daf-16;sgk-1

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Genetic mutants with daf-16, sgk-1 alterations

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

Temperature °C
25
Lifespan (days)
18.8
Lifespan change (compared to wild type)
7.43%
Phenotype
daf-16(m26) partially suppresses sgk-1(RNAi) at 20°C.
Lifespan comparisons
Double mutant daf-16(m26);sgk-1(RNAi) has a lifespan of 18.8 days, while single mutant daf-16(m26) has a lifespan of 16.6 days, single mutant sgk-1(RNAi) has a lifespan of 21.1 days and wild type has a lifespan of 17.5 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Hertweck M et al., 2004, C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell. 6(4):577-88 15068796 Click here to select all mutants from this PubMed ID in the graph
Abstract
The DAF-2 insulin receptor-like signaling pathway controls metabolism, development, longevity, and stress response in C. elegans. Here we show that SGK-1, the C. elegans homolog of the serum- and glucocorticoid-inducible kinase SGK, acts in parallel to the AKT kinases to mediate DAF-2 signaling. Loss of sgk-1 results in defective egg-laying, extended generation time, increased stress resistance, and an extension of life span. SGK-1 forms a protein complex with the AKT kinases, and is activated by and strictly depends on PDK-1. All three kinases of this complex are able to directly phosphorylate DAF-16/FKHRL1, yet have different functions in DAF-2 signaling. Whereas AKT-1 and AKT-2 are more important for regulating dauer formation, SGK-1 is the crucial factor for the control of development, stress response, and longevity. Our data also suggest the existence of a second pathway from DAF-2 to DAF-16 that does not depend on AKT-1, AKT-2, and SGK-1.

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

Temperature °C
20
Diet
NGM
Lifespan (days)
17.7
Lifespan change (compared to wild type)
-13.24%
Phenotype
Overexpression of sgk-1 extends lifespan, which can be fully suppressed by loss of daf-16. Sgk-1 cDNA was expressed as a transgene in the intestine, a tissue in which endogenous sgk-1 gene is enriched
Lifespan comparisons
Double mutant daf-16(mgDf47);sgk-1(xuEx1266) has a lifespan of 17.7 days, while single mutant daf-16(mgDf47) has a lifespan of 17.5 days, single mutant sgk-1(xuEx1266) has a lifespan of 25.8 days and wild type has a lifespan of 20.4 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Xiao R et al., 2013, A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell. 152(4):806-17 23415228 Click here to select all mutants from this PubMed ID in the graph
Abstract
Both poikilotherms and homeotherms live longer at lower body temperatures, highlighting a general role of temperature reduction in lifespan extension. However, the underlying mechanisms remain unclear. One prominent model is that cold temperatures reduce the rate of chemical reactions, thereby slowing the rate of aging. This view suggests that cold-dependent lifespan extension is simply a passive thermodynamic process. Here, we challenge this view in C. elegans by showing that genetic programs actively promote longevity at cold temperatures. We find that TRPA-1, a cold-sensitive TRP channel, detects temperature drop in the environment to extend lifespan. This effect requires cold-induced, TRPA-1-mediated calcium influx and a calcium-sensitive PKC that signals to the transcription factor DAF-16/FOXO. Human TRPA1 can functionally substitute for worm TRPA-1 in promoting longevity. Our results reveal a previously unrecognized function for TRP channels, link calcium signaling to longevity, and, importantly, demonstrate that genetic programs contribute to lifespan extension at cold temperatures.

Temperature °C
20
Diet
NGM
Lifespan (days)
13.8
Lifespan change (compared to wild type)
-30.30%
Phenotype
Overexpression of sgk-1 extends lifespan, which can be fully suppressed by loss of daf-16. Sgk-1 cDNA was expressed as a transgene in the intestine, a tissue in which endogenous sgk-1 gene is enriched.
Lifespan comparisons
Double mutant daf-16(mgDf47);sgk-1(xuEx1266) has a lifespan of 13.8 days, while single mutant daf-16(mgDf47) has a lifespan of 13.6 days, single mutant sgk-1(xuEx1266) has a lifespan of 24.4 days and wild type has a lifespan of 19.8 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Xiao R et al., 2013, A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell. 152(4):806-17 23415228 Click here to select all mutants from this PubMed ID in the graph
Abstract
Both poikilotherms and homeotherms live longer at lower body temperatures, highlighting a general role of temperature reduction in lifespan extension. However, the underlying mechanisms remain unclear. One prominent model is that cold temperatures reduce the rate of chemical reactions, thereby slowing the rate of aging. This view suggests that cold-dependent lifespan extension is simply a passive thermodynamic process. Here, we challenge this view in C. elegans by showing that genetic programs actively promote longevity at cold temperatures. We find that TRPA-1, a cold-sensitive TRP channel, detects temperature drop in the environment to extend lifespan. This effect requires cold-induced, TRPA-1-mediated calcium influx and a calcium-sensitive PKC that signals to the transcription factor DAF-16/FOXO. Human TRPA1 can functionally substitute for worm TRPA-1 in promoting longevity. Our results reveal a previously unrecognized function for TRP channels, link calcium signaling to longevity, and, importantly, demonstrate that genetic programs contribute to lifespan extension at cold temperatures.

