daf-15;ddr-2;let-363

There is no network for this step.

Fullscreen mode

Hide graph

Legend

Genetic mutants with daf-15, ddr-2, let-363 alterations

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

Temperature °C
25
Lifespan (days)
16.57
Lifespan change (compared to wild type)
3.76%
Phenotype
Inhibition of TOR signaling by knocking down both TOR/let-363 and Raptor/daf-15(a binding partner of TOR that is necessary for TOR activity) or TOR/let-363 alone in the EQ19 (i.e. the eIF4H/drr-2 over-expressing line) background failed to extend lifespan. This finding strongly implies that a common mechanism mediates the lifespan effects of TOR and eIF4H/drr-2, and that eIF4H/drr-2 might function genetically downstream of TOR to influence lifespan.
Lifespan comparisons
Triple mutant daf-15(RNAi);ddr-2(OE);let-363(RNAi) has a lifespan of 16.57 days, while double mutant daf-15(RNAi);let-363(RNAi) has a lifespan of 20.9 days, single mutant ddr-2(OE) has a lifespan of 16.64 days and wild type has a lifespan of 15.97 days.
Citation
View abstract
Ching TT et al., 2010, drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans. Aging Cell. 9(4):545-57 20456299 Click here to select all mutants from this PubMed ID in the graph
Abstract
Dietary restriction (DR) results in a robust increase in lifespan while maintaining the physiology of much younger animals in a wide range of species. Here, we examine the role of drr-2, a DR-responsive gene recently identified, in determining the longevity of Caenorhabditis elegans. Inhibition of drr-2 has been shown to increase longevity. However, the molecular mechanisms by which drr-2 influences longevity remain unknown. We report here that drr-2 encodes an ortholog of human eukaryotic translation initiation factor 4H (eIF4H), whose function is to mediate the initiation step of mRNA translation. The molecular function of DRR-2 is validated by the association of DRR-2 with polysomes and by the decreased rate of protein synthesis observed in drr-2 knockdown animals. Previous studies have also suggested that DR might trigger a regulated reduction in drr-2 expression to initiate its longevity response. By examining the effect of increasing drr-2 expression on DR animals, we find that drr-2 is essential for a large portion of the longevity response to DR. The nutrient-sensing target of rapamycin (TOR) pathway has been shown to mediate the longevity effects of DR in C. elegans. Results from our genetic analyses suggest that eIF4H/DRR-2 functions downstream of TOR, but in parallel to the S6K/PHA-4 pathway to mediate the lifespan effects of DR. Together, our findings reveal an important role for eIF4H/drr-2 in the TOR-mediated longevity responses to DR.

Temperature °C
25
Lifespan (days)
14.23
Lifespan change (compared to wild type)
1.35%
Phenotype
Inhibition of TOR signaling by knocking down both TOR/let-363 and Raptor/daf-15(a binding partner of TOR that is necessary for TOR activity) or TOR/let-363 alone in the EQ19 (i.e. the eIF4H/drr-2 over-expressing line) background failed to extend lifespan. This finding strongly implies that a common mechanism mediates the lifespan effects of TOR and eIF4H/drr-2, and that eIF4H/drr-2 might function genetically downstream of TOR to influence lifespan.
Lifespan comparisons
Triple mutant daf-15(RNAi);ddr-2(OE);let-363(RNAi) has a lifespan of 14.23 days, while double mutant daf-15(RNAi);let-363(RNAi) has a lifespan of 21.22 days, single mutant ddr-2(OE) has a lifespan of 14.79 days and wild type has a lifespan of 14.04 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Ching TT et al., 2010, drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans. Aging Cell. 9(4):545-57 20456299 Click here to select all mutants from this PubMed ID in the graph
Abstract
Dietary restriction (DR) results in a robust increase in lifespan while maintaining the physiology of much younger animals in a wide range of species. Here, we examine the role of drr-2, a DR-responsive gene recently identified, in determining the longevity of Caenorhabditis elegans. Inhibition of drr-2 has been shown to increase longevity. However, the molecular mechanisms by which drr-2 influences longevity remain unknown. We report here that drr-2 encodes an ortholog of human eukaryotic translation initiation factor 4H (eIF4H), whose function is to mediate the initiation step of mRNA translation. The molecular function of DRR-2 is validated by the association of DRR-2 with polysomes and by the decreased rate of protein synthesis observed in drr-2 knockdown animals. Previous studies have also suggested that DR might trigger a regulated reduction in drr-2 expression to initiate its longevity response. By examining the effect of increasing drr-2 expression on DR animals, we find that drr-2 is essential for a large portion of the longevity response to DR. The nutrient-sensing target of rapamycin (TOR) pathway has been shown to mediate the longevity effects of DR in C. elegans. Results from our genetic analyses suggest that eIF4H/DRR-2 functions downstream of TOR, but in parallel to the S6K/PHA-4 pathway to mediate the lifespan effects of DR. Together, our findings reveal an important role for eIF4H/drr-2 in the TOR-mediated longevity responses to DR.

Search genes: daf-15 ddr-2 let-363 daf-15;ddr-2;let-363

Entrez ID
Symbol
GenAge
Wormbase ID

177770
daf-15
View on GenAge (daf-15)
WBGene00000911

hypothetical protein

Locus: CELE_C10C5.6

Wormbase description: daf-15 encodes an ortholog of RAPTOR (the regulatory associated protein of mTOR), and is regulated by DAF-16; daf-15 is required for non-dauer development, at least in some tissues or stages; daf-15(m81) mutants constitutively and irreversibly form abnormal dauer-like larvae (and are thus effectively lethal/sterile); mutants do not form true dauers when exposed to dauer pheromone, yet execute only two molts.

Entrez ID
Symbol
GenAge
Wormbase ID

180622
ddr-2
View on GenAge (ddr-2)
WBGene00017381

Discoidin domain-containing receptor tyrosine kinase B

Locus: CELE_F11D5.3

Wormbase description: F11D5.3 encodes a putative tyrosine kinase homologous to human RS1 (OMIM:312700, mutated in juvenile X-linked retinoschisis).

Entrez ID
Symbol
GenAge
Wormbase ID

172167
let-363
View on GenAge (let-363)
WBGene00002583

Target of rapamycin homolog

Locus: CELE_B0261.2

Wormbase description: none available

Orthologs of daf-15;ddr-2;let-363 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Mtor;Ddr1
Mus musculus	Mtor;Ddr2

Orthologs of daf-15 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	raptor

Orthologs of ddr-2 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Ddr1
Mus musculus	Ddr2

Orthologs of let-363 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	Tor
Mus musculus	Mtor