ABSTRACT
As the areca nut market is expanding, there is a growing concern regarding areca nut toxicity. Areca nut alkaloids are the major risky components in betel nuts, and their toxic effects are not fully understood. Here, we investigated the parental and transgenerational toxicity of varied doses of areca nut alkaloids in Caenorhabditis elegans. The results showed that the minimal effective concentration of arecoline is 0.2-0.4 mM. First, arecoline exhibited transgenerational toxicity on the worms' longevity, oviposition, and reproduction. Second, the redox homeostasis of C. elegans was markedly altered under exposure to 0.2-0.4 mM arecoline. The mitochondrial membrane potential was thereafter impaired, which was also associated with the induction of apoptosis. Moreover, antioxidant treatments such as lycopene could significantly ameliorate the toxic effects caused by arecoline. In conclusion, arecoline enhances the ROS levels, inducing neurotoxicity, developmental toxicity, and reproductive toxicity in C. elegans through dysregulated oxidative stress, cell apoptosis, and DNA damage-related gene expression. Therefore, the drug-induced production of reactive oxygen species (ROS) may be crucial for its toxic effects, which could be mitigated by antioxidants.
Subject(s)
Antioxidants , Apoptosis , Arecoline , Caenorhabditis elegans , Oxidative Stress , Reactive Oxygen Species , Animals , Caenorhabditis elegans/drug effects , Arecoline/toxicity , Apoptosis/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Antioxidants/pharmacology , DNA Damage , Reproduction/drug effects , Longevity/drug effects , Membrane Potential, Mitochondrial/drug effects , Oviposition/drug effectsSubject(s)
Interleukin-11 , Longevity , Animals , Longevity/drug effects , Mice , Interleukin-11/metabolism , Aging/drug effectsABSTRACT
Background: Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective: We sought to identify probiotics that can delay Aß-induced paralysis. Methods: Using C. elegans expressing human amyloid-ß (Aß)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results: We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-ß aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions: Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.
Subject(s)
Amyloid beta-Peptides , Bacillus subtilis , Caenorhabditis elegans , Lacticaseibacillus rhamnosus , Longevity , Probiotics , Animals , Longevity/drug effects , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/toxicity , Paralysis , Peptide Fragments/toxicity , Peptide Fragments/metabolism , Animals, Genetically Modified , Humans , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolismABSTRACT
Given the unprecedented rate of global aging, advancing aging research and drug discovery to support healthy and productive longevity is a pressing socioeconomic need. Holistic models of human and population aging that account for biomedical background, environmental context, and lifestyle choices are fundamental to address these needs, but integration of diverse data sources and large data sets into comprehensive models is challenging using traditional approaches. Recent advances in artificial intelligence and machine learning, and specifically multimodal transformer-based neural networks, have enabled the development of highly capable systems that can generalize across multiple data types. As such, multimodal transformers can generate systemic models of aging that can predict health status and disease risks, identify drivers, or breaks of physiological aging, and aid in target discovery against age-related disease. The unprecedented capacity of transformers to extract and integrate information from large and diverse data modalities, combined with the ever-increasing availability of biological and medical data, has the potential to revolutionize healthcare, promoting healthy longevity and mitigating the societal and economic impacts of global aging.
Subject(s)
Aging , Drug Discovery , Humans , Aging/physiology , Drug Discovery/methods , Artificial Intelligence , Longevity/drug effects , Machine Learning , Neural Networks, ComputerABSTRACT
The beekeeping industry plays a crucial role in local economies, contributing significantly to their growth. However, bee colonies often face the threat of American foulbrood (AFB), a dangerous disease caused by the Gram-positive bacterium Paenibacillus larvae (P. l.). While the antibiotic Tylosin has been suggested as a treatment, its bacterial resistance necessitates the search for more effective alternatives. This investigation focused on evaluating the potential of bee venom (BV) and silver nanoparticles (Ag NPs) as antibacterial agents against AFB. In vitro treatments were conducted using isolated AFB bacterial samples, with various concentrations of BV and Ag NPs (average size: 25nm) applied individually and in combination. The treatments were administered under both light and dark conditions. The viability of the treatments was assessed by monitoring the lifespans of treated bees and evaluating the treatment's efficiency within bee populations. Promising results were obtained with the use of Ag NPs, which effectively inhibited the progression of AFB. Moreover, the combination of BV and Ag NPs, known as bee venom/silver nanocomposites (BV/Ag NCs), significantly extended the natural lifespan of bees from 27 to 40 days. Notably, oral administration of BV in varying concentrations (1.53, 3.12, and 6.25 mg/mL) through sugary syrup doubled the bees' lifespan compared to the control group. The study established a significant correlation between the concentration of each treatment and the extent of bacterial inhibition. BV/Ag NCs demonstrated 1.4 times greater bactericidal efficiency under photo-stimulation with visible light compared to darkness, suggesting that light exposure enhances the effectiveness of BV/Ag NCs. The combination of BV and Ag NPs demonstrated enhanced antibacterial efficacy and prolonged honeybee lifespan. These results offer insights that can contribute to the development of safer and more efficient antibacterial agents for maintaining honeybee health.
