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

ABSTRACT

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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    • "We targeted both the routes to check the possible route for PC's anti-aging action. Downregulation of DAF-2–AGE-1–DAF-16 insulin signalling (IIS) pathway has been reported to promote longevity in C. elegans (Kenyon 2010; Narasimhan et al. 2009; Samuelson et al. 2007; Murphy and Hu 2013; Cai et al. 2011). We targeted effect of PC on IIS pathway by using C. elegans null mutants of daf-2, daf- 16, and age-1. "
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