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Exploring the anti-aging effects of chlorogenic acid and the underlying mechanisms based on a Caenorhabditis elegans model
Abstract
Objective: To explore the anti-aging effects of chlorogenic acid (CGA) and the underlying mechanisms based on a Caenorhabditis elegans (C. elegans) model. Methods: The anti-aging activity of CGA was studied based on the body length, exercise behavior, lipofuscin content, antioxidative stress ability, swallowing frequency, body-bending frequency, and head-swinging ability of C. elegans. Through DAF-16 nuclear translocation and SOD-3-GFP fluorescence experiments, the effects of CGA on ROS levels, antioxidant enzyme activities, MDA content, mutant-strain lifespan, and anti-aging molecular signaling pathways were explored, as well as the underlying mechanisms. Results: CGA improved multiple indices of the nematode: body length was increased (all P
... CGA can serve as a potential chemical chaperone and drug candidate for treatment of aggregation disorders. Recently the anti-aging potential of CGA has been observed [75]. Interaction Analysis of BSA, cyt c, and CGA Using Molecular Docking ...
Neurodegenerative disorders are associated with the accumulation of disease-related proteins intracellularly and extracellularly. Extracellular chaperones play a crucial role in clearing the extracellularly accumulated proteins. In this study, we observed the extracellular chaperone-like potential of BSA at physiological concentrations on model protein cytochrome c (cyt c). Kinetics of heat-induced aggregation of cyt c suggest the nucleation independent first order aggregation kinetics. Aggregation of cyt c was studied in the presence of varying concentrations of BSA to assess its chaperone nature. At lower concentrations of BSA when the sub molar ratio of cyt c:BSA are 1:0.6 and 1:1.2, heat-induced unfolded cyt c promotes the aggregation of BSA. However, as the ratio of cyt c:BSA increases to 1:1.8, the aggregation of cyt c is reduced. When the concentration of BSA reaches physiological levels, yielding a cyt c:BSA ratio of 1:2.4, the rate of aggregation drastically decreases reflecting its chaperone potential. These observations indicate that under physiological conditions, macromolecular crowding stabilizes the native structure of both proteins and enhances their interaction that results in the reduced aggregation of cyt c. Additionally, the presence of the phytochemical chlorogenic acid at a sub-molar ratio of 1:1 stabilizes cyt c and prevents its unfolding and facilitates the binding of cyt c to BSA at physiological concentrations. This interaction further decreases the overall aggregation of cyt c and stabilizes its native fold.
Aspirin and curcumin have been reported beneficial in anti-aging in a variety of biological models. Here, we synthesized a novel compound, curcumin acetylsalicylate (CA), by combining aspirin and curcumin. We characterized how CA affects the lifespan of Caenorhabditis elegans (C. elegans) worms. Our results demonstrated that CA extended the lifespan of worms in a dose-dependent manner and reached its most important anti-aging effect at the concentration of 20 μM. In addition, CA reduced the deposition of lipofuscin or “age pigment” without affecting the reproductivity of worms. CA also caused a rightward shift of C. elegans lifespan curves in the presence of paraquat-induced (5 mM) oxidative stress or 37 °C acute heat shock. Additionally, CA treatment decreased the reactive oxygen species (ROS) level in C. elegans and increased the expression of downstream genes superoxide dismutase (sod)-3, glutathione S-transferase (gst)-4, heat shock protein (hsp)-16.2, and catalase-1 (ctl-1). Notably, CA treatment resulted in nuclear translocation of the DAF-16 transcription factor, which is known for the stimulation of the expression of SOD-3, GST-4, HSP-16, and CTL-1. CA did not produce a longevity effect in daf-16 mutants. In sum, our data indicate that CA delayed the aging of C. elegans without affecting reproductivity, and this effect may be mediated by its activation of DAF-16 and subsequent expressions of antioxidative genes, such as sod-3 and gst-4. Our study suggests that novel anti-aging drugs may be developed by combining two individual drugs.
Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS, it follows that GSH and its precursor, N-acetyl cysteine (NAC), are among the most popular dietary supplements. However, the long- term effects of GSH or NAC on healthy animals have not been thoroughly investigated. We employed C. elegans to demonstrate that chronic administration of GSH or NAC to young or aged animals perturbs global gene expression, inhibits skn-1 -mediated transcription, and accelerates aging. In contrast, limiting the consumption of dietary thiols, including those naturally derived from the microbiota, extended lifespan. Pharmacological GSH restriction activates the unfolded protein response and increases proteotoxic stress resistance in worms and human cells. It is thus advantageous for healthy individuals to avoid excessive dietary antioxidants and, instead, rely on intrinsic GSH biosynthesis, which is fine-tuned to match the cellular redox status and to promote homeostatic ROS signaling.
Aging is associated with functional and structural declines in organisms over time. Organisms as diverse as the nematode Caenorhabditis elegans and mammals share signaling pathways that regulate aging and lifespan. In this review, we discuss recent combinatorial approach to aging research employing C. elegans and mammalian systems that have contributed to our understanding of evolutionarily conserved aging-regulating pathways. The topics covered here include insulin/IGF-1, mechanistic target of rapamycin (mTOR), and sirtuin signaling pathways; dietary restriction; autophagy; mitochondria; and the nervous system. A combinatorial approach employing high-throughput, rapid C. elegans systems, and human model mammalian systems is likely to continue providing mechanistic insights into aging biology and will help develop therapeutics against age-associated disorders.
Previous studies have revealed the importance of inter-tissue communications for lifespan regulation. However, the inter-tissue network responsible for lifespan regulation is not well understood, even in a simple organism Caenorhabditis elegans. To understand the mechanisms underlying systemic lifespan regulation, we focused on lifespan regulation by the insulin/IGF-1 signaling(IIS) pathway; IIS reduction activates the DAF-16/FOXO transcription factor, which results in lifespan extension. Our tissue-specific knockdown and knockout analyses demonstrated that IIS reduction in neurons and the intestine markedly extended lifespan. DAF-16 activation in neurons resulted in DAF-16 activation in the intestine, and vice versa. Our dual gene manipulation method revealed that intestinal and neuronal DAF-16 mediate longevity induced by daf-2 knockout in neurons and the intestine, respectively. In addition, the systemic regulation of intestinal DAF-16 required the IIS pathway in intestinal and neurons. Collectively, these results highlight the importance of the neuronal DAF-16-to-intestinal DAF-16 communication for organismal lifespan regulation.
The study of antioxidants and their implications in various fields, from food engineering to medicine and pharmacy, is of major interest to the scientific community. The present paper is a critical presentation of the most important tests used to determine the antioxidant activity, detection mechanism, applicability, advantages and disadvantages of these methods. Out of the tests based on the transfer of a hydrogen atom, the following were presented: the Oxygen Radical Absorption Capacity (ORAC) test, the Hydroxyl Radical Antioxidant Capacity (HORAC) test, the Total Peroxyl Radical Trapping Antioxidant Parameter (TRAP) test, and the Total Oxyradical Scavenging Capacity (TOSC) test. The tests based on the transfer of one electron include the Cupric Reducing Antioxidant Power (CUPRAC) test, the Ferric Reducing Antioxidant Power (FRAP) test, the Folin–Ciocalteu test. Mixed tests, including the transfer of both a hydrogen atom and an electron, include the 2,2′-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) test, and the [2,2-di(4-tert-octylphenyl)-1 -picrylhydrazyl] (DPPH) test. All these assays are based on chemical reactions and assessing the kinetics or reaching the equilibrium state relies on spectrophotometry, presupposing the occurrence of characteristic colours or the discolouration of the solutions to be analysed, which are processes monitored by specific wavelength adsorption. These assays were successfully applied in antioxidant analysis or the determination of the antioxidant capacity of complex samples. As a complementary method in such studies, one may use methods based on electrochemical (bio)sensors, requiring stages of calibration and validation. The use of chemical methods together with electrochemical methods may result in clarification of the operating mechanisms and kinetics of the processes involving several antioxidants.
