WBGene00000898 vs WBGene00000912
Refuting evidence (2)
The genetic and reporter gene expression analysis revealed that an EISO, or α- and β-santalol-mediated protective effect does not appear to rely on DAF-2/DAF-16, but selectively regulates SKN-1 and its downstream targets involved in antioxidant defense and geroprotective processes.
Ochrobactrum recruitment is blunted in the absence of DAF-2/IGFR and modulated by the competitive action of insulin signaling transcription factors DAF-16/FOXO and PQM-1/SALL2.
Supporting evidence (152)
Our results depicted that HumINS decreases α-synuclein aggregation via DAF-2/DAF-16 pathway by acting as an antagonist for DAF-2 receptor.
Specifically, DAF-2 signaling, an ortholog of human IGF, controls DAF-16/FOXO transcription factor, a master regulator of metabolism and longevity.
In addition, mutants of a major downstream factor of DAF-2, the forkhead transcription factor O (FOXO) homolog DAF-16, show defects in taste avoidance learning.
Here, we build two C. elegans PD model using 6-OHDA and transgenic animal to observe the changes of PD worms treated with or without gastrodin to confirm the function of gastrodin, then utilize mutant worms to investigate DAF-2/DAF-16 signaling pathway, and finally verify the mechanism of gastrodin in PD.
In C. elegans the innate immune response has been shown to be connected to the DAF-2 insulin/insulin-like growth factor 1 (IGF-1) signal pathway, a critical transduction pathway that mediates stress response in the worms via the DAF-16 FOXO/forkhead transcription factor.
DAF-2 acts independently of the FOXO transcription factor, DAF-16, to mediate the protective effects of fasting.
DAF-2/DAF-16 is required for neuroprotective effect of dopamine neuron in PD.
The major known longevity pathways were analyzed through mutant worms and RT-qPCR assay (DAF-2, DAF-16, SKN-1, SIR-2.1, HSF-1).
DAF-2 and its downstream signaling molecules, including the DAF-16 FOXO transcription factor, act in the ascr#3-sensing ADL neurons to regulate synaptic transmission to downstream target neurons, including the AVA command interneurons.
The genetic and reporter gene expression analysis revealed that an EISO, or α- and β-santalol-mediated protective effect does not appear to rely on DAF-2/DAF-16, but selectively regulates SKN-1 and its downstream targets involved in antioxidant defense and geroprotective processes.
Our data demonstrate a novel role for the DJ-1 homologue, djr-1.2, in mitigating Mn-dependent lifespan reduction and DA signaling alterations, involving DAF-2/DAF-16 signaling.
Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2-signaling pathway and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging.
In the insulin signaling pathway, DAF-2/insulin receptor regulated MWCNTs toxicity by suppressing function of DAF-16/FOXO transcription factor.
In the nematode Caenorhabditis elegans, bile acid-like steroid hormones known as dafachronic acids (DAs) influence longevity by binding to and regulating the activity of the conserved nuclear receptor DAF-12, and the insulin receptor (InsR) ortholog DAF-2 controls life span by inhibiting the FoxO transcription factor DAF-16.
Disruption of the DAF-2 signaling cascade promotes DAF-16 activation, and confers resistance to killing by pathogenic bacteria, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis.
DAF-2's function in regeneration is mediated by intrinsic neuronal activity of the forkhead transcription factor DAF-16/FOXO.
DAF-2/IGFR controls the activity of a conserved phosphoinositide 3-kinase (PI3K)/Akt kinase cascade, culminating in the regulation of a FoxO transcription factor, DAF-16, that governs most of the functions of this pathway.
In addition, Xoo triggers (i) the p38 MAPK signal pathway to upregulate its downstream C17H12.8 expression, and (ii) the DAF-2/DAF-16 pathway to upregulate its downstream gene expressions of mtl-1 and sod-3 under the condition of daf-2 mutation.
Using C. elegans as a model we demonstrate the DAF-2/DAF-16 insulin/IGF-1 signalling (IIS) component of the innate immune pathway modulates sensitivity to violacein-mediated killing.