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

Temperature °C
25
Lifespan (days)
11.4
Lifespan change (compared to wild type)
-22.45%
Phenotype
These data confirm that the level of sgk-1expression is a major determinant for longevity. daf-16(mgDf50), a putative null allele of daf-16, fully suppresses the life span extension of sgk-1, which is another confirmation that daf-16 is the major output of sgk-1.
Lifespan comparisons
Double mutant daf-16(mgDf50);sgk-1(RNAi) has a lifespan of 11.4 days, while single mutant sgk-1(RNAi) has a lifespan of 24.0 days, single mutant daf-16(mgDf50) has a lifespan of 11.4 days and wild type has a lifespan of 14.7 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Hertweck M et al., 2004, C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell. 6(4):577-88 15068796 Click here to select all mutants from this PubMed ID in the graph
Abstract
The DAF-2 insulin receptor-like signaling pathway controls metabolism, development, longevity, and stress response in C. elegans. Here we show that SGK-1, the C. elegans homolog of the serum- and glucocorticoid-inducible kinase SGK, acts in parallel to the AKT kinases to mediate DAF-2 signaling. Loss of sgk-1 results in defective egg-laying, extended generation time, increased stress resistance, and an extension of life span. SGK-1 forms a protein complex with the AKT kinases, and is activated by and strictly depends on PDK-1. All three kinases of this complex are able to directly phosphorylate DAF-16/FKHRL1, yet have different functions in DAF-2 signaling. Whereas AKT-1 and AKT-2 are more important for regulating dauer formation, SGK-1 is the crucial factor for the control of development, stress response, and longevity. Our data also suggest the existence of a second pathway from DAF-2 to DAF-16 that does not depend on AKT-1, AKT-2, and SGK-1.

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

Temperature °C
20
Diet
OP50
Lifespan (days)
17.6
Lifespan change (compared to wild type)
-29.88%
Lifespan comparisons
Double mutant daf-16(mu86);sgk-1(ft15) has a lifespan of 17.6 days, while single mutant sgk-1(ft15) has a lifespan of 28.5 days and wild type has a lifespan of 25.1 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Chen AT et al., 2013, Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and DAF-16/FoxO regulation. Aging Cell. 12(5):932-40 23786484 Click here to select all mutants from this PubMed ID in the graph
Abstract
The AGC family serine-threonine kinases Akt and Sgk are similar in primary amino acid sequence and in vitro substrate specificity, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode Caenorhabditis elegans, it is well established that AKT-1 controls dauer arrest and lifespan by regulating the subcellular localization of the FoxO transcription factor DAF-16. SGK-1 is thought to act similarly to AKT-1 in lifespan control by phosphorylating and inhibiting the nuclear translocation of DAF-16/FoxO. Using sgk-1 null and gain-of-function mutants, we now provide multiple lines of evidence indicating that AKT-1 and SGK-1 influence C. elegans lifespan, stress resistance, and DAF-16/FoxO activity in fundamentally different ways. Whereas AKT-1 shortens lifespan, SGK-1 promotes longevity in a DAF-16-/FoxO-dependent manner. In contrast to AKT-1, which reduces resistance to multiple stresses, SGK-1 promotes resistance to oxidative stress and ultraviolet radiation but inhibits thermotolerance. Analysis of several DAF-16/FoxO target genes that are repressed by AKT-1 reveals that SGK-1 represses a subset of these genes while having little influence on the expression of others. Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of DAF-16/FoxO, SGK-1 does not influence DAF-16/FoxO subcellular localization. Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo. Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk.

Temperature °C
20
Diet
OP50
Lifespan (days)
13.1
Lifespan change (compared to wild type)
-36.71%
Lifespan comparisons
Double mutant daf-16(mu86);sgk-1(ft15) has a lifespan of 13.1 days, while single mutant sgk-1(ft15) has a lifespan of 21.5 days and wild type has a lifespan of 20.7 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Chen AT et al., 2013, Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and DAF-16/FoxO regulation. Aging Cell. 12(5):932-40 23786484 Click here to select all mutants from this PubMed ID in the graph
Abstract
The AGC family serine-threonine kinases Akt and Sgk are similar in primary amino acid sequence and in vitro substrate specificity, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode Caenorhabditis elegans, it is well established that AKT-1 controls dauer arrest and lifespan by regulating the subcellular localization of the FoxO transcription factor DAF-16. SGK-1 is thought to act similarly to AKT-1 in lifespan control by phosphorylating and inhibiting the nuclear translocation of DAF-16/FoxO. Using sgk-1 null and gain-of-function mutants, we now provide multiple lines of evidence indicating that AKT-1 and SGK-1 influence C. elegans lifespan, stress resistance, and DAF-16/FoxO activity in fundamentally different ways. Whereas AKT-1 shortens lifespan, SGK-1 promotes longevity in a DAF-16-/FoxO-dependent manner. In contrast to AKT-1, which reduces resistance to multiple stresses, SGK-1 promotes resistance to oxidative stress and ultraviolet radiation but inhibits thermotolerance. Analysis of several DAF-16/FoxO target genes that are repressed by AKT-1 reveals that SGK-1 represses a subset of these genes while having little influence on the expression of others. Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of DAF-16/FoxO, SGK-1 does not influence DAF-16/FoxO subcellular localization. Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo. Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk.