The broccoli-derived isothiocyanate sulforaphane inhibits inflammation, oxidative stress and cancer, but its effect on healthspan and longevity are unclear. We used the C. elegans nematode model and fed the wildtype and 9 mutant strains ±sulforaphane. The lifespan, phenotype, pharyngeal pumping, mobility, lipofuscin accumulation, and RNA and protein expression of the nematodes were assessed by using Kaplan-Meier survival analysis, in vivo live imaging, fluorescence microscopy, and qRT-PCR. Sulforaphane increased the lifespan and promoted a health-related phenotype by increasing mobility, appetite and food intake and reducing lipofuscin accumulation. Mechanistically, sulforaphane inhibited DAF-2-mediated insulin/insulin-like growth factor signaling and its downstream targets AGE-1, AKT-1/AKT-2. This was associated with increased nuclear translocation of the FOXO transcription factor homolog DAF-16. In turn, the target genes sod-3, mtl-1 and gst-4, known to enhance stress resistance and lifespan, were upregulated. These results indicate that sulforaphane prolongs the lifespan and healthspan of C. elegans through insulin/IGF-1 signaling. Our results provide the basis for a nutritional sulforaphane-enriched strategy for the promotion of healthy aging and disease prevention.
Background
Momordica saponin extract (MSE) was found to not only improve longevity and neuroprotection but also alleviate fat accumulation in Caenorhabditis elegans in our previous study. However, the lipid-lowering activity of MSE alone could not fully explain its ability to improve health, so the antistress effects of MSE were further studied.Methods
Using C. elegans as an in vivo animal, the lifespan of MSE-treated C. elegans under various stressors (H2O2, paraquat and heat) and normal conditions was studied. Furthermore, the antioxidant activities of MSE were discussed. To study the underlying mechanisms, the expression of stress resistance genes and the resistance of related mutants to H2O2 stress were tested.ResultsMSE significantly improved the lifespan of C. elegans under stress and normal conditions. Meanwhile, the mobility of C. elegans was also improved. Moreover, the activities of SOD and CAT and the ratio of GSH/GSSG were elevated. Consistently, the levels of ROS and lipid oxidation (the NEFA and MDA content) were reduced. Furthermore, MSE treatment upregulated the expression of the sod-3, sod-5, clt-1, clt-2, hsp-16.1 and hsp-16.2 genes. All biomarkers indicated that the antistress and anti-aging activities of MSE were due to its strong antioxidant activities. Finally, MSE induced nuclear DAF-16::GFP localization. Studies with mutants revealed that skn-1 and hsf-1 were involved in the activity of MSE, which might upregulate the expression of downstream stress-responsive genes.Conclusions
Therefore, in addition to its lipid-lowering property, the ability of MSE to improve healthspan was also attributed to the stress resistance effect. Together, MSE might serve as a lead nutraceutical in geriatric research.
DAF-16, the only forkhead box transcription factors class O (FoxO) homolog in Caenorhabditis elegans, integrates signals from upstream pathways to elicit transcriptional changes in many genes involved in aging, development, stress, metabolism, and immunity. The major regulator of DAF-16 activity is the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway, reduction of which leads to lifespan extension in worms, flies, mice, and humans. In C. elegans daf-2 mutants, reduced IIS leads to a heterochronic activation of a dauer survival program during adulthood. This program includes elevated antioxidant defense and a metabolic shift toward accumulation of carbohydrates (i.e., trehalose and glycogen) and triglycerides, and activation of the glyoxylate shunt, which could allow fat-to-carbohydrate conversion. The longevity of daf-2 mutants seems to be partially supported by endogenous trehalose, a nonreducing disaccharide that mammals cannot synthesize, which points toward considerable differences in downstream mechanisms by which IIS regulates aging in distinct groups.
