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D-chiro-inositol (DCI) is an isomer of inositol, abundant in many foods, such as beans and buckwheat, with insulin-sensitizing, anti-inflammatory, and antioxidant effects. DCI has been used to relieve insulin resistance in diabetes and polycystic ovary syndrome in combination with inositol or D-pinitol. Here, we investigated the effect of DCI on aging and stress resistance in C. elegans. We found that DCI could prolong the lifespan of C. elegans by up to 29.6 %. DCI significantly delayed the onset of neurodegenerative diseases in models of C. elegans. DCI decreased the accumulation of Aβ 1 - 42 , alpha-synuclein, and poly-glutamine, the pathological causes of Alzheimer's, Parkinson's, and Huntington's diseases, respectively. DCI significantly increased the stress resistances against pathogens, oxidants and heat shock. Moreover, D-chiro-inositol reduced the content of ROS and malondialdehyde by increasing the total antioxidant capacity and the activity of superoxide dismutase and catalase. Above effects of DCI requires the transcription factors FOXO/DAF-16 and Nrf-2/SKN-1. DCI also increased the expression of downstream genes regulated by FOXO/DAF-16 and Nrf-2/SKN-1. In conclusion, DCI enhanced the antioxidant capacity and healthy lifespan of C. elegans by activating DAF-16, SKN-1, and HSF-1. Our results showed that DCI could be a promising antiaging agent that is worth further research on the mechanism and health supplemental application of DCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Age is the major risk factor for most of the deadliest diseases. Developing small molecule drugs with antiaging effects could improve the health of aged people and retard the onset and progress of aging-associated disorders. Bioactive secondary metabolites from medicinal plants are the main source for development of medication. Orientin is a water-soluble flavonoid monomer compound widely found in many medicinal plants. Orientin inhibits fat production, antioxidation, and anti-inflammatory activities. In this study, we explored whether orientin could affect the aging of C. elegans . We found that orientin improved heat, oxidative, and pathogenic stress resistances through activating stress responses, including HSF-1-mediated heat shock response, SKN-1-mediated xenobiotic and oxidation response, mitochondria unfolded responses, endoplasmic unfolded protein response, and increased autophagy activity. Orientin also could activate key regulators of the nutrient sensing pathway, including AMPK and insulin downstream transcription factor FOXO/DAF-16 to further improve the cellular health status. The above effects of orientin reduced the accumulation of toxic proteins ( α -synuclein, β -amyloid, and poly-Q) and delayed the onset of neurodegenerative disorders in AD, PD, and HD models of C. elegans and finally increased the longevity and health span of C. elegans . Our results suggest that orientin has promising antiaging effects and could be a potential natural source for developing novel therapeutic drugs for aging and its related diseases., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2022 Yuan Qu et al.)

Trigonelline is the main alkaloid with bioactivity presented in fenugreek, which was used in traditional medicine in Asian countries for centuries. It is reported that trigonelline has anti-inflammatory, anti-oxidant, and anti-pathogenic effects. We are wondering whether trigonelline have anti-aging effect. We found that 50  μ M of trigonelline had the best anti-aging activity and could prolong the lifespan of Caenorhabditis elegans ( C. elegans ) by about 17.9%. Trigonelline can enhance the oxidative, heat, and pathogenic stress resistance of C. elegans . Trigonelline could also delay the development of neurodegenerative diseases, such as AD, PD, and HD, in models of C. elegans . Trigonelline could not prolong the lifespan of long-lived worms with loss-of-function mutations in genes regulating energy and nutrition, such as clk-1 , isp-1 , eat-2 , and rsks-1 . Trigonelline requires daf-16 , hsf-1 , and aak-2 to extend the lifespan of C. elegans . Trigonelline can also up-regulate the expression of daf-16 and hsf-1 targeted downstream genes, such as sod-3 , gst-4 , hsp-16.1 , and hsp-12.6 . Our results can be the basis for developing trigonelline-rich products with health benefits, as well as for further research on the pharmacological usage of trigonelline., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2021 Wen-Yu Zeng et al.)