Subject(s)
Anti-Bacterial Agents , Bee Venoms , Metal Nanoparticles , Paenibacillus larvae , Silver , Animals , Bees/microbiology , Bee Venoms/pharmacology , Metal Nanoparticles/chemistry , Silver/pharmacology , Silver/chemistry , Anti-Bacterial Agents/pharmacology , Paenibacillus larvae/drug effects , Longevity/drug effectsABSTRACT
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
Subject(s)
Aging , Interleukin-11 , Longevity , Signal Transduction , Animals , Female , Male , Mice , Aging/drug effects , Aging/genetics , Aging/metabolism , Aging/pathology , AMP-Activated Protein Kinases/metabolism , Frailty/genetics , Frailty/metabolism , Frailty/prevention & control , Inflammation/metabolism , Inflammation/drug therapy , Interleukin-11/antagonists & inhibitors , Interleukin-11/deficiency , Interleukin-11/genetics , Interleukin-11/metabolism , Interleukin-11 Receptor alpha Subunit/metabolism , Interleukin-11 Receptor alpha Subunit/deficiency , Longevity/drug effects , Longevity/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Mice, Inbred C57BL , Signal Transduction/drug effects , Humans , Extracellular Signal-Regulated MAP Kinases/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiologyABSTRACT
Investigations into human longevity are increasingly focusing on healthspan enhancement, not just lifespan extension. Lifestyle modifications and nutritional choices, including food supplements, can significantly affect aging and general health. Phytochemicals in centenarians' diets, such as those found in Timut pepper, a Nepalese spice with various medicinal properties, may contribute to their longevity. Similarly, Sichuan pepper, a related species, has demonstrated anti-inflammatory and neuroprotective activities. With the broader purpose of uncovering a novel treatment to address aging and its comorbidities, this study aims to investigate the potential lifespan- and healthspan-promoting effects of Timut pepper using the model organism Caenorhabditis elegans. We show that Timut pepper extract extends C. elegans' lifespan at different maintenance temperatures and increases the proportion of active nematodes in their early adulthood. In addition, we show that Timut pepper extract enhances speed and distance moved as the nematodes age. Finally, Timut pepper extract assures extracellular matrix homeostasis by slowing the age-dependent decline of collagen expression.
Subject(s)
Caenorhabditis elegans , Capsicum , Collagen , Longevity , Plant Extracts , Caenorhabditis elegans/drug effects , Longevity/drug effects , Animals , Plant Extracts/pharmacology , Collagen/metabolism , Capsicum/chemistry , Aging/drug effects , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Extracellular Matrix/drug effects , Extracellular Matrix/metabolismABSTRACT
Glucose metabolism plays an important role for formation of normal physiological state of organisms. However, association between altered glucose metabolism and toxicity of 6-PPD quinone (6-PPDQ) remains largely unknown. In 1-100 µg/L 6-PPDQ exposed Caenorhabditis elegans, we observed increased glucose content. After 6-PPDQ exposure (1-100 µg/L), expressions of F47B8.10 and fbp-1 governing gluconeogenesis were increased, and expressions of hxk-1, hxk-3, pfk-1.1, pyk-1, and pyk-2 governing glycolysis were decreased. Under 6-PPDQ exposure condition, glucose content could be changed by RNAi of F47B8.10, hxk-1, and hxk-3, key genes for gluconeogenesis and glycolysis. In 6-PPDQ exposed nematodes, RNAi of daf-16 and aak-2 elevated glucose content, increased expressions of F47B8.10 and/or fbp-1, and decreased expressions of hxk-1, hxk-3, and/or pfk-1.1. Additionally, lifespan and locomotion during aging were increased by RNAi of F47B8.10 and decreased by RNAi of hxk-1 and hxk-3 in 6-PPDQ exposed nematodes. Moreover, after 6-PPDQ exposure, RNAi of F47B8.10 decreased expressions of insulin peptide genes (ins-7 and daf-28) and insulin receptor gene daf-2 and increased expressions of daf-16 and aak-2. In 6-PPDQ exposed nematodes, RNAi of hxk-1 and hxk-3 further increased expressions of ins-7, daf-28, and daf-2 and decreased expressions of daf-16 and aak-2. Our results demonstrated important association between altered glucose metabolism and toxicity of 6-PPDQ in inducing lifespan reduction in organisms.