Gene activities that mediate increased life span of C elegans insulin-like signaling mutants

Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Genes & Development (Impact Factor: 10.8). 12/2007; 21(22):2976-94. DOI: 10.1101/gad.1588907
Source: PubMed


Genetic and RNA interference (RNAi) screens for life span regulatory genes have revealed that the daf-2 insulin-like signaling pathway plays a major role in Caenorhabditis elegans longevity. This pathway converges on the DAF-16 transcription factor and may regulate life span by controlling the expression of a large number of genes, including free-radical detoxifying genes, stress resistance genes, and pathogen resistance genes. We conducted a genome-wide RNAi screen to identify genes necessary for the extended life span of daf-2 mutants and identified approximately 200 gene inactivations that shorten daf-2 life span. Some of these gene inactivations dramatically shorten daf-2 mutant life span but less dramatically shorten daf-2; daf-16 mutant or wild-type life span. Molecular and behavioral markers for normal aging and for extended life span in low insulin/IGF1 (insulin-like growth factor 1) signaling were assayed to distinguish accelerated aging from general sickness and to examine age-related phenotypes. Detailed demographic analysis, molecular markers of aging, and insulin signaling mutant test strains were used to filter progeric gene inactivations for specific acceleration of aging. Highly represented in the genes that mediate life span extension in the daf-2 mutant are components of endocytotic trafficking of membrane proteins to lysosomes. These gene inactivations disrupt the increased expression of the DAF-16 downstream gene superoxide dismutase sod-3 in a daf-2 mutant, suggesting trafficking between the insulin-like receptor and DAF-16. The activities of these genes may normally decline during aging.

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Available from: Andrew Samuelson, Jun 26, 2014
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    • "In addition, disruption of other PB components, such as the 5'→3' exonuclease XRN-1, the translation repressor GCH-1/DHH1/RCK or the core miRNA complex components ALG-1 or AIN-1/GW182 leads to reduced worm's lifespan (Kato et al., 2011; Rousakis et al., 2014; Samuelson et al., 2007). It was also shown that deficiency of SIR- 2.4, the worm homolog of mammalian SIRT6 and SIRT7 sirtuins, F. Borbolis, P. Syntichaki / Mechanisms of Ageing and Development 152 (2015) 32–42 renders worms hypersensitive to heat and oxidative stress; SIR- 2.4 promotes formation of P granules in germ cells of C. elegans or SGs in mammalian cells (Jedrusik-Bode et al., 2013) and modulates localization and function of DAF-16/FOXO transcription factor under stress (Chiang et al., 2012). "
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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.
    Mechanisms of ageing and development 10/2015; 152. DOI:10.1016/j.mad.2015.09.006 · 3.40 Impact Factor
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    • "To conduct the RNAi screen, we compiled a list of candidate genes and/or proteins with clear human orthologs that are upregulated in the daf-2 background (Murphy et al., 2003; McElwee et al., 2004; Halaschek-Wiener et al., 2005; Dong et al., 2007) and genes that mediate daf-2 lifespan extension (Samuelson et al., 2007). We included genes upregulated upon pan-neuronal overexpression of a-syn (Vartiainen et al., 2006) and previously identified genetic modifiers of a-syn misfolding and toxicity in worms (Hamamichi et al., 2008; Kuwahara et al., 2008; van Ham et al., 2008). "
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    Cell Metabolism 05/2014; 20(1). DOI:10.1016/j.cmet.2014.04.017 · 17.57 Impact Factor
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    • "Although other neuroendocrine pathways such as the transforming growth factor-β (TGF-β) pathway and the nuclear hormone receptor (NR) pathway have the capability to modulate stress tolerance, the ILS pathway has gained most attention over the past years (Prahlad and Morimoto, 2009). High temperature, starvation and oxidative stress are conditions shown to inhibit this signaling cascade, leading to de-phosphorylation of the transcription factor DAF-16 and its subsequent translocation into the nucleus where it upregulates the transcription of heat shock-and other stressinducible genes (Baumeister et al., 2006; Samuelson et al., 2007). Moreover, the ILS pathway not only requires DAF-16 but also depends on HSF-1 function (Morley and Morimoto, 2004). "
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