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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    • "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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    • "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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    • "DAF-2 is C. elegans homolog for mammalian IGF-1 receptor and is the only IGF-1/insu- lin signaling receptor present in C. elegans whereas AGE-1 is homolog for mammalian PI3K catalytic subunit (Finch and Ruvkun 2001). Mutants of both age-1 and daf-2 have been reported to result in increased life span (Samuelson et al. 2007;Murphy and Hu 2013). PE treatment enhanced the life span significantly for both daf-2(e1370) and age-1(hx546) mutant strains with mean survival time±standard error of mean value of 35.2±1.3 days (p<0.001, "
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    ABSTRACT: In the present study, we tested the antioxidant activity of phycoerythrin (PE, an oligomeric light harvesting protein isolated from Lyngbya sp. A09DM) to curtail aging effects in Caenorhabditis elegans. Purified PE (100 μg/ml) dietary supplement was given to C. elegans and investigated for its anti-aging potential. PE treatment improved the mean life span of wild type (N2)-animals from 15 ± 0.1 to 19.9 ± 0.3 days. PE treatment also moderated the decline in aging-associated physiological functions like pharyngeal pumping and locomotion with increasing age of N2 worms. Moreover, PE treatment also enhanced the stress tolerance in 5-day-aged adults with increase in mean survival rate from 22.2 ± 2.5 to 41.6 ± 2.5 % under thermo stress and from 30.1 ± 3.2 to 63.1 ± 6.4 % under oxidative (hydrogen peroxide)-stress. PE treatment was also noted to moderate the heat-induced expression of human amyloid-beta(Aβ1-42) peptide and associated paralysis in the muscle tissues of transgenic C. elegans CL4176 (Alzheimer's disease model). Effectiveness of PE in expanding the life span of mutant C. elegans, knockout for some up (daf-2 and age-1)- and down (daf-16)-stream regulators of insulin/IGF-1 signaling (IIS), shows the independency of PE effect from DAF-2-AGE-1-DAF-16 signaling pathway. Moreover, the inability of PE in expanding the life span of hsf-1 knockout C. elegans(sy441) suggests the dependency of PE effect on heat shock transcription factor (HSF-1) controlling stress-induced gene expression. In conclusion, our results demonstrated a novel anti-aging activity of PE which conferred increased resistance to cellular stress resulting in improved life span and health span of C. elegans.
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