Mutations in the DAF-2/DAF-16 insulin-like signaling pathway promote such survival.
Here, we report that ARR-1 functions to positively regulate DAF-2 signaling in C. elegans. arr-1 mutant animals exhibit increased longevity and enhanced nuclear localization of DAF-16, an indication of decreased DAF-2 signaling, whereas animals overexpressing ARR-1 have decreased longevity.
The EGF pathway appears to work in a manner largely independent of the insulin/IGF-like pathway, in that effects are additive with reduction of DAF-2/InsR activity and are not affected by DAF-16/FOXO transcription factor deficiency.
While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions.
We also report a genetic interaction between Klotho and the DAF-2 (Ins/IGF1R)/DAF-16 (FOXO) pathway.
In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16.
Progression of neuronal aging is regulated by DAF-2 and DAF-16 signaling, which also modulate adult life span.
The effects of EGF signaling on lifespan are largely independent of Insulin/IGF-like Signaling (IIS), as the effects of EGF signaling mutants on lifespan and heathspan are not affected by mutations in the DAF-2 insulin receptor or the DAF-16 FOXO transcription factor.
According to our epistasis analysis, the effect of DAF-2 on learning acts via phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) production, but not the DAF-16 FOXO transcription factor.
This pathway is comprised of many genes including the insulin/IGF-1 receptor (DAF-2) that signals through a conserved PI 3-kinase/AKT pathway and ultimately down-regulates DAF-16, a forkhead transcription factor (FOXO).
This implies that the signaling pathway from DAF-2 affecting this learning paradigm branches between PIP(3) production and DAF-16.
In C. elegans, the sole insulin/IGF-1 receptor, DAF-2, negatively regulates the FOXO transcription factor, DAF-16.
The emerging picture is that insulin-like molecules, through the activity of the DAF-2/insulin/ IGF-I-like receptor, and the DAF-16/FKHRL1/FOXO transcription factor, control the ability of the organism to deal with oxidative stress, and interfere with metabolic programs that help to determine lifespan.
In C. elegans the DAF-2/DAF-16 pathway, an IGF-1/insulin-like signaling pathway, is involved with dauer formation, longevity, and stress resistance.
Mutations in DAF-2/insulin receptor and AGE-1/phosphatidylinositol 3 (PI-3)-kinase partially suppressed the defect of ins-1 mutants, and a mutation in DAF-16, a forkhead-type transcriptional factor, caused a weak defect.
Blocking the inhibitory signal of the DAF-2 insulin like receptor, which acts upstream DAF-16, also results in an enhanced HSF-1 dependent immunity.
The PMK-1 p38 mitogen-activated protein kinase pathway and the DAF-2-DAF-16 insulin signaling pathway control Caenorhabditis elegans intestinal innate immunity. pmk-1 loss-of-function mutants have enhanced sensitivity to pathogens, while daf-2 loss-of-function mutants have enhanced resistance to pathogens that requires upregulation of the DAF-16 transcription factor.
Lack of immune inhibition by DAF-2, which negatively regulates the FOXO transcription factor DAF-16, rescues the hypersusceptibility to pathogens phenotype of elt-2(RNAi) animals.
Here we describe how serotonin (5HT) governs stress behavior by regulating DAF-2 insulin/IGF-1 receptor signaling to the DAF-16/FOXO transcription factor at the nexus of development, metabolism, immunity, and stress responses in C. elegans.
Reduced DAF-2 signaling leads to enhanced transcription of this globin and DAF-16 is required for this effect.
Our data indicate that the DAF-2 regulated transcription factor DAF-16/FOXO positively modulates hif-1 transcription under anoxia but opposes expression of the HIF-1 responsive globin genes itself.
We have identified a 14-3-3 C. elegans homolog which promotes life span by both DAF-2-dependent and -independent mechanisms and by an unexpected DAF-16-independent mechanism.