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Glucose , Insulin , Longevity , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Animals , Longevity/drug effects , Glucose/metabolism , Insulin/metabolism , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , AMP-Activated Protein Kinases/metabolism , Signal Transduction/drug effects , Gluconeogenesis/drug effects , Glycolysis/drug effects , PQQ Cofactor , Forkhead Transcription FactorsABSTRACT
The mutations in Caenorhabditis elegans (C. elegans) that extend lifespan slow down aging by interfering with several signaling pathways, including the insulin/IGF-1 signaling (IIS) pathway, AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR). The tumor suppressor pRb (retinoblastoma protein) is believed to be involved in almost all human cancers. Lin-35, the C. elegans orthologue of the tumor suppressor pRb, was included in the study to explore the effects of insulin and IGF-1 because it has been linked to cancer-related pRb function in mammals and exhibits a tumor suppressor effect by inhibiting mTOR or IIS signaling. According to our results, IGF-1 or insulin increased the lifespan of lin-35 worms compared to N2 worms by increasing fertilization efficiency, also causing a significant increase in body size. It was concluded that the expression of daf-2 and rsks-1 decreased after insulin or IGF-1 administration, thus extending the lifespan of C. elegans lin-35 worms through both IIS and mTOR-dependent mechanisms. This suggests that it was mediated by the combined effect of the TOR and IIS pathways. These results, especially obtained in cancer-associated mutant lin-35 worms, will be useful in elucidating the C. elegans cancer model in the future.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Insulin-Like Growth Factor I , Insulin , Longevity , Signal Transduction , TOR Serine-Threonine Kinases , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Insulin/metabolism , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/genetics , Longevity/drug effects , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/genetics , Receptor, Insulin/metabolism , Receptor, Insulin/genetics , Ribosomal Protein S6 Kinases, 70-kDa , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolismABSTRACT
Chlorella pyrenoidos polysaccharides (CPPs) are the main active components of Chlorella pyrenoidos. They possess beneficial health properties, such as antioxidant, anti-inflammatory, and immune-enhancing. This study aims to investigate the protective function and mechanism of CPPs against high-temperature stress injury. Results showed that supplementation with 20 mg/mL CPPs significantly extended the lifespan of Drosophila melanogaster under high-temperature stress, improved its motility, and enhanced its resistance to starvation and oxidative stress. These effects were mainly attributed to the activation of Nrf2 signaling and enhanced antioxidant capacity. Additionally, it has been discovered that CPPs supplementation enhanced Drosophila resilience by preventing the disruption of the intestinal barrier and accumulation of reactive oxygen species caused by heat stress. Overall, these studies suggest that CPPs could be a useful natural therapy for preventing heat stress-induced injury.
