raga-1;skn-1

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Genetic mutants with raga-1, skn-1 alterations

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
20
Diet
NGM
Lifespan (days)
21.46
Lifespan change (compared to wild type)
-6.41%
Phenotype
Knockdown of TORC1 pathway gene (raga-1) failed to increase lifespan in a skn-1 mutant.
Lifespan comparisons
Double mutant raga-1(RNAi);skn-1(zu67) has a lifespan of 21.46 days, while single mutant raga-1(RNAi) has a lifespan of 28.91 days, single mutant skn-1(zu67) has a lifespan of 20.13 days and wild type has a lifespan of 22.93 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Robida-Stubbs S et al., 2012, TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15(5):713-24 22560223 Click here to select all mutants from this PubMed ID in the graph
Abstract
The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity.

Temperature °C
20
Diet
NGM
Lifespan (days)
21.37
Lifespan change (compared to wild type)
-3.26%
Phenotype
Knockdown of TORC1 pathway gene (raga-1) failed to increase lifespan in a skn-1 mutant.
Lifespan comparisons
Double mutant raga-1(RNAi);skn-1(zu67) has a lifespan of 21.37 days, while single mutant raga-1(RNAi) has a lifespan of 24.02 days, single mutant skn-1(zu67) has a lifespan of 20.67 days and wild type has a lifespan of 22.09 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Robida-Stubbs S et al., 2012, TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15(5):713-24 22560223 Click here to select all mutants from this PubMed ID in the graph
Abstract
The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity.

Temperature °C
20
Diet
NGM
Lifespan (days)
22.6
Lifespan change (compared to wild type)
-2.38%
Phenotype
Knockdown of TORC1 pathway gene (raga-1) failed to increase lifespan in a skn-1 mutant.
Lifespan comparisons
Double mutant raga-1(RNAi);skn-1(zu67) has a lifespan of 22.6 days, while single mutant raga-1(RNAi) has a lifespan of 32.9 days, single mutant skn-1(zu67) has a lifespan of 19.37 days and wild type has a lifespan of 23.15 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Robida-Stubbs S et al., 2012, TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15(5):713-24 22560223 Click here to select all mutants from this PubMed ID in the graph
Abstract
The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity.

Temperature °C
20
Diet
NGM
Lifespan (days)
20.59
Lifespan change (compared to wild type)
-12.16%
Phenotype
Knockdown of TORC1 pathway gene (raga-1) failed to increase lifespan in a skn-1 mutant.
Lifespan comparisons
Double mutant raga-1(RNAi);skn-1(zu67) has a lifespan of 20.59 days, while single mutant raga-1(RNAi) has a lifespan of 28.15 days, single mutant skn-1(zu67) has a lifespan of 20.28 days and wild type has a lifespan of 23.44 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Robida-Stubbs S et al., 2012, TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15(5):713-24 22560223 Click here to select all mutants from this PubMed ID in the graph
Abstract
The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity.

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
20
Diet
NGM
Lifespan (days)
12.5
Lifespan comparisons
Double mutant raga-1(ok386);skn-1(zu169) has a lifespan of 12.5 days, while single mutant skn-1(zu169) has a lifespan of 11.3 days.
Citation
View abstract
Schreiber MA et al., 2010, Manipulation of behavioral decline in Caenorhabditis elegans with the Rag GTPase raga-1. PLoS Genet. 6(5):e1000972 20523893 Click here to select all mutants from this PubMed ID in the graph
Abstract
Normal aging leads to an inexorable decline in motor performance, contributing to medical morbidity and decreased quality of life. While much has been discovered about genetic determinants of lifespan, less is known about modifiers of age-related behavioral decline and whether new gene targets may be found which extend vigorous activity, with or without extending lifespan. Using Caenorhabditis elegans, we have developed a model of declining neuromuscular function and conducted a screen for increased behavioral activity in aged animals. In this model, behavioral function suffers from profound reductions in locomotory frequency, but coordination is strikingly preserved until very old age. By screening for enhancers of locomotion at advanced ages we identified the ras-related Rag GTPase raga-1 as a novel modifier of behavioral aging. raga-1 loss of function mutants showed vigorous swimming late in life. Genetic manipulations revealed that a gain of function raga-1 curtailed behavioral vitality and shortened lifespan, while a dominant negative raga-1 lengthened lifespan. Dietary restriction results indicated that a raga-1 mutant is relatively protected from the life-shortening effects of highly concentrated food, while RNAi experiments suggested that raga-1 acts in the highly conserved target of rapamycin (TOR) pathway in C. elegans. Rag GTPases were recently shown to mediate nutrient-dependent activation of TOR. This is the first demonstration of their dramatic effects on behavior and aging. This work indicates that novel modulators of behavioral function can be identified in screens, with implications for future study of the clinical amelioration of age-related decline.

