Nuclear Localization Of DAF-16 Research Articles

Rosavin extends lifespan via the insulin/IGF-1 signaling pathway in Caenorhabditis elegans.

Rosavin, a phenylpropanoid glycoside, is the specific index component and one of the main active components of Rhodiola rosea. Currently, there are few studies describing the antiaging effect of rosavin, and most of them are mainly based on in vitro antioxidant research. Our study aimed to investigate the antiaging activities and mechanisms of rosavin in Caenorhabditis elegans. Using Caenorhabditis elegans as the model, the lifespan of Caenorhabditis elegans under various stressors (heat and juglone) and normal conditions was studied, and the antioxidant activities of rosavin were discussed. To discover the underlying mechanisms, we analyzed daf-16 nuclear localization, the expression of the sod-3p::GFP fusion protein, mRNA levels, and loss-of-function mutants of IIS-associated genes. The results showed that rosavin significantly improved the lifespan of Caenorhabditis elegans under stress and normal conditions. Rosavin can increase the expression and activity of antioxidant enzymes and suppress the generation of malondialdehyde and ROS in nematodes. Additionally, it promotes the nuclear localization of daf-16 and improves the expression of the sod-3 gene in Caenorhabditis elegans. The data revealed that rosavin activated the insulin/IGF-1 signaling pathway by downregulating the upstream components daf-2 and age-1. In summary, these results verify that rosavin could increase the lifespan of Caenorhabditis elegans through the insulin/IGF-1 signaling pathway.

Neurotoxicity of bisphenol A exposure on Caenorhabditis elegans induced by disturbance of neurotransmitter and oxidative damage

Bisphenol A (BPA) is putatively regarded as an environmental neurotoxicant found in everyday plastic products and materials, however, the possible neurobehavioral adverse consequences and molecular mechanisms in animals have not been clearly characterized. The nematode Caenorhabditis elegans has become a promising animal model for neurotoxicological researches. To investigate the dose-effect relationships of BPA-induced neurotoxicity effects, the locomotion behavior and developmental parameters of the nematode were determined after BPA exposure. The present data demonstrated that BPA caused neurobehavioral toxicities, including head thrashes and body bends inhibition. In addition, when C. elegans was exposed to BPA at a concentration higher than 2 μM, growth and survival rate were decreased. The serotonergic, dopaminergic and GABAergic neurons were damaged by BPA. Furthermore, lower levels of mRNA expression related to dopamine, serotonin and GABA were detected in the worms exposed to 50 μM BPA. Increased SOD-3 expression might be adaptive response to BPA exposure. Moreover, oxidative damage triggered by BPA was manifested by changes in GST-4 expression, accompany with abnormity of ATP synthesis, but not nuclear localization of DAF-16/FOXO. Finally, we showed that epigallocatechin-3-gallate partially rescued BPA-induced reactive oxygen species (ROS) production and neurobehavioral toxicity. Altogether, the neurobehavioral and developmental toxicity of BPA may be induced by neurotransmission abnormity and oxidative damage. The present data imply that oxidative stress is linked to neuronal damage and neurobehavioral harm resulting from developmental BPA exposure.

Anti-Oxidant and Anti-Aging Effects of Phlorizin Are Mediated by DAF-16-Induced Stress Response and Autophagy in Caenorhabditis elegans.

Phlorizin (phloridzin) is a polyphenolic phytochemical primarily found in unripe Malus (apple). It is a glucoside of phloretin and acts as an inhibitor of renal glucose transport, thus lowering blood glucose. The objective of this study was to determine effects of dietary supplementation with phlorizin on stress response, aging, and age-related diseases using Caenorhabditis elegans as a model system. Survival after oxidative stress or ultraviolet irradiation was significantly increased by pre-treatment of phlorizin. Dietary supplementation with phlorizin also significantly extended lifespans without reducing fertility. Age-related decline of muscle function was delayed by supplementation with phlorizin. Phlorizin induced the expression of stress-responsive genes hsp-16.2 and sod-3 and nuclear localization of DAF-16, a FOXO transcription factor modulating stress response and lifespan in C. elegans. Amyloid-beta-induced toxicity was significantly reduced by phlorizin. This effect was dependent on DAF-16 and SKN-1. Increased mortality induced with a high-glucose diet was partially prevented by phlorizin via SKN-1. Inactivation of dopaminergic neurons observed in a Parkinson’s disease model was completely recovered by supplementation with phlorizin. Genetic analysis suggests that lifespan extension by phlorizin is mediated through oxidative stress response and autophagy. Taken together, these data suggest that phlorizin has strong anti-oxidant and anti-aging activities with potential to be developed as a novel anti-oxidant nutraceutical against aging and age-related diseases.