Subject(s)
Antioxidants , Chlorella , Drosophila melanogaster , Hot Temperature , Longevity , Oxidative Stress , Polysaccharides , Animals , Drosophila melanogaster/drug effects , Polysaccharides/pharmacology , Polysaccharides/chemistry , Longevity/drug effects , Chlorella/chemistry , Oxidative Stress/drug effects , Antioxidants/pharmacology , Dietary Supplements , Reactive Oxygen Species/metabolism , Heat-Shock Response/drug effects , Signal Transduction/drug effects , NF-E2-Related Factor 2/metabolismABSTRACT
PURPOSE: While reactive oxygen species (ROS) have been identified as key redox signaling agents contributing to aging process, which and how specific oxidants trigger healthy longevity remain unclear. This paper aimed to explore the precise role and signaling mechanism of superoxide (O2â¢-) in health and longevity. METHODS: A tool for precise regulation of O2â¢- levels in vivo was developed based on the inhibition of superoxide dismutase 1 (SOD1) by tetrathiomolybdate (TM) in Caenorhabditis elegans (C. elegans). Then, we examined the effects of TM on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the signaling mechanism for longevity induced by TM-O2â¢- was screened by transcriptome analysis and tested in sod-1 and argk-1 RNAi strains, sod-2, sod-3, and daf-16 mutants. RESULTS: TM promoted longevity in C. elegans with a concomitant extension of healthy lifespan as indicated by increasing fertility and mobility and reducing lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanically, TM could precisely regulate O2â¢- levels in nematodes via modulating SOD1 activity. An O2â¢- scavenger Mn(III)TBAP abolished TM-induced lifespan extension, while an O2â¢- generator paraquat at low concentration mimicked the life prolongation effects. The longevity in TM-treated worms was abolished by sod-1 RNAi but was not affected in sod-2 or sod-3 mutants. Further transcriptome analysis revealed arginine kinase ARGK-1 and its downstream insulin/insulin-like growth factor 1 signaling (IIS) as potential effectors for TM-O2â¢â¾-induced longevity, and argk-1 RNAi or daf-16 mutant nullified the longevity. CONCLUSIONS: These findings indicate that it is feasible to precisely control specific oxidant in vivo and O2â¢- orchestrates TM-induced health and longevity in C. elegans via ARGK-1-IIS axis.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Longevity , Molybdenum , Signal Transduction , Superoxide Dismutase , Superoxides , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Caenorhabditis elegans/drug effects , Longevity/drug effects , Longevity/genetics , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase/genetics , Molybdenum/pharmacology , Molybdenum/metabolism , Superoxides/metabolism , Superoxide Dismutase-1/metabolism , Superoxide Dismutase-1/genetics , Oxidative Stress/drug effects , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Reactive Oxygen Species/metabolism , RNA InterferenceABSTRACT
Two monophyletic Daphnia species (Daphnia magna and D. similis) were exposed to a sub-lethal concentration of Pb (50 µg/L) for nine generations under two food regimes (usual and restricted) and analyzed for acetylcholinesterase (AChE) activity, first reproduction delay, lifespan, and net reproductive rate (R0) at the subcellular, individual, and population levels, respectively. In the sixth generation, Pb-acclimated neonates were moved to clean media for three more generations to check for recovery. The net reproductive rate (R0) of D. magna was not affected by Pb. However, Pb stimulated reproduction, reduced lifespan, and decreased AChE activity. First reproduction delay and lifespan did not improve during the recovery process, suggesting a possible genetic adaptation. Food restriction reduced R0, lifespan, delayed hatching, and increased AChE activity; the opposite outcomes were observed for D. similis. The full recovery shown by R0 suggests the physiological acclimation of D. similis. Under food restriction, the animals exhibited a reduction of R0 and lifespan, delayed first reproduction, and increased AChE activity; however, there was no effect of Pb. The recovery process under food restriction showed that D. similis might not cope with Pb exposure, indicating a failed recovery. Such outcomes indicate that one model species' sensitivity may not represent another's sensitivity.
Subject(s)
Daphnia , Lead , Reproduction , Water Pollutants, Chemical , Animals , Daphnia/physiology , Daphnia/drug effects , Lead/toxicity , Water Pollutants, Chemical/toxicity , Reproduction/drug effects , Acetylcholinesterase/metabolism , Longevity/drug effectsABSTRACT
BACKGROUND: Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. METHODS: Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. RESULTS: We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo. CONCLUSIONS: Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.
Subject(s)
Aging , DNA Methylation , Longevity , Humans , Animals , DNA Methylation/drug effects , Longevity/drug effects , Aging/drug effects , Epigenesis, Genetic/drug effects , Drug Discovery/methods , Cellular Senescence/drug effects , Drug Evaluation, Preclinical/methods , Drosophila , Cells, Cultured , Sirolimus/pharmacologyABSTRACT
Imiqualines are analogues of the immunomodulatory drug imiquimod. EAPB02303, the lead of the second-generation imiqualines, is characterized by significant anti-tumor effects with IC50s in the nanomolar range. We used Caenorhabditis elegans transgenic and mutant strains of two key signaling pathways (PI3K-Akt and Ras-MAPK) disrupted in human cancers to investigate the mode of action of EAPB02303. The ability of this imiqualine to inhibit the insulin/IGF1 signaling (IIS) pathway via the PI3K-Akt kinase cascade was explored through assessing the lifespan of wild-type worms. Micromolar doses of EAPB02303 significantly enhanced longevity of N2 strain and led to the nuclear translocation and subsequent activation of transcription factor DAF-16, the only forkhead box transcription factor class O (Fox O) homolog in C. elegans. Moreover, EAPB02303 significantly reduced the multivulva phenotype in let-60/Ras mutant strains MT2124 and MT4698, indicative of its mode of action through the Ras pathway. In summary, we showed that EAPB02303 potently reduced the activity of IIS and Ras-MAPK signaling in C. elegans. Our results revealed the mechanism of action of EAPB02303 against human cancers associated with hyperactivated IIS pathway and oncogenic Ras mutations.