Temperature °C
20
Diet
OP50
Lifespan (days)
13.3
Lifespan change (compared to wild type)
-19.88%
Phenotype
sgk-1(gf) increased mean and median lifespan, compared with wild-type siblings. This lifespan extension was suppressed by a null mutation in daf-16/FoxO.
Lifespan comparisons
Double mutant daf-16(mu86);sgk-1(ft15) has a lifespan of 13.3 days, while single mutant daf-16(mu86) has a lifespan of 13.3 days, single mutant sgk-1(ft15) has a lifespan of 15.9 days and wild type has a lifespan of 16.6 days.
Type of interaction
See methods
Dependent
Citation
View abstract
Chen AT et al., 2013, Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and DAF-16/FoxO regulation. Aging Cell. 12(5):932-40 23786484 Click here to select all mutants from this PubMed ID in the graph
Abstract
The AGC family serine-threonine kinases Akt and Sgk are similar in primary amino acid sequence and in vitro substrate specificity, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode Caenorhabditis elegans, it is well established that AKT-1 controls dauer arrest and lifespan by regulating the subcellular localization of the FoxO transcription factor DAF-16. SGK-1 is thought to act similarly to AKT-1 in lifespan control by phosphorylating and inhibiting the nuclear translocation of DAF-16/FoxO. Using sgk-1 null and gain-of-function mutants, we now provide multiple lines of evidence indicating that AKT-1 and SGK-1 influence C. elegans lifespan, stress resistance, and DAF-16/FoxO activity in fundamentally different ways. Whereas AKT-1 shortens lifespan, SGK-1 promotes longevity in a DAF-16-/FoxO-dependent manner. In contrast to AKT-1, which reduces resistance to multiple stresses, SGK-1 promotes resistance to oxidative stress and ultraviolet radiation but inhibits thermotolerance. Analysis of several DAF-16/FoxO target genes that are repressed by AKT-1 reveals that SGK-1 represses a subset of these genes while having little influence on the expression of others. Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of DAF-16/FoxO, SGK-1 does not influence DAF-16/FoxO subcellular localization. Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo. Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk.

Search genes: daf-16 sgk-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

181697
sgk-1
View on GenAge (sgk-1)
WBGene00004789

Serine/threonine-protein kinase sgk-1

Locus: CELE_W10G6.2

Wormbase description: sgk-1 encodes a serine/threonine protein kinase that is orthologous to the mammalian serum- and glucocorticoid-inducible kinases (SGKs); in C. elegans, sgk-1 activity is required for normal egg laying, generation time, stress response, and adult life span; SGK-1 forms a complex with the AKT kinases with which it functions in parallel to mediate certain aspects of DAF-2/insulin-signaling; SGK-1 phosphorylates DAF-16 in vitro in a manner strictly dependent upon pdk-1 which encodes a 3-phosphoinositide-dependent kinase; an SGK-1::GFP fusion protein is expressed beginning in late embryonic stages and in larvae is seen in sensory and motor neurons as well as in the intestine; in neurons SGK-1::GFP localizes to the cytoplasm and the nucleus, while in the intestine SGK-1::GFP is found exclusively in the cytoplasm.

Orthologs of daf-16;sgk-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6;Sgk3
Mus musculus	Foxo6;Sgk2
Mus musculus	Foxo6;Sgk1
Mus musculus	Foxo1;Sgk3
Mus musculus	Foxo1;Sgk2
Mus musculus	Foxo1;Sgk1
Mus musculus	Foxo4;Sgk3
Mus musculus	Foxo4;Sgk2
Mus musculus	Foxo4;Sgk1
Mus musculus	Foxo3;Sgk3
Mus musculus	Foxo3;Sgk2
Mus musculus	Foxo3;Sgk1
Mus musculus	Sgk3;Foxo6
Mus musculus	Sgk3;Foxo1
Mus musculus	Sgk3;Foxo4
Mus musculus	Sgk3;Foxo3
Mus musculus	Sgk2;Foxo6
Mus musculus	Sgk2;Foxo1
Mus musculus	Sgk2;Foxo4
Mus musculus	Sgk2;Foxo3
Mus musculus	Sgk1;Foxo6
Mus musculus	Sgk1;Foxo1
Mus musculus	Sgk1;Foxo4
Mus musculus	Sgk1;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 sgk-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Sgk3
Mus musculus	Sgk2
Mus musculus	Sgk1