Hsu AL, Murphy CT, 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


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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    • "In aged cells, increased oxidative damage of proteins can also lead to aggregates such as lipofuscin and advanced glycation end-products (AGEs) (Squier, 2001). A decline in proteostatic control with age further aggravates the ageing phenotypes and a causal link between ageing and proteotoxicity has been established by several studies, as genes and signaling pathways that extend lifespan can also restore proteostasis (Cohen et al., 2006; David et al., 2010; Hsu et al., 2003; Morley et al., 2002). The cellular protein quality control networks include molecular chaperones , in the cytosol or organelles, which facilitate the proper folding of proteins but can also recognize misfolded proteins and assist in their refolding, at a first level of proteome protection (Buchberger et al., 2010; Hartl et al., 2011). "
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    • "We also tested whether mutations that shorten lifespan could influence the aging-associated declines in neuronal function. A whole animal knockdown of the stress-induced heat shock factor 1 (hsf-1) was shown to be short-lived (Hsu et al., 2003). We found that animals with hsf-1 knocked down had similarly unreliable day 5 aged ASEL and AWB secondary neuron responses to BZ compared to wild-type (Figure 5—figure-supplement 5). "
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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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