Subject(s)
Antineoplastic Agents , Caenorhabditis elegans Proteins , Caenorhabditis elegans , Forkhead Transcription Factors , Quinoxalines , Signal Transduction , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Animals , Quinoxalines/pharmacology , Quinoxalines/chemistry , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Signal Transduction/drug effects , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Longevity/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Humans , Imidazoles/pharmacology , Imidazoles/chemistry , Animals, Genetically ModifiedABSTRACT
Today, plastic pollution is one of the biggest threats to the environment and public health. In the tissues of exposed species, micro- and nano-fragments accumulate, leading to genotoxicity, altered metabolism, and decreased lifespan. A model to investigate the genotoxic and tumor-promoting potential of nanoplastics (NPs) is Drosophila melanogaster. Here we tested polystyrene, which is commonly used in food packaging, is not well recycled, and makes up at least 30% of landfills. In order to investigate the biological effects and carcinogenic potential of 100 µm polystyrene nanoparticles (PSNPs), we raised Oregon [R] wild-type flies on contaminated food. After prolonged exposure, fluorescent PSNPs accumulated in the gut and fat bodies. Furthermore, PSNP-fed flies showed considerable alterations in weight, developmental time, and lifespan, as well as a compromised ability to recover from starvation. Additionally, we noticed a decrease in motor activity in DNAlig4 mutants fed with PSNPs, which are known to be susceptible to dietary stressors. A qPCR molecular investigation of the larval intestines revealed a markedly elevated expression of the genes drice and p53, suggesting a response to cell damage. Lastly, we used warts-defective mutants to assess the carcinogenic potential of PSNPs and discovered that exposed flies had more aberrant masses than untreated ones. In summary, our findings support the notion that ingested nanopolystyrene triggers metabolic and genetic modifications in the exposed organisms, eventually delaying development and accelerating death and disease.
Subject(s)
Drosophila melanogaster , Nanoparticles , Polystyrenes , Animals , Drosophila melanogaster/drug effects , Drosophila melanogaster/genetics , Polystyrenes/toxicity , Nanoparticles/toxicity , Nanoparticles/chemistry , Carcinogens/toxicity , Larva/drug effects , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Longevity/drug effects , Fat Body/metabolism , Fat Body/drug effectsABSTRACT
Macauba (Acrocomia aculeata) is a Brazilian palm tree whose oil in the pulp is rich in oleic acid and carotenoids. However, its physiological function remains unknown. This study aimed to investigate the effects of macauba pulp oil (MPO) on the metabolic link between lipid metabolism and lifespan using Caenorhabditis elegans (C. elegans). C. elegans were treated with 5.0 mg/mL of MPO for analyzing triglyceride and glycerol accumulation, fatty acid profile, gene expression of lipid and oxidative metabolism proteins under cold (4°C) stress conditions, and lifespan analysis under stress conditions such as cold (4°C), heat (37°C), and oxidative (paraquat) stress. MPO significantly suppressed fat accumulation and increased glycerol (a lipolysis index) and the lifespan of C. elegans at low temperature (4°C). This was accompanied by decreased mRNA levels of the genes involved in lipogenesis (spb-1 and pod-2) and increased levels of the genes involved in fatty acid ß-oxidation (acs-2 and nhr-49) and fat mobilization genes (hosl-1 and aak-2). Additionally, MPO treatment modulated fatty acid pools in C. elegans at low temperatures in that MPO treatment decreased saturated fatty acid levels and shifted the fatty acid profile to long-chain fatty acids. Moreover, the effect of MPO on fat accumulation at low temperatures was abolished in fat-7 mutants, whereas both fat-1 and fat-7 contribute, at least in part, to MPO-elevated survival of C. elegans under cold conditions. PRACTICAL APPLICATION: The results obtained in the present study may contribute to the understanding of the health benefits of consuming macauba pulp oil and consequently stimulate economic growth and the industrial application of this new type of oil, which may result in the creation of new jobs and increased value of small producers.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Cold Temperature , Lipid Metabolism , Longevity , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/physiology , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Longevity/drug effects , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Lipid Metabolism/drug effects , Plant Oils/pharmacology , Arecaceae/chemistry , Fatty Acids/metabolism , Triglycerides/metabolism , Glycerol/metabolism , Glycerol/pharmacology , Oxidative Stress/drug effects , Palm Oil/pharmacologyABSTRACT