Temperature °C
20
Diet
NGM
Lifespan (days)
11.8
Lifespan comparisons
Double mutant raga-1(ok386);skn-1(zu169) has a lifespan of 11.8 days, while single mutant skn-1(zu169) has a lifespan of 10.7 days.
Citation
View abstract
Schreiber MA et al., 2010, Manipulation of behavioral decline in Caenorhabditis elegans with the Rag GTPase raga-1. PLoS Genet. 6(5):e1000972 20523893 Click here to select all mutants from this PubMed ID in the graph
Abstract
Normal aging leads to an inexorable decline in motor performance, contributing to medical morbidity and decreased quality of life. While much has been discovered about genetic determinants of lifespan, less is known about modifiers of age-related behavioral decline and whether new gene targets may be found which extend vigorous activity, with or without extending lifespan. Using Caenorhabditis elegans, we have developed a model of declining neuromuscular function and conducted a screen for increased behavioral activity in aged animals. In this model, behavioral function suffers from profound reductions in locomotory frequency, but coordination is strikingly preserved until very old age. By screening for enhancers of locomotion at advanced ages we identified the ras-related Rag GTPase raga-1 as a novel modifier of behavioral aging. raga-1 loss of function mutants showed vigorous swimming late in life. Genetic manipulations revealed that a gain of function raga-1 curtailed behavioral vitality and shortened lifespan, while a dominant negative raga-1 lengthened lifespan. Dietary restriction results indicated that a raga-1 mutant is relatively protected from the life-shortening effects of highly concentrated food, while RNAi experiments suggested that raga-1 acts in the highly conserved target of rapamycin (TOR) pathway in C. elegans. Rag GTPases were recently shown to mediate nutrient-dependent activation of TOR. This is the first demonstration of their dramatic effects on behavior and aging. This work indicates that novel modulators of behavioral function can be identified in screens, with implications for future study of the clinical amelioration of age-related decline.

Search genes: raga-1 skn-1

Entrez ID
Symbol
GenAge
Wormbase ID

174726
raga-1
View on GenAge (raga-1)
WBGene00006414

RAs-related GTP-binding protein A

Locus: CELE_T24F1.1

Wormbase description: raga-1 encodes the C. elegans ortholog of the ras-related GTPase RagA; in C. elegans RAGA-1 functions as a modifier of behavioral aging and adult lifespan (particularly under high food concentration); raga-1 mutations also affect body size and reproduction; genetic analyses suggest that raga-1 functions in the let-363/Tor pathway to regulate behavioral aging and lifespan and also interacts with the daf-2/daf-16 insulin signaling pathway and skn-1; raga-1 reporter fusions are widely expressed in larvae, with more restricted expression (gut, head and tail neurons, somatic gonad, hypodermis) seen in adults.

Entrez ID
Symbol
GenAge
Wormbase ID

177343
skn-1
View on GenAge (skn-1)
WBGene00004804

Protein skinhead-1;SKiNhead

Locus: CELE_T19E7.2

Wormbase description: skn-1 encodes a bZip transcription factor orthologous to the mammalian Nrf (Nuclear factor-erythroid-related factor) transcription factors; during early embryogenesis, maternally provided SKN-1 is required for specification of the EMS blastomere, a mesendodermal precursor that gives rise to pharyngeal, muscle, and intestinal cells; later, during postembryonic development, SKN-1 functions in the p38 MAPK pathway to regulate the oxidative stress response and in parallel to DAF-16/FOXO in the DAF-2-mediated insulin/IGF-1-like signaling pathway to regulate adult lifespan; in vitro assays indicate that SKN-1 can be directly phosphorylated by the AKT-1, AKT-2, and SGK-1 kinases that lie downstream of DAF-2 in the insulin signaling pathway and in vivo experiments suggest that this phosphorylation is essential for regulation of SKN-1 nuclear accumulation and hence, transcriptional regulator activity; in the early embryo, SKN-1 is detected at highest levels in nuclei of the P1 blastomere and its descendants through the 8-cell stage of embryogenesis; later in embryogenesis, SKN-1 is observed in all hypodermal and intestinal nuclei, with reporter constructs indicating that intestinal expression begins as early as the 50-100-cell stage; in larvae and young adults, SKN-1::GFP reporters are expressed in the intestine and ASI neurons, with expression in intestinal nuclei enhanced under conditions of stress or reduced DAF-2 signaling.

Orthologs of raga-1;skn-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Nfe2;Rragb
Mus musculus	Nfe2l2;Rragb
Mus musculus	Nfe2l1;Rragb
Mus musculus	Nfe2;Rraga
Mus musculus	Nfe2l2;Rraga
Mus musculus	Nfe2l1;Rraga
Mus musculus	Rragb;Nfe2
Mus musculus	Rragb;Nfe2l2
Mus musculus	Rragb;Nfe2l1
Mus musculus	Rraga;Nfe2
Mus musculus	Rraga;Nfe2l2
Mus musculus	Rraga;Nfe2l1

Orthologs of raga-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	RagA-B
Mus musculus	Rragb
Mus musculus	Rraga

Orthologs of skn-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Nfe2
Mus musculus	Nfe2l2
Mus musculus	Nfe2l1