Inositol polyphosphate multikinase (IPMK) is a conserved protein that initiates the production of inositol phosphate intracellular messengers and is critical for regulating a variety of cellular processes. Here, we report that the C. elegans IPMK-1, which is homologous to the mammalian inositol polyphosphate multikinase, plays a crucial role in regulating rhythmic behavior and development. The deletion mutant ipmk-1(tm2687) displays a long defecation cycle period and retarded postembryonic growth. The expression of functional ipmk-1::GFP was detected in the pharyngeal muscles, amphid sheath cells, the intestine, excretory (canal) cells, proximal gonad, and spermatheca. The expression of IPMK-1 in the intestine was sufficient for the wild-type phenotype. The IP3-kinase activity of IPMK-1 is required for defecation rhythms and postembryonic development. The defective phenotypes of ipmk-1(tm2687) could be rescued by a loss-of-function mutation in type I inositol 5-phosphatase homolog (IPP-5) and improved by a supplemental Ca 2+ in the medium. Our work demonstrates that IPMK-1 and the signaling molecule inositol triphosphate (IP3) pathway modulate rhythmic behaviors and development by dynamically regulating the concentration of intracellular Ca 2+ in C. elegans. Advances in understanding the molecular regulation of Ca 2+ homeostasis and regulation of organism development may lead to therapeutic strategies that modulate Ca 2+ signaling to enhance function and counteract disease processes. Unraveling the physiological role of IPMK and the underlying functional mechanism in C. elegans would contribute to understanding the role of IPMK in other species, especially in mammals, and benefit further research on the involvement of IPMK in disease., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aging is related to the lowered overall functioning and increased risk for various age-related diseases in humans. Tectochrysin is a flavonoid compound and rich in a traditional Chinese Medicine Alpinia oxyphylla Miq., which has antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, anti-diarrhea, hepatoprotective, and neuro-protective effects. Therefore, we tested if tectochrysin had an effect on aging in Caenorhabditis elegans (C. elegans). Our results showed that tectochrysin could extend the lifespan of C. elegans by up to 21.0%, delay the age-related decline of body movement, improve high temperature-stress resistance and anti-infection capacity, and protected worms against Aβ1-42-induced toxicity. Tectochrysin could not extend the lifespan of the mutants from genes daf-2, daf-16, eat-2, aak-2, skn-1, and hsf-1. Tectochrysin could increase the expression of DAF-16 regulated genes. The extension of lifespan by tectochrysin requires FOXO/DAF-16 and HSF-1. Overall, our findings suggest that tectochrysin may have a potential effect on extending lifespan and age-related diseases.

Aging is a complex life process, and a unified view is that metabolism plays key roles in all biological processes. Here, we determined the lipidomic profile of Caenorhabditis elegans ( C. elegans ) using ultraperformance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS). Using a nontargeted approach, we detected approximately 3000 species. Analysis of the lipid metabolic profiles at young adult and ten-day-old ages among wild-type N2, glp-1 defective mutant, and double mutant daf-16;glp-1 uncovered significant age-related differences in the total amount of phosphatidylcholines (PC), sphingomyelins (SM), ceramides (Cer), diglycerides (DG), and triglycerides (TG). In addition, the age-associated lipid profiles were characterized by ratio of polyunsaturated (PUFA) over monounsaturated (MUFA) lipid species. Lipid metabolism modulation plays an important role in reproduction-regulated aging; to identify the variations of lipid metabolites during germ line loss-induced longevity, we investigated the lipidomic profiles of long-lived glp-1 /notch receptor mutants, which have reproductive deficiency when grown at nonpermissive temperature. The results showed that there was some age-related lipid variation, including TG 40:2, TG 40:1, and TG 41:1, which contributed to the long-life phenotype. The longevity of glp-1 mutant was daf-16 -dependent; the lipidome analysis of daf-16;glp-1 double mutant revealed that the changes of some metabolites in the glp-1 mutant were daf-16 -dependent, while other metabolites displayed more complex epistatic patterns. We first conducted a comprehensive lipidome analysis to provide novel insights into the relationships between longevity and lipid metabolism regulated by germ line signals in C. elegans .

