aak-2;daf-2

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Genetic mutants with aak-2, daf-2 alterations

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

Temperature °C
25
Lifespan (days)
24.5
Lifespan change (compared to wild type)
66.67%
Phenotype
Forty-one gene inactivations functioned specifically within the daf-2 pathway to shorten life span, not decreasing the life span of daf-2;daf-16 animals
Lifespan comparisons
Double mutant aak-2(RNAi);daf-2(e1370) has a lifespan of 24.5 days, while single mutant daf-2(e1370) has a lifespan of 36.7 days, single mutant aak-2(RNAi) has a lifespan of 6.8 days and wild type has a lifespan of 14.7 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Samuelson AV et al., 2007, Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. Genes Dev. 21(22):2976-94 18006689 Click here to select all mutants from this PubMed ID in the graph
Abstract
Genetic and RNA interference (RNAi) screens for life span regulatory genes have revealed that the daf-2 insulin-like signaling pathway plays a major role in Caenorhabditis elegans longevity. This pathway converges on the DAF-16 transcription factor and may regulate life span by controlling the expression of a large number of genes, including free-radical detoxifying genes, stress resistance genes, and pathogen resistance genes. We conducted a genome-wide RNAi screen to identify genes necessary for the extended life span of daf-2 mutants and identified approximately 200 gene inactivations that shorten daf-2 life span. Some of these gene inactivations dramatically shorten daf-2 mutant life span but less dramatically shorten daf-2; daf-16 mutant or wild-type life span. Molecular and behavioral markers for normal aging and for extended life span in low insulin/IGF1 (insulin-like growth factor 1) signaling were assayed to distinguish accelerated aging from general sickness and to examine age-related phenotypes. Detailed demographic analysis, molecular markers of aging, and insulin signaling mutant test strains were used to filter progeric gene inactivations for specific acceleration of aging. Highly represented in the genes that mediate life span extension in the daf-2 mutant are components of endocytotic trafficking of membrane proteins to lysosomes. These gene inactivations disrupt the increased expression of the DAF-16 downstream gene superoxide dismutase sod-3 in a daf-2 mutant, suggesting trafficking between the insulin-like receptor and DAF-16. The activities of these genes may normally decline during aging.

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

Temperature °C
25
Diet
NGM
Lifespan (days)
23.3
Lifespan change (compared to wild type)
14.78%
Lifespan comparisons
Double mutant aak-2(ok524);daf-2(RNAi) has a lifespan of 23.3 days, while single mutant daf-2(RNAi) has a lifespan of 30.6 days, single mutant aak-2(ok524) has a lifespan of 17.1 days and wild type has a lifespan of 20.3 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Rogers AN et al., 2011, Life span extension via eIF4G inhibition is mediated by posttranscriptional remodeling of stress response gene expression in C. elegans. Cell Metab. 14(1):55-66 21723504 Click here to select all mutants from this PubMed ID in the graph
Abstract
Reducing protein synthesis slows growth and development but can increase adult life span. We demonstrate that knockdown of eukaryotic translation initiation factor 4G (eIF4G), which is downregulated during starvation and dauer state, results in differential translation of genes important for growth and longevity in C. elegans. Genome-wide mRNA translation state analysis showed that inhibition of IFG-1, the C. elegans ortholog of eIF4G, results in a relative increase in ribosomal loading and translation of stress response genes. Some of these genes are required for life span extension when IFG-1 is inhibited. Furthermore, enhanced ribosomal loading of certain mRNAs upon IFG-1 inhibition was correlated with increased mRNA length. This association was supported by changes in the proteome assayed via quantitative mass spectrometry. Our results suggest that IFG-1 mediates the antagonistic effects on growth and somatic maintenance by regulating mRNA translation of particular mRNAs based, in part, on transcript length.

