Resveratrol
Researchers have used a single compound to increase the lifespan of obese mice, and found that the drug reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets--some of which are associated with diabetes, heart disease, and other significant diseases related to obesity. The research, led by investigators at Harvard Medical School and the National Institute on Aging, is the first time that the small molecule resveratrol has been shown to offer survival benefits in a mammal.- Calorie restriction mimetics: an emerging research field
When considering all possible aging interventions evaluated to date, it is clear that calorie restriction (CR) remains the most robust. Studies in numerous species have demonstrated that reduction of calories 30-50% below ad libitum levels of a nutritious diet can increase lifespan, reduce the incidence and delay the onset of age-related diseases, improve stress resistance, and decelerate functional decline. A current major focus of this research area is whether this nutritional intervention is relevant to human aging. Evidence emerging from studies in rhesus monkeys suggests that their response to CR parallels that observed in rodents. To assess CR effects in humans, clinical trials have been initiated. However, even if results from these studies could eventually substantiate CR as an effective pro-longevity strategy for humans, the utility of this intervention would be hampered because of the degree and length of restriction required. As an alternative strategy, new research has focused on the development of 'CR mimetics'. The objective of this strategy is to identify compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. For example, drugs that inhibit glycolysis (2-deoxyglucose), enhance insulin action (metformin), or affect stress signaling pathways (resveratrol), are being assessed as CR mimetics (CRM). Promising results have emerged from initial studies regarding physiological responses which resemble those observed in CR (e.g. reduced body temperature and plasma insulin) as well as protection against neurotoxicity (e.g. enhanced dopamine action and up-regulated neurotrophic factors). Ultimately, lifespan analyses in addition to expanded toxicity studies must be accomplished to fully assess the potential of any CRM. Nonetheless, this strategy clearly offers a very promising and expanding research endeavor. - Vertebrate aging research 2006
This Hot Topics review, the first in a projected annual series, discusses those articles, published in the last year, which seem likely to have a major impact on our understanding of the aging process in mammals and the links between aging and late-life illnesses. The year's highlights include studies of oxidation damage in the very-long-lived naked mole-rat, and of caloric restriction in monkeys, humans, and growth hormone-unresponsive mice. Two studies of resveratrol, one showing its ability to extend lifespan in a short-lived fish, the other demonstrating beneficial effects in mice subjected to a diet high in fat, may well be harbingers of a parade of intervention studies in the coming decade. - Resveratrol in cell fate decisions
Resveratrol, a polyphenolic phytoalexin, is one of the most extensively studied natural products, with wide ranging biological activity and tremendous clinical potential. First identified from fruits and plants, in particular grapes and wines, its positive effects on a variety of disease states have been unraveled over the past decade or so. Most noticeable are its anti-thrombogenic, anti-inflammatory, cardio-protective, neuro-protective, anti-aging, and cancer preventive and therapeutic activities. Recent data also indicate that depending upon the concentration/dose, resveratrol can trigger or block cell death signaling in tumor cells. Considering the heightened interest in this compound, here we present a short review on the biological activity of this remarkable compound, with a specific focus on its effects on cell survival and death signals. - Resveratrol--a boon for treating Alzheimer's disease?