Caenorhabditis elegans DAF-16 regulates lifespan and immune responses to Cryptococcus neoformans and Cryptococcus gattii infections

BackgroundCryptococcosis is a life-threatening infection is primarily caused by two sibling species Cryptococcus neoformans and Cryptococcus gattii. Several virulence-related factors of these cryptococci have been widely investigated in Caenorhabditis elegans, representing a facile in vivo model of host–pathogen interaction. While recent studies elucidated cryptococcal virulence factors, intrinsic host factors that affect susceptibility to infections by cryptococci remain unclear and poorly investigated.ResultsHere, we showed that defects in C. elegans insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway influenced animal lifespan and mechanisms of host resistance in cryptococcal infections, which required the activation of aging regulator DAF-16/Forkhead box O transcription factor. Moreover, accumulation of lipofuscin, DAF-16 nuclear localization, and expression of superoxide dismutase (SOD-3) were elevated in C. elegans due to host defenses during cryptococcal infections.ConclusionThe present study demonstrated the relationship between longevity and immunity, which may provide a possibility for novel therapeutic intervention to improve host resistance against cryptococcal infections.

Synthesis of Novel Pinocembrin Amino Acid Derivatives and Their Antiaging Effect on Caenorhabditis elegans via the Modulating DAF-16/FOXO.

PurposePinocembrin is a dihydroflavonoid, which is widely found in several plant species. Although pinocembrin has good pharmacological activity, it has poor water solubility and low bioavailability. Therefore, we have modified the structure of pinocembrin with a combination of different amino acids to solve this problem. Moreover, the effect of the antiaging activity of them has not been explored. We aim to investigate the effect of pinocembrin and its amino acid derivatives on the aging of Caenorhabditis elegans.MethodsPinocembrin was spliced with different amino acids in order to obtain their corresponding derivatives. The preliminary research of pinocembrin and its amino acid derivatives on antiaging effect was studied by using the C. elegans model. Among all the compounds, the one shows the best antiaging effect was then studied on antiaging mechanism. The protective effect on nematodes under emergency conditions was explained by detecting the ROS content and sod-3p::GFP fusion protein expression in nematodes; the possible anti-aging mechanism of nematodes was determined by DAF-16 nuclear localization experiment and the survival curve of transgenic nematodes model under stress conditions.ResultsPb-3 showed the best effect on increasing tolerance to thermal and oxidative stress and reduce the accumulation of lipofuscin. In the assay of C. elegans, pb-3 reduced intracellular ROS accumulation. Application of pb-3 to the transgenic mutant TJ356 induced the translocation of the transcription factor DAF-16 from the cytosol to the nucleus, and modulated the expression of SOD-3 (downstream genes of daf-16), which regulates longevity in C. elegans. Moreover, pb-3 did not prolong the lifespan of daf-16, age-1, daf-2 and hsp16.2 mutants, suggesting that these genetic pathways are involved in mediating the antiaging effects of pb-3.ConclusionThe antioxidant and antiaging properties of pb-3 may involve in the DAF-16/FOXO transcription process. Pinocembrin amino acid derivatives might be a novel agent for antiaging therapy.

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity.

Transcriptome‐based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age‐related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf‐16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA‐approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf‐16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc‐38. We found unc‐38 RNAi to improve healthspan, lifespan, and stimulate DAF‐16 nuclear localization, similar to atracurium treatment. Finally, using RNA‐seq transcriptomics, we identify atracurium activation of DAF‐16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF‐16 longevity pathway.

The potential antioxidant ability of hydroxytyrosol on Caenorhabditis elegans against oxidative damage via the insulin signaling pathway

Hydroxytyrosol (HY) deriving from olive leaves is a phenolic component which has been proven to possess a strong antioxidant ability. However, the underling mechanism is still unclear. To evaluate the antioxidant ability of HY comprehensively, assays in vitro and in vivo (Caenorhabditis elegans (C. elegans) was used as a model organism) were conducted. The results showed HY could scavenge 2,2-Diphenyl-1-picryl-hydrazyl (DPPH) radicals with a strong total reducing power. Pretreated with HY for 48 h, the cell viability of Chinese hamster ovary (CHO) cells was enhanced under oxidative stress by reducing the level of reactive oxygen species (ROS) and malondialdehyde (MDA). A suitable concentration of HY showed no side effects on the development, fertility, and movement of C. elegans. With the treatment of HY, the survival was enhanced by 15.79% under thermal stress. The ROS and MDA contents were also reduced, which might be associated with the increasing abilities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the heat shock protein HSP-16.2. Nuclear localization of DAF-16 was greatly increased after treated with HY. More outcomes demonstrated HY exhibited an excellent antioxidant capacity via the insulin signaling pathway by upregulating daf-16 and sod-3 and downregulating the genes of age-1 and daf-2.

