptor mutations to extend life-span. Our findings suggest this is because HSF-1 and DAF-16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.

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Available from: Ao-Lin Hsu, Sep 27, 2015
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    • "Interestingly, this lifespan extension depends on both, the activity of the FOXO transcription factor daf-16 and autophagy (Hansen et al. 2008; Hars et al. 2007; Hsu et al. 2003; Melendez et al. 2003). TOR (target of rapamycin) signalling is an aminoacid and nutrient sensor pathway that regulates several processes like protein translation and autophagy in response to food availability (Hansen et al. 2008, 2007; Kaeberlein et al. 2005c; Kapahi et al. 2004). "
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    ABSTRACT: Ageing is accompanied by the accumulation of damaged molecules in cells due to the injury produced by external and internal stressors. Among them, reactive oxygen species produced by cell metabolism, inflammation or other enzymatic processes are considered key factors. However, later research has demonstrated that a general mitochondrial dysfunction affecting electron transport chain activity, mitochondrial biogenesis and turnover, apoptosis, etc., seems to be in a central position to explain ageing. This key role is based on several effects from mitochondrial-derived ROS production to the essential maintenance of balanced metabolic activities in old organisms. Several studies have demonstrated caloric restriction, exercise or bioactive compounds mainly found in plants, are able to affect the activity and turnover of mitochondria by increasing biogenesis and mitophagy, especially in postmitotic tissues. Then, it seems that mitochondria are in the centre of metabolic procedures to be modified to lengthen life- or health-span. In this review we show the importance of mitochondria to explain the ageing process in different models or organisms (e.g. yeast, worm, fruitfly and mice). We discuss if the cause of aging is dependent on mitochondrial dysfunction of if the mitochondrial changes observed with age are a consequence of events taking place outside the mitochondrial compartment.
    Biogerontology 06/2015; 16(5). DOI:10.1007/s10522-015-9585-9 · 3.29 Impact Factor
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    • "To assess the in vivo importance of Sip1, we investigated the lifespan of WT and Dsip1 worms. Our results revealed a decline from $21 days for N2 to $14 days for Dsip1 nematodes (Figure 1B), in agreement with a reported decrease in N2 lifespan by sip1 RNAi (Hsu et al., 2003). Since Sip1 is a sHsp, we investigated its importance in preventing proteotoxic stress via a thermotolerance experiment. "
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    ABSTRACT: Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that prevent the aggregation of unfolding proteins during proteotoxic stress. In Caenorhabditis elegans, Sip1 is the only sHsp exclusively expressed in oocytes and embryos. Here, we demonstrate that Sip1 is essential for heat shock survival of reproducing adults and embryos. X-ray crystallography and electron microscopy revealed that Sip1 exists in a range of well-defined globular assemblies consisting of two half-spheres, each made of dimeric "spokes." Strikingly, the oligomeric distribution of Sip1 as well as its chaperone activity depend on pH, with a trend toward smaller species and higher activity at acidic conditions such as present in nematode eggs. The analysis of the interactome shows that Sip1 has a specific substrate spectrum including proteins that are essential for embryo development. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 05/2015; 58(6). DOI:10.1016/j.molcel.2015.04.019 · 14.02 Impact Factor
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    • "HSPs were most en - riched in the insoluble fraction of daf - 2 mutant worms , consistent with the view that they may play a role as ' ' extrinsic ' ' promoters of aggregation . In support of this possibility , individual RNAi knockdown of several small HSPs , including SIP - 1 , caused a 25% shortening of lifespan in WT and daf - 2 mutant worms ( Hsu et al . , 2003 ) and overexpression resulted in lifespan exten - sion ( Walker and Lithgow , 2003 ) . Having multi - valent binding ability for aberrant proteins , the small HSPs may act to seed and concentrate aggregate material , consistent with findings in vivo ( Escusa - Toret et al . , 2013 ; Kaganovich et al . , 2008 ; Specht et al . , 2011 ) an"
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    ABSTRACT: Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. These changes are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant. While ribosomal proteins decline and lose normal stoichiometry, proteasome complexes increase. Proteome imbalance is accompanied by widespread protein aggregation, with abundant proteins that exceed solubility contributing most to aggregate load. Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed. We suggest that sequestering proteins into chaperone-enriched aggregates is a protective strategy to slow proteostasis decline during nematode aging.
    Cell 05/2015; 161(4):919. · 32.24 Impact Factor
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