Caenorhabditis elegans life span, stress resistance and metabolism are regulated by the Insulin/IGF-1/DAF-2/DAF-16 pathway.
We show here that C17ISO is an essential constituent in a novel mechanism that acts in parallel with the food-sensing DAF-2 (insulin receptor)/DAF-16 (FOXO) signaling pathway to promote post-embryonic development, and that the two pathways converge on a common target repressing cell cycle.
The DAF-2/DAF-16 pathway is important for the regulation of many aspects of organismal physiology, including metabolism, stress response, longevity, and immune function.
We present evidence that Pseudomonas aeruginosa is able to suppress the expression of a subset of immune defense genes in the animal host Caenorhabditis elegans by activating the DAF-2/DAF-16 insulin-like signaling pathway.
Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei.
In the nematode Caenorhabditis elegans, dauer formation, stress resistance, and longevity are determined in part by DAF-2 (insulin receptor-like protein), AGE-1 (phosphatidylinositol-3-OH kinase catalytic subunit), and DAF-16 (forkhead transcription factor).
Signaling from the DAF-2/insulin receptor to the DAF-16/FOXO transcription factor controls longevity, metabolism, and development in disparate phyla.
Our data also suggest the existence of a second pathway from DAF-2 to DAF-16 that does not depend on AKT-1, AKT-2, and SGK-1.
Genetic inhibition of DAF-2 or its downstream target, the AGE-1 phosphatidylinositol 3-kinase, confers striking resistance to a normally lethal hypertonic shock in a DAF-16-dependent manner.
In mammals and nematodes, inhibition of signaling from the DAF-2/IGF-1 insulin receptor activates the DAF-16/FOXO transcription factor, resulting in increased life span and resistance to some types of stress.
This process is regulated by TGF-beta and insulin-signalling pathways and is connected with the control of life span through the insulin pathway components DAF-2 and DAF-16.
We show that both interventions act either antagonistically or in concert, depending on the parameter examined and that axenic culture medium, unlike DAF-2 signaling, does not need DAF-16 for generating these effects.
DAF-2 signaling cascade includes the PI3 kinase homolog AGE-1 and the FOXO transcription factor DAF-16.
An insulin-like signaling pathway, from the DAF-2 receptor, the AGE-1 phosphoinositide 3-kinase, and the AKT-1/AKT-2 serine/threonine kinases to the DAF-16 Fork head transcription factor, regulates the metabolism, development, and life span of Caenorhabditis elegans.
We found that the loss of insulin receptor DAF-2 promoted 'ventral targeting' in a DAF-16-dependent manner.
Ochrobactrum recruitment is blunted in the absence of DAF-2/IGFR and modulated by the competitive action of insulin signaling transcription factors DAF-16/FOXO and PQM-1/SALL2.
By contrast, DAF-2 depletion in the muscle of middle-age animals improved their motility independently of DAF-16/FOXO but required UNC-120/SRF.
In 1-day-old adults, DAF-2/IIRc depletion in neurons reduced motility in a DAF-16/FOXO dependent manner, while muscle depletion had no effect.
Notably, intestine-specific loss of DAF-2 activates DAF-16 in and outside the intestine, causes almost no adverse effects on development and reproduction, and extends lifespan by 94% in a way that partly requires non-intestinal DAF-16.
Using tissue-specific targeted protein degradation, we determined that intracellular DAF-2-to-DAF-16 signaling in the intestine plays a major role in lifespan regulation, while that in the hypodermis, neurons, and germline plays a minor role.
Through the genetic screening in C. elegans, we found that Luteolin promoted innate immunity via DAF-2/DAF-16 insulin-like signaling pathway rather than p38 MAPK pathway and SKN-1.
The DAF-2/DAF-16 insulin-like signaling pathway was an evolutionarily conserved pathway, which regulated many aspects of organismal physiology, such as pathogen resistance, metabolism, stress response, longevity.
Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12.
In the insulin signaling pathway, DAF-2 restricted the function of DAF-16 to activate downstream targets (SOD-3 and HSP-6), which in turn controlled the toxicity of 6-PPDQ on lifespan and healthspan.
