asm-2;daf-18;rrf-3

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Genetic mutants with asm-2, daf-18, rrf-3 alterations

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

Temperature °C
20
Lifespan (days)
10.4
Phenotype
The lifespan extension phenotypes produced by inactivation of asm-2 gene was suppressed by a null mutation of daf-18, daf-18(nr2037)
Lifespan comparisons
Triple mutant asm-2(RNAi);daf-18(nr2037);rrf-3(pk1426) has a lifespan of 10.4 days, while double mutant daf-18(nr2037);rrf-3(pk1426) has a lifespan of 9.9 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-2 daf-18 rrf-3 asm-2;daf-18;rrf-3

Entrez ID
Symbol
GenAge
Wormbase ID

181323
asm-2
View on GenAge (asm-2)
WBGene00000212

Sphingomyelin phosphodiesterase 2

Locus: CELE_ZK455.4

Wormbase description: asm-2 encodes a protein similar to human acid sphingomyelinase (ASM) or sphingomyelin phosphodiesterase 1; the ASM-2 protein has a putative secretory signal peptide at the N-terminus, saposin-like and proline-rich domains and putative N-linked glycosylation sites; asm-2 shows phosphodiesterase activity when expressed in COS-7 cells; like mammalian ASM, asm-2 is probably both intracellular and secreted; northern blot analysis indicates that asm-2 is expressed during post-embryonic development as compared to asm-1 which is expressed at higher levels in the embryo; human ASM is implicated in Niemann-Pick disease type B (OMIM:607608).

Entrez ID
Symbol
GenAge
Wormbase ID

176869
daf-18
View on GenAge (daf-18)
WBGene00000913

Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase daf-18

Locus: CELE_T07A9.6

Wormbase description: daf-18 encodes a lipid phosphatase homologous to the human PTEN tumor suppresor (OMIM:601728, mutated in Cowden disease and several cancers); DAF-18 negatively regulates insulin-like signaling mediated by DAF-2/IR and AGE-1/PI3K and thus plays a role in metabolism, development, and longevity; based on sequence and genetic analysis, DAF-18 is predicted to dephosphorylate AGE-1-generated PIP3 in order to limit activation of the downstream AKT-1 and AKT-2 kinases that negatively regulate DAF-16.

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-2;daf-18;rrf-3 in SynergyAge

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Species	Gene

Orthologs of asm-2 in SynergyAge

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Orthologs of daf-18 in SynergyAge

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Species	Gene

Orthologs of rrf-3 in SynergyAge

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Species	Gene