aak-2;daf-2;rsks-1

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

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

Temperature °C
20
Diet
HT115
Lifespan (days)
40.28
Lifespan change (compared to wild type)
175.89%
Lifespan comparisons
Triple mutant aak-2(OE);daf-2(e1370);rsks-1(ok1255) has a lifespan of 40.28 days, while single mutant aak-2(OE) has a lifespan of 21.98 days, double mutant daf-2(e1370);rsks-1(ok1255) has a lifespan of 50.51 days and wild type has a lifespan of 14.6 days.
Citation
View abstract
Hou L et al., 2016, A Systems Approach to Reverse Engineer Lifespan Extension by Dietary Restriction. Cell Metab. 23(3):529-40 26959186 Click here to select all mutants from this PubMed ID in the graph
Abstract
Dietary restriction (DR) is the most powerful natural means to extend lifespan. Although several genes can mediate responses to alternate DR regimens, no single genetic intervention has recapitulated the full effects of DR, and no unified system is known for different DR regimens. Here we obtain temporally resolved transcriptomes during calorie restriction and intermittent fasting in Caenorhabditis elegans and find that early and late responses involve metabolism and cell cycle/DNA damage, respectively. We uncover three network modules of DR regulators by their target specificity. By genetic manipulations of nodes representing discrete modules, we induce transcriptomes that progressively resemble DR as multiple nodes are perturbed. Targeting all three nodes simultaneously results in extremely long-lived animals that are refractory to DR. These results and dynamic simulations demonstrate that extensive feedback controls among regulators may be leveraged to drive the regulatory circuitry to a younger steady state, recapitulating the full effect of DR.

Temperature °C
20
Diet
HT115
Lifespan (days)
36.99
Lifespan change (compared to wild type)
75.31%
Lifespan comparisons
Triple mutant aak-2(OE);daf-2(e1370);rsks-1(ok1255) has a lifespan of 36.99 days, while single mutant aak-2(OE) has a lifespan of 26.75 days, double mutant daf-2(e1370);rsks-1(ok1255) has a lifespan of 42.86 days and wild type has a lifespan of 21.1 days.
Citation
View abstract
Hou L et al., 2016, A Systems Approach to Reverse Engineer Lifespan Extension by Dietary Restriction. Cell Metab. 23(3):529-40 26959186 Click here to select all mutants from this PubMed ID in the graph
Abstract
Dietary restriction (DR) is the most powerful natural means to extend lifespan. Although several genes can mediate responses to alternate DR regimens, no single genetic intervention has recapitulated the full effects of DR, and no unified system is known for different DR regimens. Here we obtain temporally resolved transcriptomes during calorie restriction and intermittent fasting in Caenorhabditis elegans and find that early and late responses involve metabolism and cell cycle/DNA damage, respectively. We uncover three network modules of DR regulators by their target specificity. By genetic manipulations of nodes representing discrete modules, we induce transcriptomes that progressively resemble DR as multiple nodes are perturbed. Targeting all three nodes simultaneously results in extremely long-lived animals that are refractory to DR. These results and dynamic simulations demonstrate that extensive feedback controls among regulators may be leveraged to drive the regulatory circuitry to a younger steady state, recapitulating the full effect of DR.

