daf-16;raga-1

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Genetic mutants with daf-16, raga-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)
18.51
Lifespan change (compared to wild type)
-19.28%
Phenotype
RNAi against raga-1 gene did not increase lifespan in daf-16 mutants, in contrast to the daf-16 independent longevity associated with TOR kinase inhibition.
Lifespan comparisons
Double mutant daf-16(mgDf47);raga-1(RNAi) has a lifespan of 18.51 days, while single mutant raga-1(RNAi) has a lifespan of 28.91 days, single mutant daf-16(mgDf47) has a lifespan of 18.09 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)
14.95
Lifespan change (compared to wild type)
-32.32%
Phenotype
RNAi against raga-1 gene did not increase lifespan in daf-16 mutants, in contrast to the daf-16 independent longevity associated with TOR kinase inhibition.
Lifespan comparisons
Double mutant daf-16(mgDf47);raga-1(RNAi) has a lifespan of 14.95 days, while single mutant raga-1(RNAi) has a lifespan of 24.02 days, single mutant daf-16(mgDf47) has a lifespan of 15.57 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)
19.81
Lifespan change (compared to wild type)
-14.43%
Phenotype
RNAi against raga-1 gene did not increase lifespan in daf-16 mutants, in contrast to the daf-16 independent longevity associated with TOR kinase inhibition.
Lifespan comparisons
Double mutant daf-16(mgDf47);raga-1(RNAi) has a lifespan of 19.81 days, while single mutant raga-1(RNAi) has a lifespan of 32.9 days, single mutant daf-16(mgDf47) has a lifespan of 18.63 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)
19.75
Lifespan change (compared to wild type)
-15.74%
Phenotype
RNAi against raga-1 gene did not increase lifespan in daf-16 mutants, in contrast to the daf-16 independent longevity associated with TOR kinase inhibition.
Lifespan comparisons
Double mutant daf-16(mgDf47);raga-1(RNAi) has a lifespan of 19.75 days, while single mutant raga-1(RNAi) has a lifespan of 28.15 days, single mutant daf-16(mgDf47) has a lifespan of 20.0 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)
11.6
Lifespan comparisons
Double mutant daf-16(mu86);raga-1(ok386) has a lifespan of 11.6 days, while single mutant daf-16(mu86) has a lifespan of 10.9 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)
10.7
Lifespan comparisons
Double mutant daf-16(mu86);raga-1(ok386) has a lifespan of 10.7 days, while single mutant daf-16(mu86) 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: daf-16 raga-1

Entrez ID
Symbol
GenAge
Wormbase ID

172981
daf-16
View on GenAge (daf-16)
WBGene00000912

Forkhead box protein O;hypothetical protein

Locus: CELE_R13H8.1

Wormbase description: daf-16 encodes the sole C. elegans forkhead box O (FOXO) homologue; DAF-16 functions as a transcription factor that acts in the insulin/IGF-1-mediated signaling (IIS) pathway that regulates dauer formation, longevity, fat metabolism, stress response, and innate immunity; DAF-16 regulates these various processes through isoform-specific expression, isoform-specific regulation by different AKT kinases, and differential regulation of target genes; DAF-16 can interact with the CBP-1 transcription cofactor in vitro, and interacts genetically with other genes in the insulin signaling and with daf-12, which encodes a nuclear hormone receptor; DAF-16 is activated in response to DNA damage during development and co-regulated by EGL-27, alleviates DNA-damage-induced developmental arrest by inducing DAF-16-associated element (DAE)-regulated genes; DAF-16 is broadly expressed but displays isoform-specific tissue enrichment; DAF-16 localizes to both the cytoplasm and the nucleus, with the ratio between the two an important regulator of function.

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.

Orthologs of daf-16;raga-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6;Rragb
Mus musculus	Foxo6;Rraga
Mus musculus	Foxo1;Rragb
Mus musculus	Foxo1;Rraga
Mus musculus	Foxo4;Rragb
Mus musculus	Foxo4;Rraga
Mus musculus	Foxo3;Rragb
Mus musculus	Foxo3;Rraga
Mus musculus	Rragb;Foxo6
Mus musculus	Rragb;Foxo1
Mus musculus	Rragb;Foxo4
Mus musculus	Rragb;Foxo3
Mus musculus	Rraga;Foxo6
Mus musculus	Rraga;Foxo1
Mus musculus	Rraga;Foxo4
Mus musculus	Rraga;Foxo3

Orthologs of daf-16 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6
Mus musculus	Foxo1
Mus musculus	Foxo4
Mus musculus	Foxo3

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