Milk-derived peptides and milk fat globule membrane (MFGM) have gained interest as health-promoting food ingredients. However, the mechanisms by which these nutraceuticals modulate the function of biological systems often remain unclear. We utilized Caenorhabditis elegans to elucidate how MFGM-containing protein powder (MProPow), previously used in a clinical trial, affect the physiology of this model organism. Our results demonstrate that MProPow does not affect lifespan but promotes the fitness of the animals. Surprisingly, gene expression analysis revealed that MProPow decreases the expression of genes functioning on innate immunity, which also translates into reduced survival on pathogenic bacteria. One of the innate immunity-associated genes showing reduced expression upon MProPow supplementation is cpr-3, the homolog of human cathepsin B. Interestingly, knockdown of cpr-3 enhances fitness, but not in MProPow-treated animals, suggesting that MProPow contributes to fitness by downregulating the expression of this gene. In summary, this research highlights the value of C. elegans in testing the biological activity of food supplements and nutraceuticals. Furthermore, this study should encourage investigations into whether milk-derived peptides and MFGM mediate their beneficial effects through the modulation of cathepsin B expression in humans.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Dietary Supplements , Glycolipids , Glycoproteins , Lipid Droplets , Animals , Caenorhabditis elegans/drug effects , Glycolipids/pharmacology , Glycoproteins/pharmacology , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Immunity, Innate/drug effects , Cathepsin B/metabolism , Powders , Milk Proteins/pharmacology , Longevity/drug effectsABSTRACT
Mating in female Drosophila melanogaster causes midgut hypertrophy and reduced lifespan, and these effects are blocked by the drug mifepristone. Eip75B is a transcription factor previously reported to have pleiotropic effects on Drosophila lifespan. Because Eip75B null mutations are lethal, conditional systems and/or partial knock-down are needed to study Eip75B effects in adults. Previous studies showed that Eip75B is required for adult midgut cell proliferation in response to mating. To test the possible role of Eip75B in mediating the lifespan effects of mating and mifepristone, a tripartite FLP-recombinase-based conditional system was employed that provides controls for genetic background. Expression of a Hsp70-FLP transgene was induced in third instar larvae by a brief heat pulse. The FLP recombinase catalyzed the recombination and activation of an Actin5C-GAL4 transgene. The GAL4 transcription factor in turn activated expression of a UAS-Eip75B-RNAi transgene. Inhibition of Eip75B activity was confirmed by loss of midgut hypertrophy upon mating, and the lifespan effects of both mating and mifepristone were eliminated. In addition, the negative effects of mifepristone on egg production were eliminated. The data indicate that Eip75B mediates the effects of mating and mifepristone on female midgut hypertrophy, egg production, and lifespan.
Subject(s)
Drosophila Proteins , Drosophila melanogaster , Longevity , Mifepristone , Transcription Factors , Animals , Mifepristone/pharmacology , Female , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Drosophila melanogaster/drug effects , Drosophila melanogaster/genetics , Drosophila melanogaster/physiology , Longevity/drug effects , Longevity/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Male , Sexual Behavior, Animal/drug effectsABSTRACT
Sitobion miscanthi and Schizaphis graminum (Rondani) are the 2 main aphid species that occur simultaneously, causing significant loss to wheat production. Acetamiprid has been used to control a variety of pests, including aphids. In this study, the sublethal effect of acetamiprid on S. miscanthi and S. graminum was evaluated using life-table analyses. The results showed that acetamiprid has a high toxicity to S. miscanthi and S. graminum with a LC50 of 1.90 and 3.58 mg/L at 24 h, respectively. The adult longevity and fecundity of S. miscanthi and S. graminum F0 generation were significantly reduced after being exposed to a sublethal concentration of acetamiprid. Additionally, the sublethal concentration of acetamiprid had negative transgenerational effects on S. miscanthi and S. graminum, which showed a significant decrease in fecundity and population life-table parameters involving age-stage-specific survival rate (sxj), age-specific survival rate (lx), and intrinsic rate of increase (r). Furthermore, the population projections showed that the total population size of S. miscanthi and S. graminum was significantly lower in the aphid group exposed to sublethal concentration of acetamiprid compared to the control group. These results suggest that sublethal concentration of acetamiprid suppresses the population growth of S. miscanthi and S. graminum. This finding is beneficial to the control of wheat aphids, and is important to fully understand the role of acetamiprid in integrated pest management.