daf-16;sir-2.1

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Genetic mutants with daf-16, sir-2.1 alterations

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

Temperature °C
20
Lifespan (days)
15.0
Lifespan change (compared to wild type)
-25.00%
Lifespan comparisons
Double mutant daf-16(RNAi);sir-2.1(OE) has a lifespan of 15.0 days, while single mutant sir-2.1(OE) has a lifespan of 30.0 days and wild type has a lifespan of 20.0 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Berdichevsky A et al., 2006, C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell. 125(6):1165-77 16777605 Click here to select all mutants from this PubMed ID in the graph
Abstract
The longevity of Caenorhabditis elegans is promoted by extra copies of the sir-2.1 gene in a manner dependent on the forkhead transcription factor DAF-16. We identify two C. elegans 14-3-3 proteins as SIR-2.1 binding partners and show that 14-3-3 genes are required for the life-span extension conferred by extra copies of sir-2.1. 14-3-3 proteins are also required for SIR-2.1-induced transcriptional activation of DAF-16 and stress resistance. Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner. By contrast, low insulin-like signaling does not promote SIR-2.1/DAF-16 interaction, and sir-2.1 and the 14-3-3 genes are not required for the regulation of life span by the insulin-like signaling pathway. We propose the existence of a stress-dependent pathway in which SIR-2.1 and 14-3-3 act in parallel to the insulin-like pathway to activate DAF-16 and extend life span.

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

Temperature °C
20
Lifespan (days)
14.0
Lifespan change (compared to wild type)
-30.00%
Lifespan comparisons
Double mutant daf-16(RNAi);sir-2.1(ok434) has a lifespan of 14.0 days, while single mutant sir-2.1(ok434) has a lifespan of 16.0 days and wild type has a lifespan of 20.0 days.
Type of interaction
See methods
Partially known monotony. Negative epistasis
Citation
View abstract
Berdichevsky A et al., 2006, C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell. 125(6):1165-77 16777605 Click here to select all mutants from this PubMed ID in the graph
Abstract
The longevity of Caenorhabditis elegans is promoted by extra copies of the sir-2.1 gene in a manner dependent on the forkhead transcription factor DAF-16. We identify two C. elegans 14-3-3 proteins as SIR-2.1 binding partners and show that 14-3-3 genes are required for the life-span extension conferred by extra copies of sir-2.1. 14-3-3 proteins are also required for SIR-2.1-induced transcriptional activation of DAF-16 and stress resistance. Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner. By contrast, low insulin-like signaling does not promote SIR-2.1/DAF-16 interaction, and sir-2.1 and the 14-3-3 genes are not required for the regulation of life span by the insulin-like signaling pathway. We propose the existence of a stress-dependent pathway in which SIR-2.1 and 14-3-3 act in parallel to the insulin-like pathway to activate DAF-16 and extend life span.

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

Temperature °C
25
Diet
NGM; OP50
Lifespan (days)
8.5
Lifespan change (compared to wild type)
-43.71%
Lifespan comparisons
Double mutant daf-16(mgDf50);sir-2.1(OE) has a lifespan of 8.5 days, while single mutant sir-2.1(OE) has a lifespan of 17.3 days and wild type has a lifespan of 15.1 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Rizki G et al., 2011, The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 7(9):e1002235 21909281 Click here to select all mutants from this PubMed ID in the graph
Abstract
The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1) is a longevity determinant previously shown to act as a co-repressor of DAF-16. We report here that HCF-1 represents an integral player in the regulatory loop linking SIR-2.1/SIRT1 and DAF-16/FOXO in both worms and mammals. Genetic analyses showed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response in C. elegans. Gene expression profiling revealed a striking 80% overlap between the DAF-16 target genes responsive to hcf-1 mutation and sir-2.1 overexpression. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16-mediated transcription particularly important for aging and stress responses. Analogous to its role in regulating DAF-16/SIR-2.1 target genes in C. elegans, the mammalian HCF-1 also repressed the expression of several FOXO/SIRT1 target genes. Protein-protein association studies demonstrated that SIR-2.1/SIRT1 and HCF-1 form protein complexes in worms and mammalian cells, highlighting the conservation of their regulatory relationship. Our findings uncover a conserved interaction between the key longevity determinants SIR-2.1/SIRT1 and HCF-1, and they provide new insights into the complex regulation of FOXO proteins.

Temperature °C
25
Diet
NGM; OP50
Lifespan (days)
9.1
Lifespan change (compared to wild type)
-39.33%
Lifespan comparisons
Double mutant daf-16(mgDf50);sir-2.1(OE) has a lifespan of 9.1 days, while single mutant sir-2.1(OE) has a lifespan of 18.1 days and wild type has a lifespan of 15.0 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Rizki G et al., 2011, The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 7(9):e1002235 21909281 Click here to select all mutants from this PubMed ID in the graph
Abstract
The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1) is a longevity determinant previously shown to act as a co-repressor of DAF-16. We report here that HCF-1 represents an integral player in the regulatory loop linking SIR-2.1/SIRT1 and DAF-16/FOXO in both worms and mammals. Genetic analyses showed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response in C. elegans. Gene expression profiling revealed a striking 80% overlap between the DAF-16 target genes responsive to hcf-1 mutation and sir-2.1 overexpression. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16-mediated transcription particularly important for aging and stress responses. Analogous to its role in regulating DAF-16/SIR-2.1 target genes in C. elegans, the mammalian HCF-1 also repressed the expression of several FOXO/SIRT1 target genes. Protein-protein association studies demonstrated that SIR-2.1/SIRT1 and HCF-1 form protein complexes in worms and mammalian cells, highlighting the conservation of their regulatory relationship. Our findings uncover a conserved interaction between the key longevity determinants SIR-2.1/SIRT1 and HCF-1, and they provide new insights into the complex regulation of FOXO proteins.

