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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    • "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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    ABSTRACT: Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.
    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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    ABSTRACT: The ability of each cell within a metazoan to adapt to and survive environmental and physiological stress requires cellular stress-response mechanisms, such as the heat shock response (HSR). Recent advances reveal that cellular proteostasis and stress responses in metazoans are regulated by multiple layers of intercellular communication. This ensures that an imbalance of proteostasis that occurs within any single tissue 'at risk' is protected by a compensatory activation of a stress response in adjacent tissues that confers a community protective response. While each cell expresses the machinery for heat shock (HS) gene expression, the HSR is regulated cell non-autonomously in multicellular organisms, by neuronal signaling to the somatic tissues, and by transcellular chaperone signaling between somatic tissues and from somatic tissues to neurons. These cell non-autonomous processes ensure that the organismal HSR is orchestrated across multiple tissues and that transmission of stress signals between tissues can also override the neuronal control to reset cell- and tissue-specific proteostasis. Here, we discuss emerging concepts and insights into the complex cell non-autonomous mechanisms that control stress responses in metazoans and highlight the importance of intercellular communication for proteostasis maintenance in multicellular organisms.
    Journal of Experimental Biology 01/2014; 217(Pt 1):129-36. DOI:10.1242/jeb.091249 · 2.90 Impact Factor
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    • "The extended lifespan of daf-2 mutants has also been correlated with the activation of stress response genes and increased stress resistance (Murphy et al., 2003; Samuelson et al., 2007). We performed various stress assays to determine whether the synergistic longevity phenotype also correlates with increased stress resistance. "
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    ABSTRACT: Inhibition of DAF-2 (insulin-like growth factor 1 [IGF-1] receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways, respectively, extend lifespan in Caenorhabditis elegans. However, it has not been clear how and in which tissues they interact with each other to modulate longevity. Here, we demonstrate that a combination of mutations in daf-2 and rsks-1 produces a nearly 5-fold increase in longevity that is much greater than the sum of single mutations. This synergistic lifespan extension requires positive feedback regulation of DAF-16 (FOXO) via the AMP-activated protein kinase (AMPK) complex. Furthermore, we identify germline as the key tissue for this synergistic longevity. Moreover, germline-specific inhibition of rsks-1 activates DAF-16 in the intestine. Together, our findings highlight the importance of the germline in the significantly increased longevity produced by daf-2 rsks-1, which has important implications for interactions between the two major conserved longevity pathways in more complex organisms.
    Cell Reports 12/2013; 5(6). DOI:10.1016/j.celrep.2013.11.018 · 8.36 Impact Factor
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