Background
Accumulation of various damages is considered the primary cause of aging throughout the history of gerontology. No progress has been made in extending animal lifespan under guidance of this concept. This concept denies existence of longevity genes, but it has been experimentally shown that manipulating genes that affect cell division rates can increase the maximum lifespan of animals. These methods of prolonging life are unsuitable for humans because of dangerous side effects, but they undoubtedly indicate the programed nature of aging.
Objective
The objective was to understand the mechanism of programed aging to determine how to solve the problem of longevity.
Methods
Fundamental research has already explored key details relating to the mechanism of programed aging, but they are scattered across different fields of knowledge. The way was to recognize and combine them into a uniform mechanism.
Results
Only a decrease in bioenergetics is under direct genetic control. This causes many different harmful processes that serve as the execution mechanism of the aging program. The aging rate and, therefore, lifespan are determined by the rate of cell proliferation and the magnitude of the decrease in bioenergetics per cell division in critical tissues.
Conclusion
The mechanism of programed aging points the way to achieving unlimited healthy life: it is necessary to develop a means for managing bioenergetics. More concrete, we have to modify mitochondrial mechanism that controls the [ATP]/[ADP] level. It has already been substantially studied by molecular biologists and is now waiting for researchers from gerontology.
Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder resulting from the accumulation of toxic β-amyloid (Aβ) aggregates in the human brain. Epidemiological studies have shown that elevated cholesterol plasma levels are associated with the development of AD and we have previously shown that cholesterol restriction reduces the Aβ-induced paralysis in an Alzheimer model of the nematode Caenorhabditis elegans. In the present study we investigated the effects of the cholesterol homolog cholecalciferol, i.e. vitamin D, on Aβ-induced paralysis in C. elegans and its interference with the steroid-signaling pathway.
Methods: Aβ-induced paralysis was assessed in the C. elegans strain CL2006, expressing human Aβ1-42 under control of a muscle-specific promoter. Knockdown of members of the steroid-signaling pathway was achieved by RNA interference (RNAi). Nuclear translocation of foxo transcription factor DAF-16 was visualized using the strain TJ356, carrying a daf-16::gfp transgene.
Results: Cholecalciferol at a concentration of 1 µM reduced the Aβ-induced paralysis in CL2006 significantly, which was reverted by increasing the cholesterol concentration in the medium. Knockdown of nhr-8, daf-36, daf-9 or daf-12, all reduced Aβ-induced paralysis to the same extent as cholecalciferol with no additional or synergistic effects under co-application. Functional DAF-16 proved to be crucial for the effects of cholecalciferol and DAF-16 nuclear translocation was increased by cholecalciferol and also RNAi versus nhr-8, daf-36, daf-9 or daf-12 with no additive or synergistic effects.
Conclusions: Our results suggest, that cholecalciferol inhibits Aβ-induced paralysis in C. elegans through inhibition of steroid-signaling and the concomitant nuclear translocation of DAF-16.
Caenorhabditis elegans is an exceptionally valuable model for aging research because of many advantages, including its genetic tractability, short lifespan, and clear age‐dependent physiological changes. Aged C. elegans display a decline in their anatomical and functional features, including tissue integrity, motility, learning and memory, and immunity. Caenorhabditis elegans also exhibit many age‐associated changes in the expression of microRNAs and stress‐responsive genes and in RNA and protein quality control systems. Many of these age‐associated changes provide information on the health of the animals and serve as valuable biomarkers for aging research. Here, we review the age‐dependent changes in C. elegans and their utility as aging biomarkers indicative of the physiological status of aging.
Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degen-eration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age-related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidences suggest that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality. Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy-dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise-induced TORC1 and autophagy signaling share common pathways with that of CR. Therefore , the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity. K E Y W O R D S aging, autophagy, caloric restriction, exercise, mTOR, physical activity
Phenolic acids have recently gained substantial attention due to their various practical, biological and pharmacological effects. Chlorogenic Acid (CGA, 3-CQA) is a most abundant isomer among caffeoylquinic acid isomers (3-, 4-, and 5-CQA), that currently known as 5-CQA as per guidelines of IUPAC. It is one of the most available acids among phenolic acid compounds which can be naturally found in green coffee extracts and tea. CGA is an important and biologically active dietary polyphenol, playing several important and therapeutic roles such as antioxidant activity, antibacterial, hepatoprotective, cardioprotective, anti-inflammatory, antipyretic, neuroprotective, anti-obesity, antiviral, anti-microbial, anti-hypertension, free radicals scavenger and a central nervous system (CNS) stimulator. In addition, it has been found that CGA could modulate lipid metabolism and glucose in both genetically and healthy metabolic related disorders. It is speculated that CGA can perform crucial roles in lipid and glucose metabolism regulation and thus help to treat many disorders such as hepatic steatosis, cardiovascular disease, diabetes, and obesity as well. Furthermore, this phenolic acid (CGA) causes hepatoprotective effects by protecting animals from chemical or lipopolysaccharide-induced injuries. The hypocholesterolemic influence of CGA can result from the altered metabolism of nutrients, including amino acids, glucose and fatty acids (FA). The purpose of this review was to broaden the scope of knowledge of researchers to conduct more studies on this subject to both unveil and optimize its biological and pharmacological effects. As a result, CGA may be practically used as a natural safeguard food additive to replace the synthetic antibiotics and thereby reduce the medicinal cost.
Chlorogenic acid (5-O-caffeoylquinic acid) is a phenolic compound fromthe hydroxycinnamic
acid family. This polyphenol possesses many health-promoting properties, most of them related to the
treatment of metabolic syndrome, including anti-oxidant, anti-inflammatory, antilipidemic, antidiabetic,
and antihypertensive activities. The first part of this review will discuss the role of chlorogenic acid
as a nutraceutical for the prevention and treatment of metabolic syndrome and associated disorders,
including in vivo studies, clinical trials, and mechanisms of action. The second part of the review
will be dealing with the role of chlorogenic acid as a food additive. Chlorogenic acid has shown
antimicrobial activity against a wide range of organisms, including bacteria, yeasts, molds, viruses,
and amoebas. These antimicrobial properties can be useful for the food industry in its constant search
for new and natural molecules for the preservation of food products. In addition, chlorogenic acid has
antioxidant activity, particularly against lipid oxidation; protective properties against degradation
of other bioactive compounds present in food, and prebiotic activity. The combination of these
properties makes chlorogenic acid an excellent candidate for the formulation of dietary supplements
and functional foods.
Aging and cancer are the most important issues to research. The population in the world is growing older, and the incidence of cancer increases with age. There is no doubt about the linkage between aging and cancer. However, the molecular mechanisms underlying this association are still unknown. Several lines of evidence suggest that the oxidative stress as a cause and/or consequence of the mitochondrial dysfunction is one of the main drivers of these processes. Increasing ROS levels and products of the oxidative stress, which occur in aging and age-related disorders, were also found in cancer. This review focuses on the similarities between ageing-associated and cancer-associated oxidative stress and mitochondrial dysfunction as their common phenotype.
Advances in research and technology has increased our quality of life, allowed us to combat diseases, and achieve increased longevity. Unfortunately, increased longevity is accompanied by a rise in the incidences of age-related diseases such as Alzheimer’s disease (AD). AD is the sixth leading cause of death, and one of the leading causes of dementia amongst the aged population in the USA. It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively. Despite years of extensive research, the molecular mechanisms that underlie the pathology of AD remain unclear. Model organisms, such as the nematode, Caenorhabditis elegans, present a complementary approach to addressing these questions. C. elegans has many advantages as a model system to study AD and other neurodegenerative diseases. Like their mammalian counterparts, they have complex biochemical pathways, most of which are conserved. Genes in which mutations are correlated with AD have counterparts in C. elegans, including an APP-related gene, apl-1, a tau homolog, ptl-1, and presenilin homologs, such as sel-12 and hop-1. Since the neuronal connectivity in C. elegans has already been established, C. elegans is also advantageous in modeling learning and memory impairments seen during AD. This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases. Additionally, we explore the advantages and drawbacks associated with using this model.
