daf-2;hsf-1;rsks-1

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Genetic mutants with daf-2, hsf-1, rsks-1 alterations

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

Temperature °C
25
Lifespan (days)
15.0
Lifespan comparisons
Triple mutant daf-2(e1370);hsf-1(RNAi);rsks-1(ok1255) has a lifespan of 15.0 days, while double mutant daf-2(e1370);rsks-1(ok1255) has a lifespan of 50.1 days.
Citation
View abstract
Chen D et al., 2013, Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell Rep. 5(6):1600-10 24332851 Click here to select all mutants from this PubMed ID in the graph
Abstract
Inhibition of DAF-2 (insulin-like growth factor 1 [IGF-1] receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways, respectively, extend lifespan in Caenorhabditis elegans. However, it has not been clear how and in which tissues they interact with each other to modulate longevity. Here, we demonstrate that a combination of mutations in daf-2 and rsks-1 produces a nearly 5-fold increase in longevity that is much greater than the sum of single mutations. This synergistic lifespan extension requires positive feedback regulation of DAF-16 (FOXO) via the AMP-activated protein kinase (AMPK) complex. Furthermore, we identify germline as the key tissue for this synergistic longevity. Moreover, germline-specific inhibition of rsks-1 activates DAF-16 in the intestine. Together, our findings highlight the importance of the germline in the significantly increased longevity produced by daf-2 rsks-1, which has important implications for interactions between the two major conserved longevity pathways in more complex organisms.

Temperature °C
25
Lifespan (days)
12.7
Lifespan comparisons
Triple mutant daf-2(e1370);hsf-1(RNAi);rsks-1(ok1255) has a lifespan of 12.7 days, while double mutant daf-2(e1370);rsks-1(ok1255) has a lifespan of 50.8 days.
Citation
View abstract
Chen D et al., 2013, Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell Rep. 5(6):1600-10 24332851 Click here to select all mutants from this PubMed ID in the graph
Abstract
Inhibition of DAF-2 (insulin-like growth factor 1 [IGF-1] receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways, respectively, extend lifespan in Caenorhabditis elegans. However, it has not been clear how and in which tissues they interact with each other to modulate longevity. Here, we demonstrate that a combination of mutations in daf-2 and rsks-1 produces a nearly 5-fold increase in longevity that is much greater than the sum of single mutations. This synergistic lifespan extension requires positive feedback regulation of DAF-16 (FOXO) via the AMP-activated protein kinase (AMPK) complex. Furthermore, we identify germline as the key tissue for this synergistic longevity. Moreover, germline-specific inhibition of rsks-1 activates DAF-16 in the intestine. Together, our findings highlight the importance of the germline in the significantly increased longevity produced by daf-2 rsks-1, which has important implications for interactions between the two major conserved longevity pathways in more complex organisms.

Temperature °C
25
Lifespan (days)
14.2
Lifespan comparisons
Triple mutant daf-2(e1370);hsf-1(RNAi);rsks-1(ok1255) has a lifespan of 14.2 days, while double mutant daf-2(e1370);rsks-1(ok1255) has a lifespan of 51.3 days.
Citation
View abstract
Chen D et al., 2013, Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell Rep. 5(6):1600-10 24332851 Click here to select all mutants from this PubMed ID in the graph
Abstract
Inhibition of DAF-2 (insulin-like growth factor 1 [IGF-1] receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways, respectively, extend lifespan in Caenorhabditis elegans. However, it has not been clear how and in which tissues they interact with each other to modulate longevity. Here, we demonstrate that a combination of mutations in daf-2 and rsks-1 produces a nearly 5-fold increase in longevity that is much greater than the sum of single mutations. This synergistic lifespan extension requires positive feedback regulation of DAF-16 (FOXO) via the AMP-activated protein kinase (AMPK) complex. Furthermore, we identify germline as the key tissue for this synergistic longevity. Moreover, germline-specific inhibition of rsks-1 activates DAF-16 in the intestine. Together, our findings highlight the importance of the germline in the significantly increased longevity produced by daf-2 rsks-1, which has important implications for interactions between the two major conserved longevity pathways in more complex organisms.