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

Temperature °C
25
Lifespan (days)
22.1
Lifespan comparisons
Triple mutant aak-2(RNAi);daf-2(e1370);rsks-1(ok1255) has a lifespan of 22.1 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)
21.8
Lifespan comparisons
Triple mutant aak-2(RNAi);daf-2(e1370);rsks-1(ok1255) has a lifespan of 21.8 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)
20.0
Lifespan comparisons
Triple mutant aak-2(RNAi);daf-2(e1370);rsks-1(ok1255) has a lifespan of 20.0 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
25
Lifespan (days)
26.6
Lifespan change (compared to wild type)
107.81%
Phenotype
A deletion in aak-2, which encodes the alpha catalytic subunit of AMPK suppressed the synergistic longevity of daf-2 and rsks-1
Lifespan comparisons
Triple mutant aak-2(ok524);daf-2(e1370);rsks-1(ok1255) has a lifespan of 26.6 days, while double mutant daf-2(e1370);rsks-1(ok1255) has a lifespan of 58.7 days, single mutant aak-2(ok524) has a lifespan of 10.2 days and wild type has a lifespan of 12.8 days.
Type of interaction
See methods
Contains dependence
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)
22.6
Lifespan change (compared to wild type)
73.85%
Phenotype
A deletion in aak-2, which encodes the alpha catalytic subunit of AMPK suppressed the synergistic longevity of daf-2 and rsks-1
Lifespan comparisons
Triple mutant aak-2(ok524);daf-2(e1370);rsks-1(ok1255) has a lifespan of 22.6 days, while double mutant daf-2(e1370);rsks-1(ok1255) has a lifespan of 53.4 days, single mutant aak-2(ok524) has a lifespan of 11.3 days and wild type has a lifespan of 13.0 days.
Type of interaction
See methods
Contains dependence
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.

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

Entrez ID
Symbol
GenAge
Wormbase ID

181727
aak-2
View on GenAge (aak-2)
WBGene00020142

5'-AMP-activated protein kinase catalytic subunit alpha-2

Locus: CELE_T01C8.1

Wormbase description: aak-2 encodes one of two C. elegans homologs of the catalytic alpha subunit of AMP-activated protein kinases (AMPKs); in C. elegans, aak-2 functions downstream of environmental stressors, energy level signals (AMP:ATP ratio), and daf-2-mediated insulin signaling to positively regulate adult lifespan; in regulating lifespan, aak-2 likely acts in parallel with daf-16/FOXO; aak-2 activity is also required for dauer formation in daf-2 mutant animals at high temperature in a manner independent of the AMP:ATP ratio; in the germline, aak-2 functions downstream of daf-2 and daf-7, and in parallel to par-4 and aak-1, to negatively regulate germline proliferation during dauer development; in vitro, AAK-2 exhibits AMP-enhanced kinase activity against a known AMPK substrate, the SAMS peptide.

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

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 aak-2;daf-2;rsks-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	AMPKalpha;InR;S6k
Mus musculus	Insr;Prkaa1;Rps6kb1
Mus musculus	Insr;Prkaa1;Rps6kb2
Mus musculus	Igf1r;Prkaa1;Rps6kb1
Mus musculus	Igf1r;Prkaa1;Rps6kb2
Mus musculus	Insrr;Prkaa1;Rps6kb1
Mus musculus	Insrr;Prkaa1;Rps6kb2
Mus musculus	Insr;Prkaa2;Rps6kb1
Mus musculus	Insr;Prkaa2;Rps6kb2
Mus musculus	Igf1r;Prkaa2;Rps6kb1
Mus musculus	Igf1r;Prkaa2;Rps6kb2
Mus musculus	Insrr;Prkaa2;Rps6kb1
Mus musculus	Insrr;Prkaa2;Rps6kb2
Mus musculus	Rps6kb1;Insr;Prkaa1
Mus musculus	Rps6kb1;Insr;Prkaa2
Mus musculus	Rps6kb1;Igf1r;Prkaa1
Mus musculus	Rps6kb1;Igf1r;Prkaa2
Mus musculus	Rps6kb1;Insrr;Prkaa1
Mus musculus	Rps6kb1;Insrr;Prkaa2
Mus musculus	Rps6kb2;Insr;Prkaa1
Mus musculus	Rps6kb2;Insr;Prkaa2
Mus musculus	Rps6kb2;Igf1r;Prkaa1
Mus musculus	Rps6kb2;Igf1r;Prkaa2
Mus musculus	Rps6kb2;Insrr;Prkaa1
Mus musculus	Rps6kb2;Insrr;Prkaa2

Orthologs of aak-2 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	AMPKalpha
Mus musculus	Prkaa1
Mus musculus	Prkaa2

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 rsks-1 in SynergyAge

Show in SynergyAge
Species	Gene

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