The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. 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. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease.
The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway. One of two isoforms, DAF-16a, is known to regulate longevity, stress response and dauer diapause. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.
Caenorhabditis elegans has recently been developed as a model for microbial pathogenesis, yet little is known about its immunological defenses. Previous work implicated insulin signaling in mediating pathogen resistance in a manner dependent on the transcriptional regulator DAF-16, but the mechanism has not been elucidated. We present evidence that C. elegans, like mammalian phagocytes, produces reactive oxygen species (ROS) in response to pathogens. Signs of oxidative stress occur in the intestine - the site of the host-pathogen interface - suggesting that ROS release is localized to this tissue. Evidence includes the accumulation of lipofuscin, a pigment resulting from oxidative damage, at this site. In addition, SOD-3, a superoxide dismutase regulated by DAF-16, is induced in intestinal tissue after exposure to pathogenic bacteria. Moreover, we show that the oxidative stress response genes sod-3 and ctl-2 are required for DAF-16-mediated resistance to Enterococcus faecalis using a C. elegans killing assay. We propose a model whereby C. elegans responds to pathogens by producing ROS in the intestine while simultaneously inducing a DAF-16-dependent oxidative stress response to protect adjacent tissues. Because insulin-signaling mutants overproduce oxidative stress response enzymes, the model provides an explanation for their increased resistance to pathogens.
Objectives
Parkinson’s disease (PD) is the second most common neurodegenerative disease. Chlorogenic acid (CGA) is a polyphenolic substance derived from various medicinal plants. Although CGA is reported to have potential anti-PD effect, the beneficial effect and the underlying mechanism remain unclear. In this study, we aimed to further investigate the protective effect and clarify the mechanism of action of CGA in Caenorhabditis elegans (C. elegans) models of PD.
Methods
Measurements of a-synuclein aggregation, movement disorders, and lipid, ROS and malondialdehyde (MDA) contents were observed in NL5901 nematodes. Determinations of dopamine (DA) neuron degeneration, food perception, and ROS content were performed in 6-OHDA-exposed BZ555 nematodes. The autophagy activation of CGA was monitored using DA2123 and BC12921 nematodes. Meanwhile, RNAi technology was employed to knockdown the autophagy-related genes and investigate whether the anti-PD effect of CGA was associated with autophagy induction in C. elegans.
Results
CGA significantly reduced α-synuclein aggregation, improved motor disorders, restored lipid content, and decreased ROS and MDA contents in NL5901 nematodes. Meanwhile, CGA inhibited DA neuron-degeneration and improved food-sensing behavior in 6-OHDA-exposed BZ555 nematodes. In addition, CGA increased the number of GFP::LGG-1 foci in DA2123 nematodes and degraded p62 protein in BC12921 nematodes. Meanwhile, CGA up-regulated the expression of autophagy-related genes in NL5901 nematodes. Moreover, the anti-PD effect of CGA was closely related to autophagy induction via increasing the expression of autophagy-related genes, including unc-51, bec-1, vps-34, and lgg-1.
Conclusions
The present study indicates that CGA exerts neuroprotective effect in C. elegans via autophagy induction.
Chlorogenic acid (CGA) is a strong phenolic antioxidant with antibacterial properties composed by a caffeoyl ester of quinic acid. Although a number of benefits has been reported and related to interactions with the red blood cell membranes, details on its membrane action and how composition and membrane state may affect it, is not yet well defined.