Aging is a major risk factor for many prevalent diseases. Pharmacological intervention to improve the health span and extend the lifespan could be a preventive elixir for aging and age-related diseases. The non-steroid anti-inflammation medicine aspirin was reported to delay aging in Caenorhabditis elegans ( C. elegans ) and mice. We are wondering if the analogues of aspirin could also present antiaging activity. Here, we synthesized several aspirin derivatives and investigated their thermotolerance and antiaging effect in C. elegans . One of the compounds, 5-(bis(3-methylbut-2-en-1-yl)amino)-2-hydroxybenzoic acid, moderately increased the survival of C. elegans under heat stress, but could not extend the lifespan under optimum conditions. This compound could increase the mRNA level of stress response gene gst-4 , and the mRNA and protein expression level of heat shock protein hsp-16.2 under heat stress. The failure of activating the transcription factor DAF-16 might explain why this compound could not act as aspirin to extend the lifespan of C. elegans . Our results would help further the investigation of the pharmacological activity of aspirin analogues and the relationship between structures and activity.

Aspirin is a prototypic cyclooxygenase inhibitor with a variety of beneficial effects on human health. It prevents age-related diseases and delays the aging process. Previous research has shown that aspirin might act through a dietary restriction-like mechanism to extend lifespan. To explore the mechanism of action of aspirin on aging, we determined the whole-genome expression profile of Caenorhabditis elegans treated with aspirin. Transcriptome analysis revealed the RNA levels of genes involved in metabolism were primarily increased. Reproduction has been reported to be associated with metabolism. We found that aspirin did not extend the lifespan or improve the heat stress resistance of germline mutants of glp-1. Furthermore, Oil Red O staining showed that aspirin treatment decreased lipid deposition and increased expression of lipid hydrolysis and fatty acid β-oxidation-related genes. The effect of germline ablation on lifespan was mainly mediated by DAF-12 and DAF-16. Next, we performed genetic analysis with a series of worm mutants and found that aspirin did not further extend the lifespans of daf-12 and daf-16 single mutants, glp-1;daf-12 and glp-1;daf-16 double mutants, or glp-1;daf-12;daf-16 triple mutants. The results suggest that aspirin increase metabolism and regulate germline signalling to activate downstream DAF-12 and DAF-16 to extend lifespan.

Coffee and tea, two of the most popular drinks around the world, share many in common from chemical components to beneficial effects on human health. One of their shared components, the polyphenols, most notably chlorogenic acid (CGA), was supposed to account for many of the beneficial effects on ameliorating diseases occurred accompanying people aging, such as the antioxidant effect and against diabetes and cardiovascular disease. CGA is also present in many traditional Chinese medicines. However, the mechanism of these effects was vague. The aging signaling pathways were conservative from yeast and worms to mammals. So, we tested if CGA had an effect on aging in Caenorhabditis elegans. We found that CGA could extend the lifespan of C. elegans by up to 20.1%, delay the age-related decline of body movement, and improve stress resistance. We conducted genetic analysis with a series of worm mutants and found that CGA could extend the lifespan of the mutants of eat-2, glp-1, and isp-1, but not of daf-2, pdk-1, akt-1, akt-2, sgk-1, and clk-1. CGA could activate the FOXO transcription factors DAF-16, HSF-1, SKN-1, and HIF-1, but not SIR-2.1. Taken together, CGA might extend the lifespan of C. elegans mainly via DAF-16 in insulin/IGF-1 signaling pathway., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The abrogation of the germ cells in Caenorhabditis elegans (C. elegans) by either genetic means or cell ablation results in about 60% increase of longevity. Upon the inhibition of germline stem cell proliferation, certain signaling molecules inhibit the target of rapamycin (TOR), activate the transcription factors including DAF-16, DAF-12, and PHA-4, leading to altered fatty acid lipolysis, autophagy, stress resistance, and the extended lifespan. But the exact cascades and interactions of those signaling pathways are still obscure. To understand how the reproductive system affects aging at the protein level, we determined the protein expression profile of the long-lived temperature-sensitive mutant glp-1(e2141) and wild-type N2 using isobaric tags for relative and absolute quantitation (iTRAQ) technology. Our results showed that the abundance of proteins relevant to transcription, RNA processing, translation, protein folding, and proteolytic process were decreased, while collagen proteins and proteins involved in detoxification and innate immune responses were increased in C. elegans glp-1 mutant, these alterations of protein abundance might attenuate protein metabolism and enhance immune response and stress resistance, and finally contribute to germline-mediated longevity., Biological Significance: This study provides an overview of the altered protein expression upon germline ablation. Germ-cell loss results in decreased abundance of proteins involved in protein synthesis and breakdown, and increased abundance of proteins involved in detoxification and immune response, suggesting that protein synthesis and metabolism might be attenuated, while detoxification and immune responses might be increased. The altered protein abundance might result in physiological adaptations that contribute to extended longevity in germline-deficient C. elegans. This study brings new light on the role of reproductive control of lifespan., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In Caenorhabditis elegans (C. elegans) , ablation of germline stem cells (GSCs) leads to infertility, which extends lifespan. It has been reported that aging and reproduction are both inextricably associated with metabolism. However, few studies have investigated the roles of polar small molecules metabolism in regulating longevity by reproduction. In this work, we combined the nuclear magnetic resonance (NMR) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to profile the water-soluble metabolome in C. elegans . Comparing the metabolic fingerprint between two physiological ages among different mutants, our results demonstrate that aging is characterized by metabolome remodeling and metabolic decline. In addition, by analyzing the metabolic profiles of long-lived germline-less glp-1 mutants, we discovered that glp-1 mutants regulate the levels of many age-variant metabolites to attenuate aging, including elevated concentrations of the pyrimidine and purine metabolism intermediates and decreased concentrations of the citric acid cycle intermediates. Interestingly, by analyzing the metabolome of daf-16;glp-1 double mutants, our results revealed that some metabolic exchange contributing to germline-mediated longevity was mediated by transcription factor FOXO/DAF-16, including pyrimidine metabolism and the TCA cycle. Based on a comprehensive metabolic analysis, we provide novel insight into the relationship between longevity and metabolism regulated by germline signals in C. elegans .