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

Temperature °C
20
Lifespan (days)
25.1
Lifespan change (compared to wild type)
25.50%
Phenotype
Double mutants of aak-2(ok524) and stronger daf-2 reduction-of-function alleles have shortened lifespans compared with daf-2 single mutants, although they live longer than aak-2(ok524) single mutants. Therefore, aak-2-independent as well as aak-2-dependent mechanisms are required to produce the exceptionally long lifespans of daf-2 mutants.
Lifespan comparisons
Double mutant aak-2(ok524);daf-2(e1368) has a lifespan of 25.1 days, while single mutant aak-2(ok524) has a lifespan of 17.6 days, single mutant daf-2(e1368) has a lifespan of 36.7 days and wild type has a lifespan of 20.0 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Apfeld J et al., 2004, The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18(24):3004-9 15574588 Click here to select all mutants from this PubMed ID in the graph
Abstract
Although limiting energy availability extends lifespan in many organisms, it is not understood how lifespan is coupled to energy levels. We find that the AMP:ATP ratio, a measure of energy levels, increases with age in Caenorhabditis elegans and can be used to predict life expectancy. The C. elegans AMP-activated protein kinase alpha subunit AAK-2 is activated by AMP and functions to extend lifespan. In addition, either an environmental stressor that increases the AMP:ATP ratio or mutations that lower insulin-like signaling extend lifespan in an aak-2-dependent manner. Thus, AAK-2 is a sensor that couples lifespan to information about energy levels and insulin-like signals.

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

Temperature °C
25
Lifespan (days)
22.5
Lifespan change (compared to wild type)
75.78%
Lifespan comparisons
Double mutant aak-2(ok524);daf-2(e1370) has a lifespan of 22.5 days, while single mutant daf-2(e1370) has a lifespan of 31.8 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
Opposite lifespan effects of single mutants
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)
18.6
Lifespan change (compared to wild type)
43.08%
Lifespan comparisons
Double mutant aak-2(ok524);daf-2(e1370) has a lifespan of 18.6 days, while single mutant daf-2(e1370) has a lifespan of 33.7 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
Opposite lifespan effects of single mutants
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
20
Lifespan (days)
29.4
Lifespan change (compared to wild type)
47.00%
Phenotype
Double mutants of aak-2(ok524) and stronger daf-2 reduction-of-function alleles have shortened lifespans compared with daf-2 single mutants, although they live longer than aak-2(ok524) single mutants. Therefore, aak-2-independent as well as aak-2-dependent mechanisms are required to produce the exceptionally long lifespans of daf-2 mutants.
Lifespan comparisons
Double mutant aak-2(ok524);daf-2(e1370) has a lifespan of 29.4 days, while single mutant aak-2(ok524) has a lifespan of 17.6 days, single mutant daf-2(e1370) has a lifespan of 43.2 days and wild type has a lifespan of 20.0 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Apfeld J et al., 2004, The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18(24):3004-9 15574588 Click here to select all mutants from this PubMed ID in the graph
Abstract
Although limiting energy availability extends lifespan in many organisms, it is not understood how lifespan is coupled to energy levels. We find that the AMP:ATP ratio, a measure of energy levels, increases with age in Caenorhabditis elegans and can be used to predict life expectancy. The C. elegans AMP-activated protein kinase alpha subunit AAK-2 is activated by AMP and functions to extend lifespan. In addition, either an environmental stressor that increases the AMP:ATP ratio or mutations that lower insulin-like signaling extend lifespan in an aak-2-dependent manner. Thus, AAK-2 is a sensor that couples lifespan to information about energy levels and insulin-like signals.

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

Temperature °C
20
Lifespan (days)
17.2
Lifespan change (compared to wild type)
-14.00%
Phenotype
daf-2(m577); aak-2(ok524) double mutants have lifespans that are indistinguishable from those of aak-2(ok524) single mutants
Lifespan comparisons
Double mutant aak-2(ok524);daf-2(m577) has a lifespan of 17.2 days, while single mutant aak-2(ok524) has a lifespan of 17.6 days, single mutant daf-2(m577) has a lifespan of 24.2 days and wild type has a lifespan of 20.0 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Apfeld J et al., 2004, The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18(24):3004-9 15574588 Click here to select all mutants from this PubMed ID in the graph
Abstract
Although limiting energy availability extends lifespan in many organisms, it is not understood how lifespan is coupled to energy levels. We find that the AMP:ATP ratio, a measure of energy levels, increases with age in Caenorhabditis elegans and can be used to predict life expectancy. The C. elegans AMP-activated protein kinase alpha subunit AAK-2 is activated by AMP and functions to extend lifespan. In addition, either an environmental stressor that increases the AMP:ATP ratio or mutations that lower insulin-like signaling extend lifespan in an aak-2-dependent manner. Thus, AAK-2 is a sensor that couples lifespan to information about energy levels and insulin-like signals.

Search genes: aak-2 daf-2

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.

Orthologs of aak-2;daf-2 in SynergyAge

Show in SynergyAge
Species	Gene

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

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