Furthermore, via genetic screen, we showed that Cynaroside acted on IGF-1-R /DAF-2, which was followed by the activation of transcription factor DAF-16/FOXO to extend the healthy lifespan.
By utilizing CB1370, DR26 and CF1038 transgenic strains of C. elegans to identify whether the antibacterial activity of total alkaloids was dependent on DAF-2/DAF-16 pathway.
DAF-2 mutations conferred resistance, while DAF-16 mutations increased susceptibility.
Esculetin's fat-lowering effect was dependent on DAF-2 (insulin/insulin-like growth factor-1 [IGF-1] receptor homolog), DAF-16 (Forkhead box protein O homolog), and AAK-2 (5'-adenosine monophosphate-activated protein kinase [AMPK] catalytic subunit α2) in the mutant experiments.
A canonical insulin/insulin growth factor (IGF) signaling (IIS) pathway, comprising DAF-2/insulin receptor, the signal transducer AKT, and the transcription factor DAF-16/FoxO, is a major input into the global decision between reproductive development and dauer entry.1,4 Previous studies have suggested that IIS has a diffuse cellular focus for regulating dauer entry,5,6,7,8 but here we have identified a specific cellular focus by showing that low IIS activity in the somatic gonad is sufficient to promote entry into dauer diapause.
By examining worms deficient in the ILP member INS-7 under glucose-present and glucose-absent conditions, we uncovered a previously unrecognized DAF-2-AKT/SGK signaling output that drives reversible growth arrest specifically under glucose-present conditions, while allowing normal development in the absence of glucose, in a manner independent of DAF-16.
DAF-2 also promotes PAR-1 expression by inhibiting DAF-16.
DAF-2 insulin-like receptor signaling stimulates DAF-16 S249 phosphorylation, suggesting DAF-2 activates PAR-1.
In Caenorhabditis elegans, 40 insulin-like peptides (ILPs) interact with DAF-2, the sole insulin/IGF receptor, to regulate lifespan and stress responses via the FOXO transcription factor DAF-16.
In the nematode Caenorhabditis elegans, DAF-2 regulates dauer diapause, animal growth, and lifespan extension in a DAF-16/FOXO-dependent manner.
Treated worms exhibited a 57% reduction in reactive oxygen species (ROS) levels and upregulation of antioxidant genes (gst-4 and sod-3), suggesting that CSS mitigates oxidative stress through the DAF-2/DAF-16 pathway.
When DAF-2 activity is reduced or inhibited in C. elegans, DAF-16 and SKN-1 are activated and translocate to the nucleus to promote stress resistance and prolong lifespan.
Further studies demonstrated that the enhanced lifespan of the worm was depended on the function of DAF-2/DAF-16 and was associated with the colonization of strain in the worms' intestines when strain EnB-alf1 or strain EnB-alf3 was presented to the worms as food sources.
Genetic analysis is consistent with SMG-1 acting at least in part in parallel to the canonical DAF-2 receptor pathway, but converging on the transcription factor DAF-16/FOXO.
Therefore, our results demonstrated the beneficial effect of paeoniflorin administration in inhibiting glucose-induced lifespan reduction by suppressing signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16-SOD-3 in insulin signaling pathway.
The antibacterial activity of total alkaloids was primarily dependent on the DAF-2/DAF-16 pathway, and the presence of functional DAF-2 was deemed essential in total alkaloids mediated immune response against MRSA.
A further analysis demonstrated that L-theanine extends the lifespan of Caenorhabditis elegans by modulating the DAF-2/DAF-16 insulin-like signaling pathway and reducing the accumulation of advanced glycation end products (AGEs).
Enhanced DAF-2/DAF-16-mediated insulin signaling pathway was observed, suggesting that the inherited immune response could be mediated through insulin/IGF-1 signaling (IIS).
Mechanistically, baicalein suppressed the DAF-2-mediated insulin/IGF-1 signaling pathway and promoted the nuclear translocation of DAF-16, a pivotal longevity transcription factor.
