asm-3;daf-16;rrf-3

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Genetic mutants with asm-3, daf-16, rrf-3 alterations

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

Temperature °C
20
Lifespan (days)
10.35
Lifespan change (compared to wild type)
-11.76%
Lifespan comparisons
Triple mutant asm-3(RNAi);daf-16(mgDf47);rrf-3(pk1426) has a lifespan of 10.35 days, while single mutant asm-3(RNAi) has a lifespan of 17.8 days, double mutant daf-16(mgDf47);rrf-3(pk1426) has a lifespan of 10.25 days and wild type has a lifespan of 11.73 days.
Citation
View abstract
Kim Y, Sun H, 2007, Functional genomic approach to identify novel genes involved in the regulation of oxidative stress resistance and animal lifespan. Aging Cell. 6(4):489-503 17608836 Click here to select all mutants from this PubMed ID in the graph
Abstract
Genetic studies in many organisms suggest that an increased animal lifespan phenotype is often accompanied by enhanced resistance toward reactive oxygen species (ROS). In Caenorhabditis elegans, mutations in daf-2, which encode an insulin/insulin-like growth factor 1 receptor-like molecule, lead to an extended animal lifespan and increased resistance to ROS. We have optimized an assay to monitor ROS resistance in worms using the ROS-generating chemical paraquat. We have employed this assay to screen the RNAi library along chromosomes III and IV for genes that, when silenced, confer paraquat resistance. The positive RNAi clones were subsequently screened for a lifespan extension phenotype. Using this approach, we have identified 84 genes that, when inactivated by RNAi, lead to significant increases in animal lifespan. Among the 84 genes, 29 were found to act in a manner dependent on daf-16. DAF-16, a forkhead transcription factor, is known to integrate signals from multiple pathways, including the daf-2 pathway, to regulate animal lifespan. Most of the 84 genes have not been previously linked to aging, and potentially participate in important cellular processes such as signal transduction, cell-cell interaction, gene expression, protein degradation, and energy metabolism. Our screen has also identified a group of genes that potentially function in a nutrient-sensing pathway to regulate lifespan in C. elegans. Our study provides a novel approach to identify genes involved in the regulation of aging.

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

Temperature °C
20
Lifespan (days)
12.8
Lifespan change (compared to wild type)
-26.44%
Phenotype
daf-16 RNAi abolished the lifespan extension phenotype caused by asm-3(ok1744) mutation
Lifespan comparisons
Triple mutant asm-3(ok1744);daf-16(RNAi);rrf-3(pk1426) has a lifespan of 12.8 days, while double mutant asm-3(ok1744);rrf-3(pk1426) has a lifespan of 20.1 days and wild type has a lifespan of 17.4 days.
Citation
View abstract
Kim Y, Sun H, 2012;7(9):e45890., ASM-3 acid sphingomyelinase functions as a positive regulator of the DAF-2/AGE-1 signaling pathway and serves as a novel anti-aging target. PLoS One. 7(9):e45890 23049887 Click here to select all mutants from this PubMed ID in the graph
Abstract
In C. elegans, the highly conserved DAF-2/insulin/insulin-like growth factor 1 receptor signaling (IIS) pathway regulates longevity, metabolism, reproduction and development. In mammals, acid sphingomyelinase (ASM) is an enzyme that hydrolyzes sphingomyelin to produce ceramide. ASM has been implicated in CD95 death receptor signaling under certain stress conditions. However, the involvement of ASM in growth factor receptor signaling under physiological conditions is not known. Here, we report that in vivo ASM functions as a positive regulator of the DAF-2/IIS pathway in C. elegans. We have shown that inactivation of asm-3 extends animal lifespan and promotes dauer arrest, an alternative developmental process. A significant cooperative effect on lifespan is observed between asm-3 deficiency and loss-of-function alleles of the age-1/PI 3-kinase, with the asm-3; age-1 double mutant animals having a mean lifespan 259% greater than that of the wild-type animals. The lifespan extension phenotypes caused by the loss of asm-3 are dependent on the functions of daf-16/FOXO and daf-18/PTEN. We have demonstrated that inactivation of asm-3 causes nuclear translocation of DAF-16::GFP protein, up-regulates endogenous DAF-16 protein levels and activates the downstream targeting genes of DAF-16. Together, our findings reveal a novel role of asm-3 in regulation of lifespan and diapause by modulating IIS pathway. Importantly, we have found that two drugs known to inhibit mammalian ASM activities, desipramine and clomipramine, markedly extend the lifespan of wild-type animals, in a manner similar to that achieved by genetic inactivation of the asm genes. Our studies illustrate a novel strategy of anti-aging by targeting ASM, which may potentially be extended to mammals.

Search genes: asm-3 daf-16 rrf-3 asm-3;daf-16;rrf-3

Entrez ID
Symbol
GenAge
Wormbase ID

176879
asm-3
View on GenAge (asm-3)
WBGene00000213

Putative sphingomyelin phosphodiesterase asm-3;Sphingomyelin phosphodiesterase

Locus: CELE_W03G1.7

Wormbase description: none available

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

174315
rrf-3
View on GenAge (rrf-3)
WBGene00004510

RNA-dependent RNA polymerase Family

Locus: CELE_F10B5.7

Wormbase description: rrf-3 encodes an RNA-directed RNA polymerase (RdRP) homolog that inhibits somatic RNAi, and thus promotes activity of repeated genes (e.g., multicopy transgenic arrays); the effect of RRF-3 on RNAi is opposite to that of RRF-1 (which stimulates somatic RNAi), which might arise from competition by RRF-3 with RRF-1 or EGO-1 in RNAi formation; rrf-3(allele) or rrf-3(allele2) mutants are hypersensitive to somatic RNAi, and conversely suppress the activity of an integrated rol6 (su1006) transgene.

Orthologs of asm-3;daf-16;rrf-3 in SynergyAge

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Species	Gene

Not in SynergyAge
Species	Gene

Orthologs of asm-3 in SynergyAge

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Species	Gene

Orthologs of daf-16 in SynergyAge

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Species	Gene

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

Orthologs of rrf-3 in SynergyAge

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Species	Gene