In this work, the interaction of CGA with lipid monolayers and bilayers composed by 1,2-dimiristoyl-sn-glycero-3-phosphocholine (DMPC); 1,2-di-O-tetradecyl-sn-glycero-3-phosphocholine (14:0 diether PC); 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-di-O-hexadecyl-sn-glycero-3-phosphocholine (16:0 diether PC) were studied at different surface pressures (π). The kinetics of interaction was found to be more rapid in DMPC than in the absence of carbonyl groups. Measurements by FTIR-ATR at different water activities confirm specific interactions of CGA with carbonyl and phosphate groups affecting water level along hydrocarbon region.
The antioxidant activity of CGA in the presence of DMPC unilamellar vesicles, evidenced by the absorbance reduction of the radical cation ABTS•+, is significantly different with respect to aqueous solution. The influence of CGA on antiradical activity (ARA) with lipid membranes depending on the hydration state of the lipid interface is discussed.
Chlorogenic acid is a widely distributed natural compound with many important pharmacological effects, which are found in a variety of plants. It is also an important secondary metabolite in plants. As a natural plant extract from a wide range of sources, in vitro and in vivo studies have found that the main pharmacological effects of chlorogenic acid are antioxidant, antiinflammatory, antibacterial, antiviral, hypoglycemic, lipid lowering, anticardiovascular, antimutagenic, anticancer, immunomodulatory, etc. Therefore it may play an important role in promoting human health. For example, it can provide new ideas and new ways for the prevention and treatment of cardiovascular disease, cancer, diabetes, and other chronic diseases, but the specific mechanism of action is unclear. Due to the difficulty of extraction and purification, poor stability, poor solubility, low absolute bioavailability of oral administration, the possibility of allergies caused by injection, and so on, there are difficulties in its medicinal research and development. The further study of chlorogenic acid will provide an important theoretical basis for its rational use.
Aging is the main risk factor for chronic diseases and disablement in human societies with a great impact in social and health care expenditures. So far, aging and, eventually, death are unavoidable. Nevertheless, research efforts on aging-associated diseases with the aim not only to extend life span but also to increment health span in an attempt to delay, stop and even reverse the aging process have not stopped growing. Caloric restriction extends both health and life span in several short-lived experimental models and has brought to light the role of different molecular effectors involved in nutrient sensing pathways and longevity. This opens the possibility of modulating these molecular effectors also in humans to increase longevity and health span. The difficulty to implement caloric restricted diets in humans has led to the development of new bearable diets such as time-restricted feeding, intermittent fasting or diets with limited amounts of some nutrients and to the search of pharmacological agents, targeted to the effectors that mediate the extension of life and health span in response to these anti-aging diets. Pharmacological approaches that eliminate senescent cells or prevent primary causes of aging such as telomere attrition also emerge as potential anti-aging strategies. In the present article, we review these possible nutritional and pharmacological interventions designed to mitigate and/or delay the aging process and to increase health and life span.
Cyclocarya paliurus polysaccharide (CPP) has many beneficial biological activities. Although the antioxidant activity of CPP is well-known, the stress tolerance and underlying mechanism of the activities of CPP have not been determined in vivo. In this study, we applied the emerging model of Caenorhabditis elegans (C. elegans) to observe that CPP imparted stronger resistance to stress than the positive control Astragalus polysaccharide (H2O2- and paraquat-induced oxidative stress, as well as heat stress) without threatening the growth and reproduction of worms. Further studies found that CPP-treated worms had a strong antioxidant defense system that downregulated peroxidation products (ROS, MDA, NEFAs and GSSG) and upregulated antioxidant enzymes and nonenzymatic activities (SOD, CAT, GSH-Px and GSH). The CPP-treated worms also exhibited improved physiological functions, such as inhibition of age pigment and improvement of lifespan, mobility and neuroprotection. Further exploration of the mechanism of action of CPP treatment suggested that increased resistance to CPP might activate stress-inducible genes (sod-3, sod-5, ctl-1, ctl-2, hsp-16.1 and hsp-16.2) via skn-1 and hsf-1, rather than daf-16. These findings suggest that CPP may have health benefits for humans.