Resveratrol, a red wine polyphenol, is known to protect against cardiovascular diseases and cancers, as well as to promote antiaging effects in numerous organisms. It also modulates pathomechanisms of debilitating neurological disorders, such as strokes, ischemia, and Huntington's disease. The role of resveratrol in Alzheimer's disease is still unclear, although some recent studies on red wine bioactive compounds suggest that resveratrol modulates multiple mechanisms of Alzheimer's disease pathology. Emerging literature indicates that mechanisms of aging and Alzheimer's disease are intricately linked and that these mechanisms can be modulated by both calorie restriction regimens and calorie restriction mimetics, the prime mediator of which is the SIRT1 protein, a human homologue of yeast silent information regulator (Sir)-2, and a member of NAD+-dependent histone deacetylases. Calorie restriction regimens and calorie restriction-mimetics trigger sirtuins in a wide variety of organisms, ranging from bacteria to mouse. In a mouse model of Huntington's disease, resveratrol-induced SIRT1 was found to protect neurons against ployQ toxicity and in Wallerian degeneration slow mice, resveratrol was found to protect the degeneration of neurons from axotomy, suggesting that resveratrol may possess therapeutic value to neuronal degeneration. This paper mainly focuses on the role of resveratrol in modulating AD pathomechanisms. - Therapeutic potential of resveratrol: the in vivo evidence
Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans. - Vascular dysfunction in aging: potential effects of resveratrol, an anti-inflammatory phytoestrogen
Epidemiological studies demonstrated that even in the absence of other risk factors (e.g. diabetes, hypertension, hyperhomocysteinemia, hypercholesterolemia), advanced age itself significantly increases cardiovascular morbidity by enhancing vascular oxidative stress and inflammation. Because the population in the Western world is rapidly aging, there is a substantial need for pharmacological interventions that delay the functional decline of the cardiovascular system. Resveratrol is an atoxic phytoestrogen found in more than 70 plants including grapevine and berries. Recent data suggest that nutritional intake of resveratrol and other polyphenol compounds may contribute to the "French paradox", the unexpectedly low cardiovascular morbidity in the Mediterranean population. There is increasing evidence that resveratrol exerts multifaceted anti-oxidant and/or anti-inflammatory effects in various disease models. Importantly, resveratrol was reported to slow aging and increase lifespan in simple organisms and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to activate NAD-dependent histone deacetylases (sirtuins), which may contribute to its anti-aging effects. This review focuses on the role of oxidative stress and inflammation in cardiovascular dysfunction in aging, and on emerging anti-aging therapeutic strategies offered by resveratrol and other polyphenol compounds. - Neuronal protection by sirtuins in Alzheimer's disease
Silent information regulator 2, a member of NAD+-dependent histone deacetylase in yeast, and its homologs in mice and humans, participate in numerous important cell functions, including cell protection and cell cycle regulation. The sirtuin family members are highly conserved evolutionarily, and are predicted to have a role in cell survival. The science of sirtuins is an emerging field and is expected to contribute significantly to the role of sirtuins in healthy aging in humans. The role of sirtuins in neuronal protection has been studied in lower organisms, such as yeast, worms, flies and rodents. Both yeast Sir2 and mammalian sirtuin proteins are up-regulated under calorie-restricted and resveratrol treatments. Increased sirtuin expression protects cells from various insults. Caloric restriction and antioxidant treatments have shown useful effects in mouse models of aging and Alzheimer's disease (AD) and in limited human AD clinical trials. The role sirtuins may play in modifying and protecting neurons in patients with neurodegenerative diseases is still unknown. However, a recent report of Huntington's disease revealed that Sirtuin protects neurons in a Huntington's disease mouse model, suggesting that sirtuins may protect neurons in patients with neurodegenerative diseases, such as AD. In this review, we discuss the possible mechanisms of sirtuins involved in neuronal protection and the potential therapeutic value of sirtuins in healthy aging and AD. - Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications
Resveratrol is a phytoalexin polyphenolic compound found in various plants, including grapes, berries, and peanuts. Multiple lines of compelling evidence indicate its beneficial effects on neurological, hepatic, and cardiovascular systems. Also one of the most striking biological activities of resveratrol soundly investigated during the late years has been its cancer-chemopreventive potential. In fact, recently it has been demonstrated that this stilbene blocks the multistep process of carcinogenesis at various stages: tumor initiation, promotion, and progression. One of the possible mechanisms for its biological activities involves downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of activated immune cells, or inhibiting such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via its inhibitory effects on nuclear factor (kappa)B (NF-(kappa)B) or the activator protein-1 (AP-1). More recent data provide interesting insights into the effect of this compound on the lifespan of yeast and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. It is worthy to note that the phenolic compound possesses a low bioavailability and rapid clearance from the plasma. As the positive effects of resveratrol on inflammatory response regulation may comprise relevant clinical implications, the purpose of this article is to review its strong anti-inflammatory activity and the plausible mechanisms of these effects. Also, this review is intended to provide the reader an up-date of the bioavailability and pharmacokinetics of resveratrol and its impact on lifespan. - Resveratrol: preventing properties against vascular alterations and ageing