Temperature °C
25
Diet
NGM; OP50
Lifespan (days)
8.7
Lifespan change (compared to wild type)
-42.38%
Lifespan comparisons
Double mutant daf-16(mgDf50);sir-2.1(OE) has a lifespan of 8.7 days, while single mutant sir-2.1(OE) has a lifespan of 17.6 days and wild type has a lifespan of 15.1 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Rizki G et al., 2011, The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 7(9):e1002235 21909281 Click here to select all mutants from this PubMed ID in the graph
Abstract
The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1) is a longevity determinant previously shown to act as a co-repressor of DAF-16. We report here that HCF-1 represents an integral player in the regulatory loop linking SIR-2.1/SIRT1 and DAF-16/FOXO in both worms and mammals. Genetic analyses showed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response in C. elegans. Gene expression profiling revealed a striking 80% overlap between the DAF-16 target genes responsive to hcf-1 mutation and sir-2.1 overexpression. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16-mediated transcription particularly important for aging and stress responses. Analogous to its role in regulating DAF-16/SIR-2.1 target genes in C. elegans, the mammalian HCF-1 also repressed the expression of several FOXO/SIRT1 target genes. Protein-protein association studies demonstrated that SIR-2.1/SIRT1 and HCF-1 form protein complexes in worms and mammalian cells, highlighting the conservation of their regulatory relationship. Our findings uncover a conserved interaction between the key longevity determinants SIR-2.1/SIRT1 and HCF-1, and they provide new insights into the complex regulation of FOXO proteins.

Temperature °C
20
Diet
NGM
Lifespan (days)
9.81
Phenotype
The lifespan of sir-2.1 OE animals was reduced lifespan of daf-16(mgDf50);sir-2.1 OE animals, similar to the lifespan of daf-16(mgDf50) mutants alone.
Lifespan comparisons
Double mutant daf-16(mgDf50);sir-2.1(OE) has a lifespan of 9.81 days, while single mutant sir-2.1(OE) has a lifespan of 25.0 days and single mutant daf-16(mgDf50) has a lifespan of 14.0 days.
Citation
View abstract
Tissenbaum HA, Guarente L, 2001, Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 410(6825):227-30 11242085 Click here to select all mutants from this PubMed ID in the graph
Abstract
In Caenorhabditis elegans, mutations that reduce the activity of an insulin-like receptor (daf-2) or a phosphatidylinositol-3-OH kinase (age-1) favour entry into the dauer state during larval development and extend lifespan in adults. Downregulation of this pathway activates a forkhead transcription factor (daf-16), which may regulate targets that promote dauer formation in larvae and stress resistance and longevity in adults. In yeast, the SIR2 gene determines the lifespan of mother cells, and adding an extra copy of SIR2 extends lifespan. Sir2 mediates chromatin silencing through a histone deacetylase activity that depends on NAD (nicotinamide adenine dinucleotide) as a cofactor. We have surveyed the lifespan of C. elegans strains containing duplications of chromosomal regions. Here we report that a duplication containing sir-2.1-the C. elegans gene most homologous to yeast SIR2-confers a lifespan that is extended by up to 50%. Genetic analysis indicates that the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway. Our findings suggest that Sir2 proteins may couple longevity to nutrient availability in many eukaryotic organisms.

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

Temperature °C
20
Lifespan (days)
11.9
Citation
View abstract
Hashimoto Y et al., 2009, Lifespan extension by suppression of autophagy genes in Caenorhabditis elegans. Genes Cells. 14(6):717-26 19469880 Click here to select all mutants from this PubMed ID in the graph
Abstract
Lifespan is regulated by a complex combination of environmental and genetic factors. Autophagy, which is a bulk degradation system of macromolecules and organelles, has an important role in various biological events. In Caenorhabditis elegans, several autophagy genes have been shown to have a role in promoting longevity, but many other autophagy genes have not been examined for their role in the lifespan regulation. Here we have systematically examined the effect of RNAi suppression of 14 autophagy genes on lifespan. While maternal RNAi of autophagy genes in wild-type worms tended to reduce lifespan, maternal RNAi of each of seven autophagy genes in the insulin/IGF-1 receptor daf-2 mutants extended lifespan. Remarkably, RNAi of unc-51/atg-1, bec-1/atg-6 or atg-9, from young adult, i.e. after development, extended lifespan in both wild-type animals and daf-2 mutants, although RNAi of one or two genes shortened it. Moreover, our analysis suggests that the lifespan extension, which is induced by RNAi of unc-51, bec-1 or atg-9 after development, does not require the transcription factor daf-16, the NAD(+)-dependent protein deacetylase sir-2.1 or the genes related to mitochondrial functions. Collectively, our results suggest that autophagy may not always be beneficial to longevity, but may also function to restrict lifespan in C. elegans.

Search genes: daf-16 sir-2.1

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

177924
sir-2.1
View on GenAge (sir-2.1)
WBGene00004800

NAD-dependent protein deacetylase sir-2.1;yeast SIR related

Locus: CELE_R11A8.4

Wormbase description: sir-2.1 encodes an NAD-dependent protein deacetylase with similarity to Saccharomyces cerevisiae Sir2p and mammalian SIRT1.

Orthologs of daf-16;sir-2.1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6;Sirt1
Mus musculus	Foxo1;Sirt1
Mus musculus	Foxo4;Sirt1
Mus musculus	Foxo3;Sirt1
Mus musculus	Sirt1;Foxo6
Mus musculus	Sirt1;Foxo1
Mus musculus	Sirt1;Foxo4
Mus musculus	Sirt1;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 sir-2.1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Sirt1