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

Temperature °C
20
Diet
NGM
Lifespan (days)
10.0
Lifespan change (compared to wild type)
-49.24%
Lifespan comparisons
Triple mutant daf-2(e1370);hsf-1(RNAi);rsks-1(tm1714) has a lifespan of 10.0 days, while single mutant hsf-1(RNAi) has a lifespan of 9.9 days, double mutant daf-2(e1370);rsks-1(tm1714) has a lifespan of 47.0 days and wild type has a lifespan of 19.7 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Seo K et al., 2013, Heat shock factor 1 mediates the longevity conferred by inhibition of TOR and insulin/IGF-1 signaling pathways in C. elegans. Aging Cell. 12(6):1073-81 23879233 Click here to select all mutants from this PubMed ID in the graph
Abstract
Target of rapamycin (TOR) signaling is an evolutionarily well-conserved pathway that regulates various physiologic processes, including aging and metabolism. One of the key downstream components of TOR signaling is ribosomal protein S6 kinase (S6K) whose inhibition extends the lifespan of yeast, Caenorhabditis elegans, Drosophila, and mice. Here, we demonstrate that the activation of heat shock factor 1 (HSF-1), a crucial longevity transcription factor known to act downstream of the insulin/IGF-1 signaling (IIS) pathway, mediates the prolonged lifespan conferred by mutations in C. elegans S6K (rsks-1). We found that hsf-1 is required for the longevity caused by down-regulation of components in TOR signaling pathways, including TOR and S6K. The induction of a small heat-shock protein hsp-16, a transcriptional target of HSF-1, mediates the long lifespan of rsks-1 mutants. Moreover, we show that synergistic activation of HSF-1 is required for the further enhanced longevity caused by simultaneous down-regulation of TOR and IIS pathways. Our findings suggest that HSF-1 acts as an essential longevity factor that intersects both IIS and TOR signaling pathways.

Temperature °C
20
Diet
NGM
Lifespan (days)
12.7
Lifespan change (compared to wild type)
-32.80%
Lifespan comparisons
Triple mutant daf-2(e1370);hsf-1(RNAi);rsks-1(tm1714) has a lifespan of 12.7 days, while single mutant hsf-1(RNAi) has a lifespan of 11.2 days, double mutant daf-2(e1370);rsks-1(tm1714) has a lifespan of 49.4 days and wild type has a lifespan of 18.9 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Seo K et al., 2013, Heat shock factor 1 mediates the longevity conferred by inhibition of TOR and insulin/IGF-1 signaling pathways in C. elegans. Aging Cell. 12(6):1073-81 23879233 Click here to select all mutants from this PubMed ID in the graph
Abstract
Target of rapamycin (TOR) signaling is an evolutionarily well-conserved pathway that regulates various physiologic processes, including aging and metabolism. One of the key downstream components of TOR signaling is ribosomal protein S6 kinase (S6K) whose inhibition extends the lifespan of yeast, Caenorhabditis elegans, Drosophila, and mice. Here, we demonstrate that the activation of heat shock factor 1 (HSF-1), a crucial longevity transcription factor known to act downstream of the insulin/IGF-1 signaling (IIS) pathway, mediates the prolonged lifespan conferred by mutations in C. elegans S6K (rsks-1). We found that hsf-1 is required for the longevity caused by down-regulation of components in TOR signaling pathways, including TOR and S6K. The induction of a small heat-shock protein hsp-16, a transcriptional target of HSF-1, mediates the long lifespan of rsks-1 mutants. Moreover, we show that synergistic activation of HSF-1 is required for the further enhanced longevity caused by simultaneous down-regulation of TOR and IIS pathways. Our findings suggest that HSF-1 acts as an essential longevity factor that intersects both IIS and TOR signaling pathways.

Search genes: daf-2 hsf-1 rsks-1 daf-2;hsf-1;rsks-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

173078
hsf-1
View on GenAge (hsf-1)
WBGene00002004

Heat Shock Factor

Locus: CELE_Y53C10A.12

Wormbase description: hsf-1 encodes the C. elegans heat-shock transcription factor ortholog; HSF-1 functions as a transcriptional regulator of stress-induced gene expression whose activity is required for heat-shock and proteotoxicity response, larval development, innate immunity, and regulation of adult lifespan; HSF-1 binds bovine calmodulin in vitro in a calcium-dependent manner.

Entrez ID
Symbol
GenAge
Wormbase ID

176554
rsks-1
View on GenAge (rsks-1)
WBGene00012929

Ribosomal protein S6 kinase beta

Locus: CELE_Y47D3A.16

Wormbase description: rsks-1 encodes a putative ribosomal protein S6 kinase (S6K) required additively with IFG-1 for normally high levels of protein synthesis, and for normally short lifespan; RSKS-1's effect on lifespan is independent of DAF-16, ISP-1, and SIR-2.1, and does not correlate with juglone resistance, but does correlate with abnormally high resistance to starvation and (perhaps) thermotolerance; RSKS-1 is required for normal juglone resistance, as well as normally rapid growth and normal brood sizes; RSKS-1 is expressed in E-lineage embryonic cells, and in pharyngeal and hypodermal cells of larvae and adults; RSKS-1 is orthologous to human RPS6KB1 (OMIM:608938) and RPS6KB2 (OMIM:608939).

Orthologs of daf-2;hsf-1;rsks-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Rps6kb1;Insr
Mus musculus	Rps6kb1;Igf1r
Mus musculus	Rps6kb1;Insrr
Mus musculus	Rps6kb2;Insr
Mus musculus	Rps6kb2;Igf1r
Mus musculus	Rps6kb2;Insrr

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 hsf-1 in SynergyAge

Show in SynergyAge
Species	Gene

Orthologs of rsks-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	S6k
Mus musculus	Rps6kb1
Mus musculus	Rps6kb2