Cardiovascular diseases are the leading cause of death in developed countries where the common pathological substrate underlying this process is atherosclerosis. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of the vascular diseases and associated inflammatory effects. Recently, potential antioxidants (vitamin E, polyphenols) have received much attention as potential anti-atherosclerotic agents. Among the polyphenols with health benefic properties, resveratrol, a phytoalexin of grape, seem to be a good candidate protecting the vascular walls from oxidation, inflammation, platelet aggregation, and thrombus formation. In this review, we focus on the mechanism of resveratrol cardiovascular benefic effects. We analyze, in relation with the different steps of atherosclerotic process, the resveratrol properties at multiple levels, such as cellular signaling, enzymatic pathways, apoptosis, and gene expression. We show and discuss the relationship with reactive oxygen species, regulation of pro-inflammatory genes including cycloxygenases and cytokines in molecular inflammatory and aging processes, and how the regulation of these activites by resveratrol can lead to a prevention of vascular diseases - Mass spectrometry in grape and wine chemistry. Part I: polyphenols
Mass spectrometry, had and still has, a very important role for research and quality control in the viticulture and enology field, and its analytical power is relevant for structural studies on aroma and polyphenolic compounds. Polyphenols are responsible for the taste and color of wine, and confer astringency and structure to the beverage. The knowledge of the anthocyanic structure is very important to predict the aging attitude of wine, and to attempt to resolve problems about color stability. Moreover, polyphenols are the main compounds related to the benefits of wine consumption in the diet, because of their properties in the treatment of circulatory disorders such as capillary fragility, peripheral chronic venous insufficiency, and microangiopathy of the retina. Liquid Chromatography-Mass Spectrometry (LC-MS) techniques are nowadays the best analytical approach to study polyphenols in grape extracts and wine, and are the most effective tool in the study of the structure of anthocyanins. The MS/MS approach is a very powerful tool that permits anthocyanin aglycone and sugar moiety characterization. LC-MS allows the characterization of complex structures of grape polyphenols, such as procyanidins, proanthocyanidins, prodelphinidins, and tannins, and provides experimental evidence for structures that were previously only hypothesized. The matrix-assisted-laser-desorption-ionization-time-of-flight (MALDI-TOF) technique is suitable to determine the presence of molecules of higher molecular weight with high accuracy, and it has been applied with success to study procyanidin oligomers up to heptamers in the reflectron mode, and up to nonamers in the linear mode. The levels of resveratrol in wine, an important polyphenol well-known for its beneficial effects, have been determined by SPME and LC-MS, and the former approach led to the best results in terms of sensitivity. Copyright 2003 Wiley Periodicals, Inc. - Substrate-specific Activation of Sirtuins by Resveratrol
Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined. - Resveratrol, a natural chemopreventive agent against degenerative diseases
Humans have long sought the elixir to long life. Today, although advances in our understanding of the aging process have given gerontologists new insights in potential anti-aging interventions, public demand for these interventions is outpacing our current knowledge. My presentation begins with a brief historical background that outlines some of the past and present approaches to anti-aging interventions. Using the dietary restriction paradigm as a prototype, discussions center on a three-pathway model that provides the bases to design effective interventions: (1) retardation of biological aging, (2) suppression of age-related disease, and (3) modulation of cross talk between (1) and (2). One other concept useful for discussion in relation to interventions is the enhancement of an organism's resistance to deter vulnerability to aging and disease. These models are best used to explain the efficacy of currently popular interventions such as antioxidant supplementation and hormone therapies. This presentation further highlights the promises that antioxidant supplements hold in warding off oxidative damage as well as their inherent problems and biological limitations. Also discussed here are the promises and uncertainties of anti-aging interventions by genetic manipulation, as seen in animal model studies, and prophylactic treatments targeted against disease, such as hormonal approaches using estrogen and DHEA, as well as other intervening measures. - Sirtuin activators mimic caloric restriction and delay ageing in metazoans
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction. - SIRT1: linking adaptive cellular responses to aging-associated changes in organismal physiology
Sirtuins comprise a family of enzymes implicated in the determination of organismal life span in yeast and the nematode. The mammalian sirtuin SIRT1 has been shown to deacetylate several proteins in an NAD(+)-dependent manner. SIRT1 substrates are involved in the regulation of apoptosis/cell survival, endocrine signaling, differentiation, chromatin remodeling, and transcription. Thus SIRT1 provides a molecular link between nutrient availability and adaptive transcriptional responses. This review presents current evidence as to how SIRT1 functions are relevant to changes in tissue physiology that occur with ageing and its implications for future pharmacological intervention to alleviate such degenerative processes. - Development of calorie restriction mimetics as a prolongevity strategy