G protein coupled receptor kinases modulate Caenorhabditis elegans reactions to heat stresses

In this report, we explored if G protein coupled receptor kinases (GRKs) can help modulate the heat stress responses of Caenorhabditis (C.) elegans. Loss of function grk-2 C. elegans mutants were more tolerant to increases in heat and display an ability for heat stress-associated hormesis at a longer exposure time unlike the wild type N2 animals and the loss of function grk-1 C. elegans mutants. The loss of function grk-1 mutants recovered more from acute heat stress compared to the wild type N2 animals. Animals with low Ce-GRK2 protein expression showed increased DAF-16 nuclear localization during the early stages of heat stress exposure compared to the other RNAi-treated animals, demonstrating altered insulin/insulin-like growth factor signaling (IIS) pathway activity in response to the stress. pdk-1 and akt-1 may play key roles in conjunction with Ce-GRK2 in the heat stress response. Collectively, these findings demonstrate that GRKs influence C. elegans heat stress behaviors.

Pyropia haitanensis polysaccharide extends lifespan by inhibiting protein aggregation in Caenorhabditis elegans

Pyropia haitanensis polysaccharide (LP) have been found for having many excellent functions such as anti-aging. Using Caenorhabditis elegans models, we evaluated the anti-aging activity of LP by observing the lifespan, reproduction, pharyngeal pumping, stress response, quantitative fluorescence of polyglutamic acid, and nuclear localization of DAF-16 of worms. The results reveal that LP could extend the adult lifespan of wild-type and polyQ nematodes, indicating a connection of its anti-aging benefit with the toxicity-suppressing effect. The number of polyglutamic acid aggregates in high concentration groups decreased by 24.39% (P<0.05) to the control. The high-dose group strongly induced DAF-16 nuclear translocation over intermediate and cytosolic localizations compared with the control (P<0.001). Therefore, we believe that LP could extend the lifespan and reduce the protein aggregation in C. elegans through nuclear DAF-16::GFP expression.

Heat shock pretreatment induced cadmium resistance in the nematode Caenorhabditis elegans is depend on transcription factors DAF-16 and HSF-1

Cadmium (Cd) exposure poses a serious environmental problem due to the metal’s bioaccumulation and difficult to eliminate from body. Understanding the mechanisms of Cd detoxification and resistance can provide insights into methods to protect against the damaging effects of the heavy metal. In the present study, we found that heat shock (HS) pretreatment increased Cd resistance of the nematode Caenorhabditis elegans by reducing the bagging phenotype and protecting the integrity of the intestinal barrier. HS pretreatment increased the expression of heat shock protein-16.2 (HSP-16.2) prior to Cd exposure, and HS-induced Cd resistance was absent in worms with hsp-16.2 loss-of-function mutation. Worm strain with daf-2(e1370) mutation presented enhanced HS-induced Cd resistance, which was eliminated in worm strains of daf-16(mu86) and hsf-1(sy441). HS pretreatment increased DAF-16 nuclear localization and HSF-1 granule formation prior to Cd exposure. DAF-16 and HSF-1 was essential in reducing bagging formation and protecting the integrity of intestinal barrier after HS pretreatment. In conclusion, the present study demonstrated that HS-induced Cd resistance in C. elegans is regulated by the DAF-16/FOXO and HSF-1 pathways through regulation of HSP-16.2 expression.