In conclusion, DXN improved Aβ-induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic worms.
DAF-2 acts from outside of the intestine but DAF-16 acts both from outside of the intestine and from within the intestine where it binds directly to the same non-canonical target site that interacts with FKH-9.
Reductions in DAF-2 signaling, either through a hypomorphic allele or neuronally targeted RNAi, decreases the abundance of aggregated SOD1 and results in improved locomotion in a DAF-16 dependant manner.
This effect was independent of the canonical DAF-2/DAF-16 longevity pathway and mitochondrial dynamics.
Our study demonstrated that gastrodin rescued dopaminergic neurons and reduced accumulation of α-synuclein protein, and the activity of gastrodin against Parkinson's disease depended on the insulin-like DAF-2/DAF-16 signaling pathway.
Further analysis shows that resistance to violacein can occur due to a loss of DAF-2 function and/or an increased function of DAF-16 controlled genes involved in antimicrobial production (spp-1) and detoxification (sod-3).
Genetic analyses imply that DAF-2 is a downstream target of 5HT signaling and that distinct serotonergic neurons act through distinct 5HT receptors to influence distinct DAF-16-mediated stress responses.
Using in vivo model, we found that the EAPS can expand the lifespan and increase the disease resistance of Caenorhabditis elegans against Klebsiella pneumoniae infection via the DAF-2/DAF-16 pathway.
Using mutant nematode strains, we evaluated the implication of the insulin-like DAF-2/DAF-16 and the p38 MAPK pathways in the phenomenon of increased longevity and oxidative-stress resistance mechanisms.
By contrast, the insulin receptor DAF-2 and its effector, the FOXO transcription factor DAF-16, function solely in the intestine to regulate the decision to enter diapause.
Our results demonstrated that freeze-dried raw goat milk cheese, and its extracts, induced the activation of the DAF-2/DAF-16 pathway, increasing longevity.
We further show that the prolongevity effect of B. subtilis biofilms depends on the DAF-2/DAF-16/HSF-1 signalling axis and the downregulation of the insulin-like signalling (ILS) pathway.
DAF-2 further acted upstream of DAF-16 and suppressed the function of DAF-16 to regulate outdoor PM2.5 toxicity.
In the nematode Caenorhabditis elegans, inactivating mutations in the insulin/IGF-1 receptor, DAF-2, result in a 2-fold increase in lifespan mediated by DAF-16, a FOXO-family transcription factor.
The latter genes are negatively regulated by DAF-2 signaling and positively regulated by DAF-16.
In contrast, the DAF-2-DAF-16 axis contributed to the age-related decline in Netrin expression in muscle.
Additionally, quercitrin's effects on aging were examined by measuring SIR2.1 and DAF-2 expression in the insulin signaling pathway (IIS) and analyzing its concentration-dependent regulation of DAF-16 using GFP transgenic worms.
Regulation by DAF-2 is most likely DAF-16 independent for dao-3 and hsp-90.
In this study, we discovered that Chr extends both lifespan and healthspan in Caenorhabditis elegans by activating the DAF-2/DAF-16 insulin signaling pathway.
DAF-2 abundance is not dependent on downstream PI-3 kinase to DAF-16 transcription factor signaling.
The DAF-2 pathway acts synergistically with the pathway activated by a nematode TGF-beta-type signal, DAF-7, suggesting that DAF-16 cooperates with nematode SMAD proteins in regulating the transcription of key metabolic and developmental control genes.
Specifically, DAF-2 signaling, an ortholog of human IGF, controls DAF-16/FOXO transcription factor, a master regulator of metabolism and longevity.
Our results demonstrated that freeze-dried raw goat milk cheese, and its extracts, induced the activation of the DAF-2/DAF-16 pathway, increasing longevity.
DAF-2/DAF-16 is required for neuroprotective effect of dopamine neuron in PD.
In conclusion, DXN improved Aβ-induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic worms.