With the growth of aging population, there is increasing demand to develop strategy to improve the aging process and aging-related diseases. Benzimidazole and its derivatives are crucial heterocyclic backbone of many drugs and compounds with diverse therapeutic applications, including alleviation of aging-related diseases. Here, we investigate if the benzimidazole derivative n-butyl-[1H]-benzimidazol-2-amine (M084), a novel inhibitor of TRPC4 and TRPC5 channels and antidepressant, could affect the lifespan of Caenorhabditis elegans (C. elegans). Our results showed that M084 could extend the lifespan of C. elegans, delay age-related decline of phenotypes, and improve stress resistance. M084 could not extend the lifespan of the loss-of-function mutants of daf-16, daf-2, pdk-1, aak-2, clk-1, isp-1, sir-2.1, and skn-1. M084 could decrease the ATP level and increase the gene expression of mitochondrial unfolded protein response factors. Thus, M084 might inhibit the mitochondrial respiration, activate mitochondrial unfolded protein response and AMPK, recruite SIR-2.1 and SKN-1, and finally through the transcription factor DAF-16, delay the aging process of C. elegans. Our findings reveal the new pharmaceutical potential of benzimidazole derivatives and provide clue for developing novel anti-aging agents.

Aspirin has been revealed to have many beneficial effects for health since it was discovered as a nonsteroidal anti-inflammatory drug (NSAID) to treat pain and inflammation. Here, we investigated the molecular mechanism of aspirin on the lifespan extension of Caenorhabditis elegans. Our results showed that aspirin could extend the lifespan of C. elegans, and increase its health span and stress resistance. The extension of lifespan by aspirin requires DAF-16/FOXO, AMPK, and LKB1, but not SIR-2.1. Aspirin could not extend the lifespan of the mutants of eat-2, clk-1, and isp-1. Aspirin could marginally extend the lifespan of long-live insulin-like receptor mutant daf-2(e1370) III. Taken together, aspirin might act through a dietary restriction-like mechanism, via increasing the AMP:ATP ratio and activating LKB1, subsequently activating AMPK, which stimulates DAF-16 to induce downstream effects through a DAF-16 translocation independent manner., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Caenorhbditis elegans has being vigorously used as a model organism in many research fields and often accompanied by administrating with various drugs. The methods of delivering drugs to worms are varied from one study to another, which make difficult in comparing results between studies., Methodology/principal Findings: We evaluated the drug absorption efficiency in C. elegans using five frequently used methods with resveratrol with low aqueous solubility and water-soluble 5-Fluoro-2'-deoxyuridine (FUDR) as positive compounds. The drugs were either applied to the LB medium with bacteria OP50, before spreading onto Nematode Growth Medium (NGM) plates (LB medium method), or to the NGM with live (NGM live method) or dead bacteria (NGM dead method), or spotting the drug solution to the surface of plates directly (spot dead method), or growing the worms in liquid medium (liquid growing method). The concentration of resveratrol and FUDR increased gradually within C. elegans and reached the highest during 12 hours to one day and then decreased slowly. At the same time point, the higher the drug concentration, the higher the metabolism rate. The drug concentrations in worms fed with dead bacteria were higher than with live bacteria at the same time point. Consistently, the drug concentration in medium with live bacteria decreased much faster than in medium with dead bacteria, reach to about half of the original concentration within 12 hours., Conclusion: Resveratrol with low aqueous solubility and water-soluble FUDR have the same absorption and metabolism pattern. The drug metabolism rate in worms was both dosage and time dependent. NGM dead method and liquid growing method achieved the best absorption efficiency in worms. The drug concentration within worms was comparable with that in mice, providing a bridge for dose translation from worms to mammals.