N,N’ bis-(2-mercaptoethyl) isophthalamide induces developmental delay in Caenorhabditis elegans by promoting DAF-16 nuclear localization

N,N’ bis-(2-mercaptoethyl) isophthalamide (NBMI) is a lipophilic thiol-containing agent that has high affinity for toxic metal ions, such as Hg2+, Pb2+, and Cd2+. Studies have shown that NBMI is a potent chelator of heavy metals, yet its potential toxicity in animals has yet to be determined. Using the model organism Caenorhabditis elegans (C. elegans), we show no significant change in worms’ death rate or lifespan following NBMI treatment (10−1000 μM). However, NBMI treatment was associated with a significant developmental delay. To determine if the daf-2/age-1/daf-16 pathway is involved in NBMI toxicity, mRNA levels of these genes were assessed in worms treated with NBMI. Here, we found that while NBMI failed to significantly alter the expression of daf-16 or daf-2; age-1 was significantly downregulated by NBMI. Furthermore, NBMI significantly increased DAF-16 nuclear localization. Consistent with a role for this pathway in NBMI toxicity, the developmental arrest by NBMI was more prominent in the DAF-16 transgenic strain than in the wild type N2 strain. Moreover, in the mutant strains harboring null alleles of daf-16, NBMI had no effect on development. In addition, NBMI repressed the expression of detoxifying genes (skn-1, gst-4 and gcs-1). In summary, NBMI has a low developmental toxicity in the C. elegans model, and the nuclear translocation of DAF-16 is involved in the developmental effect of NBMI.

Toxicity assessment of parabens in Caenorhabditis elegans.

Parabens, the alkyl esters of p-hydroxybenzoic acid such as methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), butylparaben (BuP) are used as a preservative in food, personal care products (PCPs), and pharmaceuticals, due to their antimicrobial properties. Parabens are continuously released into the environment, during washout of PCPs, disposal of industrial waste from the pharmaceutical and paper industries. Parabens have been detected in the indoor dust, wastewater stream, surface water of rivers, and the marine system. Recent eco-toxicological data and the environmental presence of parabens, has raised concerns regarding the safety and health of environment/humans. Thus, to further understand the toxicity of parabens, the present study was carried out in the soil nematode and well established biological model organism Caenorhabditis elegans. In the present study, LC50 of MeP, EtP, PrP and BuP for 72h exposures from L1 larva to adult stage was found to be 278.1, 217.8, 169.2, and 131.88μg/ml, respectively. Further exposure to 1/5th of LC50 of parabens yielded an internal concentration ranging from 1.67 to 2.83μg/g dry weight of the organism. The toxicity of parabens on the survival, growth, behavior, and reproduction of the C.elegans was found in the order of BuP>PrP>EtP>MeP. Worms exposed to parabens show significant down-regulation of vitellogenin genes, high levels of reactive oxygen species and anti-oxidant transcripts, the latter being concordant with nuclear localization of DAF-16 and up-regulation of HSF-1 and SKN-1/Nrf. Hence, parabens caused endocrine disruption, oxidative stress and toxicity in C.elegans at environment relevant internal concentration of parabens.

Saponin-rich extracts from Holothuria leucospilota mediate lifespan extension and stress resistance in Caenorhabditis elegans via daf-16.

Saponins are secondary metabolite compounds that can be found in sea cucumbers (Holothuroidea spp.). However, little is known about how saponin-rich extracts from Holothuria leucospilota can delay and prolong the lifespan of the whole organism. In this study, anti-aging effects of H. leucospilota extracts were studied on Caenorhabditis elegans. NMR analysis revealed that body wall n-butanol-extract of H. leucospilota (BW-BU) is saponin-rich. BW-BU extracts exhibited antioxidant activities by 2,2'-diphenyl-2-picrylhydrazyl assay (EC50 =10.23±0.12mg/ml) and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid assay (EC50 =3.91±0.04mg/ml). BW-BU extracts increased lifespan of L4 and L1 C. elegans (5.92% and 15.76%, respectively), which also increased worm growth, stress resistance, and reduced biomarkers for aging. BW-BU extracts activated DAF-16 nuclear localization and upregulated daf-16 and DAF-16 target genes expression. Taken together, this study revealed the evidences on anti-aging activities of saponin-rich extracts from H. leucospilota, which can extend lifespan of C. elegans via daf-16. PRACTICAL APPLICATIONS: In recent years, age-associated chronic diseases have had a significant impact on quality of life. Many natural compounds exhibit anti-aging activities, especially in sea cucumber, H. leucospilota. Our results indicated that H. leucospilota is good for health. Extracts from H. leucospilota contain a bioactive compound that can be potentially used to promote longevity and disease prevention in aging.