DAF-2 and its downstream signaling molecules, including the DAF-16 FOXO transcription factor, act in the ascr#3-sensing ADL neurons to regulate synaptic transmission to downstream target neurons, including the AVA command interneurons.
DAF-2 acts from outside of the intestine but DAF-16 acts both from outside of the intestine and from within the intestine where it binds directly to the same non-canonical target site that interacts with FKH-9.
In the insulin signaling pathway, DAF-2/insulin receptor regulated MWCNTs toxicity by suppressing function of DAF-16/FOXO transcription factor.
DAF-2 further acted upstream of DAF-16 and suppressed the function of DAF-16 to regulate outdoor PM2.5 toxicity.
Disruption of the DAF-2 signaling cascade promotes DAF-16 activation, and confers resistance to killing by pathogenic bacteria, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis.
DAF-2/IGFR controls the activity of a conserved phosphoinositide 3-kinase (PI3K)/Akt kinase cascade, culminating in the regulation of a FoxO transcription factor, DAF-16, that governs most of the functions of this pathway.
By contrast, the insulin receptor DAF-2 and its effector, the FOXO transcription factor DAF-16, function solely in the intestine to regulate the decision to enter diapause.
Using C. elegans as a model we demonstrate the DAF-2/DAF-16 insulin/IGF-1 signalling (IIS) component of the innate immune pathway modulates sensitivity to violacein-mediated killing.
Mutations in the DAF-2/DAF-16 insulin-like signaling pathway promote such survival.
Progression of neuronal aging is regulated by DAF-2 and DAF-16 signaling, which also modulate adult life span.
This pathway is comprised of many genes including the insulin/IGF-1 receptor (DAF-2) that signals through a conserved PI 3-kinase/AKT pathway and ultimately down-regulates DAF-16, a forkhead transcription factor (FOXO).
In C. elegans, the sole insulin/IGF-1 receptor, DAF-2, negatively regulates the FOXO transcription factor, DAF-16.
Blocking the inhibitory signal of the DAF-2 insulin like receptor, which acts upstream DAF-16, also results in an enhanced HSF-1 dependent immunity.
Here we describe how serotonin (5HT) governs stress behavior by regulating DAF-2 insulin/IGF-1 receptor signaling to the DAF-16/FOXO transcription factor at the nexus of development, metabolism, immunity, and stress responses in C. elegans.
Reduced DAF-2 signaling leads to enhanced transcription of this globin and DAF-16 is required for this effect.
Our data indicate that the DAF-2 regulated transcription factor DAF-16/FOXO positively modulates hif-1 transcription under anoxia but opposes expression of the HIF-1 responsive globin genes itself.
We present evidence that Pseudomonas aeruginosa is able to suppress the expression of a subset of immune defense genes in the animal host Caenorhabditis elegans by activating the DAF-2/DAF-16 insulin-like signaling pathway.
We have identified a 14-3-3 C. elegans homolog which promotes life span by both DAF-2-dependent and -independent mechanisms and by an unexpected DAF-16-independent mechanism.
Caenorhabditis elegans life span, stress resistance and metabolism are regulated by the Insulin/IGF-1/DAF-2/DAF-16 pathway.
In conclusion, 14-3-3 can be considered as an acute stress-responsive regulator as well as a sustained modulator of the Insulin/IGF-1/DAF-2/DAF-16 regulatory pathway in promoting life expectancy of growing old worms.
We show here that C17ISO is an essential constituent in a novel mechanism that acts in parallel with the food-sensing DAF-2 (insulin receptor)/DAF-16 (FOXO) signaling pathway to promote post-embryonic development, and that the two pathways converge on a common target repressing cell cycle.
Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei.
The latter genes are negatively regulated by DAF-2 signaling and positively regulated by DAF-16.
Signaling from the DAF-2/insulin receptor to the DAF-16/FOXO transcription factor controls longevity, metabolism, and development in disparate phyla.
This process is regulated by TGF-beta and insulin-signalling pathways and is connected with the control of life span through the insulin pathway components DAF-2 and DAF-16.
In mammals and nematodes, inhibition of signaling from the DAF-2/IGF-1 insulin receptor activates the DAF-16/FOXO transcription factor, resulting in increased life span and resistance to some types of stress.
We found that the loss of insulin receptor DAF-2 promoted 'ventral targeting' in a DAF-16-dependent manner.
Notably, intestine-specific loss of DAF-2 activates DAF-16 in and outside the intestine, causes almost no adverse effects on development and reproduction, and extends lifespan by 94% in a way that partly requires non-intestinal DAF-16.
The DAF-2/DAF-16 insulin-like signaling pathway was an evolutionarily conserved pathway, which regulated many aspects of organismal physiology, such as pathogen resistance, metabolism, stress response, longevity.
Through the genetic screening in C. elegans, we found that Luteolin promoted innate immunity via DAF-2/DAF-16 insulin-like signaling pathway rather than p38 MAPK pathway and SKN-1.
Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12.
In the insulin signaling pathway, DAF-2 restricted the function of DAF-16 to activate downstream targets (SOD-3 and HSP-6), which in turn controlled the toxicity of 6-PPDQ on lifespan and healthspan.
A further analysis demonstrated that L-theanine extends the lifespan of Caenorhabditis elegans by modulating the DAF-2/DAF-16 insulin-like signaling pathway and reducing the accumulation of advanced glycation end products (AGEs).
Esculetin's fat-lowering effect was dependent on DAF-2 (insulin/insulin-like growth factor-1 [IGF-1] receptor homolog), DAF-16 (Forkhead box protein O homolog), and AAK-2 (5'-adenosine monophosphate-activated protein kinase [AMPK] catalytic subunit α2) in the mutant experiments.
In this study, we discovered that Chr extends both lifespan and healthspan in Caenorhabditis elegans by activating the DAF-2/DAF-16 insulin signaling pathway.
A canonical insulin/insulin growth factor (IGF) signaling (IIS) pathway, comprising DAF-2/insulin receptor, the signal transducer AKT, and the transcription factor DAF-16/FoxO, is a major input into the global decision between reproductive development and dauer entry.1,4 Previous studies have suggested that IIS has a diffuse cellular focus for regulating dauer entry,5,6,7,8 but here we have identified a specific cellular focus by showing that low IIS activity in the somatic gonad is sufficient to promote entry into dauer diapause.
When DAF-2 activity is reduced or inhibited in C. elegans, DAF-16 and SKN-1 are activated and translocate to the nucleus to promote stress resistance and prolong lifespan.
In the nematode Caenorhabditis elegans, DAF-2 regulates dauer diapause, animal growth, and lifespan extension in a DAF-16/FOXO-dependent manner.
In Caenorhabditis elegans, 40 insulin-like peptides (ILPs) interact with DAF-2, the sole insulin/IGF receptor, to regulate lifespan and stress responses via the FOXO transcription factor DAF-16.
Mechanistically, baicalein suppressed the DAF-2-mediated insulin/IGF-1 signaling pathway and promoted the nuclear translocation of DAF-16, a pivotal longevity transcription factor.
DAF-2 also promotes PAR-1 expression by inhibiting DAF-16.
Furthermore, via genetic screen, we showed that Cynaroside acted on IGF-1-R /DAF-2, which was followed by the activation of transcription factor DAF-16/FOXO to extend the healthy lifespan.
Additionally, quercitrin's effects on aging were examined by measuring SIR2.1 and DAF-2 expression in the insulin signaling pathway (IIS) and analyzing its concentration-dependent regulation of DAF-16 using GFP transgenic worms.
Uncertain evidence (2)
DAF-2 insulin-like receptor signaling stimulates DAF-16 S249 phosphorylation, suggesting DAF-2 activates PAR-1.
Genetic analyses imply that DAF-2 is a downstream target of 5HT signaling and that distinct serotonergic neurons act through distinct 5HT receptors to influence distinct DAF-16-mediated stress responses.