Aging is a process characterized by accumulating degenerative damages, resulting in the death of an organism ultimately. The main goal of aging research is to develop therapies that delay age-related diseases in human. Since signaling pathways in aging of Caenorhabditis elegans ( C. elegans), fruit flies and mice are evolutionarily conserved, compounds extending lifespan of them by intervening pathways of aging may be useful in treating age-related diseases in human. Natural products have special resource advantage and with few side effect. Recently, many compounds or extracts from natural products slowing aging and extending lifespan have been reported. Here we summarized these compounds or extracts and their mechanisms in increasing longevity of C. elegans or other species, and the prospect in developing anti-aging medicine from natural products. [ABSTRACT FROM AUTHOR]

Coffee and tea, two of the most popular drinks around the world, share many in common from chemical components to beneficial effects on human health. One of their shared components, the polyphenols, most notably chlorogenic acid (CGA), was supposed to account for many of the beneficial effects on ameliorating diseases occurred accompanying people aging, such as the antioxidant effect and against diabetes and cardiovascular disease. CGA is also present in many traditional Chinese medicines. However, the mechanism of these effects was vague. The aging signaling pathways were conservative from yeast and worms to mammals. So, we tested if CGA had an effect on aging in Caenorhabditis elegans. We found that CGA could extend the lifespan of C. elegans by up to 20.1%, delay the age-related decline of body movement, and improve stress resistance. We conducted genetic analysis with a series of worm mutants and found that CGA could extend the lifespan of the mutants of eat-2, glp-1, and isp-1, but not of daf-2, pdk-1, akt-1, akt-2, sgk-1, and clk-1. CGA could activate the FOXO transcription factors DAF-16, HSF-1, SKN-1, and HIF-1, but not SIR-2.1. Taken together, CGA might extend the lifespan of C. elegans mainly via DAF-16 in insulin/IGF-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Caenorhbditis elegans has being vigorously used as a model organism in many research fields and often accompanied by administrating with various drugs. The methods of delivering drugs to worms are varied from one study to another, which make difficult in comparing results between studies. Methodology/Principal Findings: We evaluated the drug absorption efficiency in C. elegans using five frequently used methods with resveratrol with low aqueous solubility and water-soluble 5-Fluoro-2′-deoxyuridine (FUDR) as positive compounds. The drugs were either applied to the LB medium with bacteria OP50, before spreading onto Nematode Growth Medium (NGM) plates (LB medium method), or to the NGM with live (NGM live method) or dead bacteria (NGM dead method), or spotting the drug solution to the surface of plates directly (spot dead method), or growing the worms in liquid medium (liquid growing method). The concentration of resveratrol and FUDR increased gradually within C. elegans and reached the highest during 12 hours to one day and then decreased slowly. At the same time point, the higher the drug concentration, the higher the metabolism rate. The drug concentrations in worms fed with dead bacteria were higher than with live bacteria at the same time point. Consistently, the drug concentration in medium with live bacteria decreased much faster than in medium with dead bacteria, reach to about half of the original concentration within 12 hours. Conclusion: Resveratrol with low aqueous solubility and water-soluble FUDR have the same absorption and metabolism pattern. The drug metabolism rate in worms was both dosage and time dependent. NGM dead method and liquid growing method achieved the best absorption efficiency in worms. The drug concentration within worms was comparable with that in mice, providing a bridge for dose translation from worms to mammals. [ABSTRACT FROM AUTHOR]