The anti-aging effects of Gracilaria lemaneiformis polysaccharide in Caenorhabditis elegans

The anti-aging activity of marine macroalgae Gracilaria lemaneiformis polysaccharide (GP) on Caenorhabditis elegans was evaluated by observing the lifespan, reproduction, pharyngeal pumping and stress response of worms. Moreover, quantitative fluorescence of polyglutamic acid and nuclear localization of DAF-16 were observed. The results showed that GP treatment enhanced the mean lifespan by over 16.47% and significantly increased the reproduction duration of worm in the high dose group (1000 μg/mL). GP exhibited little potent effects under the thermotolerance and oxidative stress. The number of polyglutamic acid aggregates in three dosage groups decreased by 24.82%, 32.08% and 30.93% (p < 0.05) compared to the control. The middle dose group strongly induced DAF-16 nuclear translocation over intermediate and cytosolic localizations compared to the control (p < 0.001). It was inferred that GP extended the adult lifespan of wild-type and polyQ nematodes through the insulin pathway DAF-16.

Epimedium flavonoids mitigate proteotoxicity and extend healthspan via DAF-16 inC. elegans

Objective: Epimedium flavonoids (EF), the raw extract of medicinal herb Epimedium, have been shown to have broad beneficial effects in the elderly including those with neurodegeneration. The goal of this study is to investigate whether EF is protective against proteotoxicity and whether it extends healthspan in C. elegans.Methods: Animals were treated with EF supplemented in the growth medium. Two C. elegans models of human proteotoxic disease, CL4176 expressing an aggregated amyloid-[Formula: see text] (1–42) peptide (A[Formula: see text]1–42) and AM140 expressing a polyglutamine (polyQ) protein, were exploited to test the anti-proteotoxicity of EF. Proteotoxicity-induced paralysis in CL4176 and AM140 was evaluated. Lifespan, stress resistance, and locomotion were tested in wild-type N2 C. elegans. Lifespan assays were also performed in CF1038, a daf-16 null mutant strain. DAF-16 nuclear translocation was analyzed in TJ356, a strain expressing a functional DAF-16::GFP fusion protein. The mRNA levels of downstream targets of DAF-16 were measured by qPCR.Results: EF significantly reduced A[Formula: see text]1–42- and polyQ-induced paralysis in CL4176 and AM140, indicating the anti-proteotoxic potency of EF. EF significantly extended the lifespan and promoted stress resistance and locomotion in N2, demonstrating a healthspan extension effect of EF. DAF-16 nuclear localization and its downstream targets, sod-3 and hsp-16.2 mRNA levels, were significantly elevated with EF. EF did not increase the lifespan of daf-16 null mutant CF1038, revealing a DAF-16-dependent mechanism of EF effect on lifespan.Conclusion: We found that EF, a natural extract from a widely used medicinal herb Epimedium, protects against proteotoxicity and extends the healthspan via DAF-16 in C. elegans. Our work may provide molecular insights into the clinical benefits of EF and Epimedium.

Chronic exposure to triadimenol at environmentally relevant concentration adversely affects aging biomarkers in Caenorhabditis elegans associated with insulin/IGF-1 signaling pathway

Triadimenol, an agricultural fungicide, is an emerging environmental concern due to its wide usage, detection in the environment, and its chemical persistency. Triadimenol has been found to disrupt endocrine signaling and alter function of several transcription factors, yet its age-related toxicity effects remain unclear. This study used Caenorhabditis elegans as an in vivo model organism to elucidate the age-related effects of triadimenol and its underlying mechanisms. The results showed that chronic exposure to triadimenol at environmentally relevant concentrations (3, 30, and 300 μg/L) adversely affected several toxicity endpoints including growth, total brood size, and locomotive behaviors. In addition, triadimenol (300 μg/L) significantly reduced the mean lifespan of wild-type N2 C. elegans from 17.9 to 16 days. Chronic exposure to triadimenol (300 μg/L) also significantly affected age-related behavioral changes, with a decreased pharyngeal pumping rate and an increased defecation cycle. Moreover, an increased accumulation of aging biomarkers including lipofuscin, lipid peroxidation, and reactive oxygen species (H2O2 and O2−) level upon chronic triadimenol exposure was observed in aged worms. Furthermore, chronic triadimenol exposure increased the transcriptional factor DAF-16 nuclear localization. Finally, mutation of daf-2, age-1, pdk-1, akt-1, or akt-2 restored the accumulation of lipofuscin in aged worms upon chronic triadimenol exposure, while mutation of daf-16 led to more enhanced lipofuscin accumulation. Therefore, the insulin/IGF-1 signaling pathway may serve as an important molecular basis for triadimenol induced aging declines in C. elegans.

DAF-16: FOXO in the Context of C. elegans.