The beneficial effects promoted from the use of biomolecular substances into the formulations of personal care products are considered useful ingredients in cosmetic and therapeutic applications. Innovations in cosmetics are based on new bioactive formulations such as vitamins, oils, peptides, and protein hydrolysates. In skin care, the monomeric amino acids such as serine, threonine, alanine are common ingredients in cosmetics as they function as natural moisturizing factors which act as water-binding molecules. Amino acids and their salts e.g., arginine, glycine, etc. are also used as hair- and skin-conditioning agents in cosmetic formulations. The peptides are composed of short chain of amino acids and are used in cosmetics due to their numerous pathophysiological properties including anti-aging. There is growing interest in bioactive peptides in products for stimulating collagen and elastin synthesis in skin and improve surface healing. The main benefit of using proteins in cosmeceuticals is to improve the hydration of skin. Proteins increase the dehydration in the skin which helps to reduce wrinkles and improves the functions of the skin barrier. This review article describes the peptides, proteins that are most frequently used in cosmeceuticals and their potential benefits and practical use in cosmetic science and skincare.
The increase in life expectancy has boosted the incidence of age-related pathologies beyond social and economic sustainability. Consequently, there is an urgent need for interventions that revert or at least prevent the pathogenic age-associated deterioration. The permanent or periodic reduction of calorie intake without malnutrition (caloric restriction and fasting) is the only strategy that reliably extends healthspan in mammals including non-human primates. However, the strict and life-long compliance with these regimens is difficult, which has promoted the emergence of caloric restriction mimetics (CRMs). We define CRMs as compounds that ignite the protective pathways of caloric restriction by promoting autophagy, a cytoplasmic recycling mechanism, via a reduction in protein acetylation. Here, we describe the current knowledge on molecular, cellular, and organismal effects of known and putative CRMs in mice and humans. We anticipate that CRMs will become part of the pharmacological armamentarium against aging and age-related cardiovascular, neurodegenerative, and malignant diseases.
Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.
Caenorhabditis elegans (C. elegans) is a free-living nematode that has been extensively utilized as an animal model for research involving aging and neurodegenerative diseases, like Alzheimer's and Parkinson's, etc. Compared with traditional animal models, this small nematode possesses many benefits, such as small body size, short lifespan, completely sequenced genome and more than 65% of the genes associated with humans. All these characteristics make this organism an ideal living system for obesity and aging studies. This review gives a brief introduction of C. elegans as an animal model, highlights some advantages of research using this model and describes some methods to evaluate the effect of treatments on obesity and aging of this organism.
Lipofuscin (age pigment) is a brown-yellow, electron-dense, autofluorescent material that accumulates progressively over time in lysosomes of postmitotic cells, such as neurons and cardiac myocytes. The exact mechanisms behind this accumulation are still unclear. This review outlines the present knowledge of age pigment formation, and considers possible mechanisms responsible for the increase of lipofuscin with age. Numerous studies indicate that the formation of lipofuscin is due to the oxidative alteration of macromolecules by oxygen-derived free radicals generated in reactions catalyzed by redox-active iron of low molecular weight. Two principal explanations for the increase of lipofuscin with age have been suggested. The first one is based on the notion that lipofuscin is not totally eliminated (either by degradation or exocytosis) even at young age, and, thus, accumulates in postmitotic cells as a function of time. Since oxidative reactions are obligatory for life, they would act as age-independent enhancers of lipofuscin accumulation, as well as of many other manifestations of senescence. The second explanation is that the increase of lipofuscin is an effect of aging, caused by an age-related enhancement of autophagocytosis, a decline in intralysosomal degradation, and/or a decrease in exocytosis.
Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS.