daf-2;vhl-1

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Genetic mutants with daf-2, vhl-1 alterations

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

Temperature °C
20
Diet
OP50;NGM
Lifespan (days)
45.0
Lifespan change (compared to wild type)
157.14%
Phenotype
daf-2(RNAi) further extended the already long lifespan of vhl-1(ok161) animals.
Lifespan comparisons
Double mutant daf-2(RNAi);vhl-1(ok161) has a lifespan of 45.0 days, while single mutant daf-2(RNAi) has a lifespan of 28.125 days, single mutant vhl-1(ok161) has a lifespan of 26.25 days and wild type has a lifespan of 17.5 days.
Type of interaction
See methods
Synergistic (positive)
Citation
View abstract
Mehta R et al., 2009, Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science. 324(5931):1196-8 19372390 Click here to select all mutants from this PubMed ID in the graph
Abstract
The Caenorhabditis elegans von Hippel-Lindau tumor suppressor homolog VHL-1 is a cullin E3 ubiquitin ligase that negatively regulates the hypoxic response by promoting ubiquitination and degradation of the hypoxic response transcription factor HIF-1. Here, we report that loss of VHL-1 significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF-1 was epistatic to VHL-1, indicating that HIF-1 acts downstream of VHL-1 to modulate aging and proteotoxicity. VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.

Temperature °C
20
Diet
NGM; OP50; HT116
Lifespan (days)
27.0
Lifespan change (compared to wild type)
50.00%
Phenotype
Knockdown of daf-2 resulted in an increased lifespan in the wild-type N2 worms.
Lifespan comparisons
Double mutant daf-2(RNAi);vhl-1(ok161) has a lifespan of 27.0 days, while single mutant daf-2(RNAi) has a lifespan of 35.6 days, single mutant vhl-1(ok161) has a lifespan of 21.8 days and wild type has a lifespan of 18.0 days.
Type of interaction
See methods
Dependent
Citation
View abstract
Müller RU et al., 2009, The von Hippel Lindau tumor suppressor limits longevity. J Am Soc Nephrol. 20(12):2513-7 19797165 Click here to select all mutants from this PubMed ID in the graph
Abstract
Many genes are responsible for the modulation of lifespan in model organisms. In addition to regulating adaptive biologic responses that control stress signaling and longevity, some of these genes participate in tumor formation. The mechanisms that determine longevity and link regulation of lifespan with tumorigenesis are poorly understood. Here, we show that the tumor suppressor von Hippel-Lindau (VHL), which has widely known roles in renal carcinogenesis and the formation of kidney cysts, controls longevity in Caenorhabditis elegans. Loss of vhl-1 significantly increased lifespan and resulted in accelerated basal signaling of the p38 mitogen-activated protein kinase PMK-3. Furthermore, the VHL-1 effect on the regulation of lifespan was independent of the insulin/IGF-1-like signaling pathway, suggesting a mechanism for stress resistance that controls both lifespan and tumorigenesis. These findings define VHL-1 as a player in longevity signaling and connect aging, regulation of lifespan, and stress responses with formation of renal cell carcinomas.

Search genes: daf-2 vhl-1

Entrez ID
Symbol
GenAge
Wormbase ID

175410
daf-2
View on GenAge (daf-2)
WBGene00000898

Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein

Locus: CELE_Y55D5A.5

Wormbase description: daf-2 encodes a receptor tyrosine kinase that is the C. elegans insulin/IGF receptor ortholog; DAF-2 activity is required for a number of processes in C. elegans, including embryonic and larval development, formation of the developmentally arrested dauer larval stage (diapause), larval developmental timing, adult longevity, reproduction, fat storage, salt chemotaxis learning, and stress resistance, including response to high temperature, oxidative stress, and bacterial infection; DAF-2 signals through a conserved PI 3-kinase pathway to negatively regulate the activity of DAF-16, a Forkhead-related transcription factor, by inducing its phosphorylation and nuclear exclusion; in addition, DAF-2 negatively regulates the nuclear localization, and hence transcriptional activity, of SKN-1 in intestinal nuclei; amongst the 38 predicted insulin-like molecules in C. elegans, genetic and microarray analyses suggest that at least DAF-28, INS-1, and INS-7 are likely DAF-2 ligands; genetic mosaic and tissue-specific promoter studies indicate that daf-2 can function cell nonautonomously and within multiple cell types to influence dauer formation and adult lifespan, likely by regulating the production of secondary endocrine signals that coordinate growth and longevity throughout the animal; temporal analysis of daf-2 function indicates that daf-2 regulates lifespan, reproduction, and diapause independently, at distinct times during the animal's life cycle.

Entrez ID
Symbol
GenAge
Wormbase ID

181321
vhl-1
View on GenAge (vhl-1)
WBGene00006922

von Hippel-Lindau tumor suppressor homolog

Locus: CELE_F08G12.4

Wormbase description: vhl-1 is orthologous to the mammalian von Hippel-Landau tumor suppressor VHL, which is a cullin E3 ubiquitin ligase; vhl-1 promotes the ubiquitination and degradation of the hif-1 hypoxic response transcription factor; vhl-1 and hif-1 act to modulate life span and proteotoxicity, vhl-1 mutants live longer compared to wild-type, by a mechanism separate from dietary restriction and insulin signaling; vhl-1 may also have a hif-1 independent function related to the extracellular matrix.

Orthologs of daf-2;vhl-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	InR;Vhl
Mus musculus	Vhl;InR

Orthologs of daf-2 in SynergyAge

Show in SynergyAge
Species	Gene
Drosophila melanogaster	InR

Not in SynergyAge
Species	Gene
Mus musculus	Insr
Mus musculus	Igf1r
Mus musculus	Insrr

Orthologs of vhl-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	Vhl