In Caenorhabditis elegans, there is a single FOXO transcription factor homolog, encoded by the gene, daf-16. As a central regulator for multiple signaling pathways, DAF-16 integrates these signals which results in modulation of several biological processes including longevity, development, fat storage, stress resistance, innate immunity, and reproduction. Using C. elegans allows for studies of FOXO in the context of the whole animal. Therefore, manipulating levels or the activity of daf-16 results in phenotypic changes. Genetic and molecular analysis revealed that similar to other systems, DAF-16 is the downstream target of the conserved insulin/IGF-1 signaling (IIS) pathway; a PI 3-kinase/AKT signaling cascade that ultimately controls the regulation of DAF-16 nuclear localization. In this chapter, I will focus on understanding how a single gene daf-16 can incorporate signals from multiple upstream pathways and in turn modulate different phenotypes as well as the study of FOXO in the context of a whole organism.

Arbutin increases Caenorhabditis elegans longevity and stress resistance.

Arbutin (p-hydroxyphenyl-β-D-glucopyranoside), a well-known tyrosinase inhibitor, has been widely used as a cosmetic whitening agent. Although its natural role is to scavenge free radicals within cells, it has also exhibited useful activities for the treatment of diuresis, bacterial infections and cancer, as well as anti-inflammatory and anti-tussive activities. Because function of free radical scavenging is also related to antioxidant and the effects of arbutin on longevity and stress resistance in animals have not yet been confirmed, here the effects of arbutin on Caenorhabditis elegans were investigated. The results demonstrated that optimal concentrations of arbutin could extend lifespan and enhance resistance to oxidative stress. The underlying molecular mechanism for these effects involves decreased levels of reactive oxygen species (ROS), improvement of daf-16 nuclear localization, and up-regulated expression of daf-16 and its downstream targets, including sod-3 and hsp16.2. In this work the roles of arbutin in lifespan and health are studied and the results support that arbutin is an antioxidant for maintaining overall health.

Echinacoside, a phenylethanoid glycoside from Cistanche deserticola, extends lifespan of Caenorhabditis elegans and protects from Aβ-induced toxicity.

Cistanche deserticola has been found to exert protection against aging and age-related diseases, but mechanisms underlying its longevity effects remain largely unclear. Here, the multicellular model organism Caenorhabditis elegans was employed to identify lifespan extending and protective effects against β-amyloid (Aβ) induced toxicity by echinacoside (ECH), a phenylethanoid glycoside isolated from C. deserticola. Our results showed that ECH extends the mean lifespan of worms and increases their survival under oxidative stress. Levels of intracellular reactive oxygen species and fat accumulation were also significantly suppressed by ECH. Moreover, ECH-mediated lifespan extension was found to be dependent on mev-1, eat-2, daf-2, and daf-16, but not sir-2.1 or hsf-1 genes. Furthermore, ECH triggered DAF-16 nuclear localization and upregulated two of its downstream targets, sod-3 and hsp-16.2. In addition, ECH significantly improved the survival of CL4176 worms in response to proteotoxic stress induced by Aβ protein aggregation. Collectively, these findings suggested that reactive oxygen species scavenging, dietary restriction, and insulin/insulin-like growth factor signaling pathways could be partly involved in ECH-mediated lifespan extension. Thus, ECH may target multiple longevity mechanisms to extend lifespan and have a potency to prevent Alzheimer's disease progression.

N-acetyl-l-cysteine mimics the effect of dietary restriction on lifespan and reduces amyloid beta-induced toxicity in Caenorhabditis elegans.

The effects of antioxidants on lifespan have been widely studied. Our previous study showed supplementation with N-acetyl-l-cysteine (NAC) extends the lifespan of Caenorhabditis elegans. Here we aimed to determine the lifespan-extending mechanism involved with NAC and the effect of NAC on Alzheimer's disease (AD). NAC further increased the lifespan of age-1 and clk-1 mutants, which have increased lifespan owing to reduced insulin/IGF-1-like signaling and mitochondrial function, respectively. There was no additional lifespan extension in eat-2 background, a genetic model of dietary restriction (DR), by NAC. Gene knockdown experiments revealed that the effect of NAC is not dependent on SKN-1, a protein-sensing DR status, whereas DAF-16, a transcription factor regulating stress-responsive genes, is required for lifespan extension by NAC. NAC delayed paralysis caused by amyloid beta. Our results show that NAC mimics the effect of DR on lifespan, possibly through the induction of DAF-16 nuclear localization and may retard the incidence of AD.