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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    ABSTRACT: Messenger RNA (mRNA) turnover that determines the lifetime of cytoplasmic mRNAs is a means to control gene expression under both normal and stress conditions, whereas its impact on ageing and age-related disorders has just become evident. Gene expression control is achieved at the level of the mRNA clearance as well as mRNA stability and accessibility to other molecules. All these processes are regulated by cis-acting motifs and trans-acting factors that determine the rates of translation and degradation of transcripts. Specific messenger RNA granules that harbor the mRNA decay machinery or various factors, involved in translational repression and transient storage of mRNAs, are also part of the mRNA fate regulation. Their assembly and function can be modulated to promote stress resistance in adverse conditions and over time affect the ageing process and the lifespan of the organism. Here, we provide insights into the complex relationships of ageing modulators and mRNA turnover mechanisms.
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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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    ABSTRACT: Chemosensory neurons extract information about chemical cues from the environment. How is the activity in these sensory neurons transformed into behavior? Using Caenorhabditis elegans, we map a novel sensory neuron circuit motif that encodes odor concentration. Primary neurons, AWC(ON) and AWA, directly detect the food odor benzaldehyde (BZ) and release insulin-like peptides and acetylcholine, respectively, which are required for odor-evoked responses in secondary neurons, ASEL and AWB. Consistently, both primary and secondary neurons are required for BZ attraction. Unexpectedly, this combinatorial code is altered in aged animals: odor-evoked activity in secondary, but not primary, olfactory neurons is reduced. Moreover, experimental manipulations increasing neurotransmission from primary neurons rescues aging-associated neuronal deficits. Finally, we correlate the odor responsiveness of aged animals with their lifespan. Together, these results show how odors are encoded by primary and secondary neurons and suggest reduced neurotransmission as a novel mechanism driving aging-associated sensory neural activity and behavioral declines.
    Full-text · Article · Sep 2015 · eLife Sciences
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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.
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