By applying calorie restriction (CR) at 30-50% below ad libitum levels, studies in numerous species have reported increased life span, reduced incidence and delayed onset of age-related diseases, improved stress resistance, and decelerated functional decline. Whether this nutritional intervention is relevant to human aging remains to be determined; however, evidence emerging from CR studies in nonhuman primates suggests that response to CR in primates parallels that observed in rodents. To evaluate CR effects in humans, clinical trials have been initiated. Even if evidence could substantiate CR as an effective antiaging strategy for humans, application of this intervention would be problematic due to the degree and length of restriction required. To meet this challenge for potential application of CR, new research to create "caloric restriction mimetics" has emerged. This strategy focuses on identifying compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. Microarray studies show that gene expression profiles of key enzymes in glucose (energy) handling pathways are modified by CR. Drugs that inhibit glycolysis (2-deoxyglucose) or enhance insulin action (metformin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiological responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicity, enhanced dopamine action, and upregulated brain-derived neurotrophic factor. Further life span analyses in addition to expanded toxicity studies must be completed to assess the potential of any CR mimetic, but this strategy now appears to offer a very promising and expanding research field. - Toward a unified theory of caloric restriction and longevity regulation
The diet known as calorie restriction (CR) is the most reproducible way to extend the lifespan of mammals. Many of the early hypotheses to explain this effect were based on it being a passive alteration in metabolism. Yet, recent data from yeast, worms, flies, and mammals support the idea that CR is not simply a passive effect but an active, highly conserved stress response that evolved early in life's history to increase an organism's chance of surviving adversity. This perspective updates the evidence for and against the various hypotheses of CR, and concludes that many of them can be synthesized into a single, unifying hypothesis. This has important implications for how we might develop novel medicines that can harness these newly discovered innate mechanisms of disease resistance and survival. - Resveratrol improves health and survival of mice on a high-calorie diet
Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing. - Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha
Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis. - Substrate-specific Activation of Sirtuins by Resveratrol
Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined. - Calorie restriction--the SIR2 connection
A nutritious diet low in calories improves the health and extends the life span of rodents. Recent studies identified a gene, SIR2, which encodes an NAD-dependent deacetylase and may mediate the effects of calorie restriction. In this review, we discuss SIR2 genes and calorie restriction in the lower organisms yeast and Drosophila. We then describe the physiological changes in mammals during calorie restriction and how they may lead to the observed health benefits. We summarize the roles of mammalian Sirt1 in mediating these changes in tissues and endocrine systems and propose that Sirt1 regulates calorie restriction by sensing low calories and triggering physiological changes linked to health and longevity. - Resveratrol, a natural chemopreventive agent against degenerative diseases
Resveratrol (3,5,4'-trihydroxystilbene) is a naturally occurring compound shown to modulate the risk of cardiovascular degenerative diseases (atherosclerosis) and inhibit chemical carcinogenesis in rodents. Various studies have demonstrated the effect of this phytoalexin on biological mechanisms involved in cardioprotection. These include modulation of lipid turnover, inhibition of eicosanoid production, prevention of the low-density lipoprotein oxidation and inhibition of platelet aggregation. Carcinogenesis in animal models can be divided at least into three stages: initiation, promotion and progression. Initiation occurs as result of interaction of a reactive form of carcinogen with DNA. Chemical carcinogens like polycyclic aromatic hydrocarbons are metabolized to reactive species by cytochrome P450 dependent enzymes activated through aryl hydrocarbon (Ah) receptor. The inhibition of tumor initiation by resveratrol most probably occurs through preventing the activation of Ah receptor. Resveratrol affects also several factors involved in tumor promotion and progression. Since tumor promoting agents alter the expression of genes whose products are associated with inflammation, chemoprevention of cardiovascular diseases and cancer may share the same common mechanisms. This includes principally modulation of the expression of growth factors and cytokines. Recently, chemopreventive properties of resveratrol have been associated with the inhibition of NF-kappaB. This transcription factor is strongly linked to inflammatory and immune responses, regulation of cell proliferation and apoptosis, thus it is important for tumor development and many other diseases including atherosclerosis. Although the mechanisms by which resveratrol interferes with the activation of NF-KB are not clear, it seems that inhibition of its degradation which is necessary for its cellular activation is the principal target. Based on the quantity and diversity of data available on the biological activity of resveratrol, it has to be considered a very promising chemoprotector and chemotherapeutic. Urgent investigations on its bioavailability and effects on in vivo systems, especially in humans, are necessary. - In vitro electrophysiological mechanisms for antiarrhythmic efficacy of resveratrol, a red wine antioxidant
Resveratrol (trans-3, 4', 5-trihydroxystilbene), a natural antioxidant derived from grapes, has beneficial effects against coronary heart disease. Its electrophysiological characteristics for antiarrhythmic efficacy are largely unknown; thus, this study aims to explore the resveratrol's antiarrhythmic effects and conduction system in isolated hearts as well as its electrophysiological effects on cardiac myocytes. In the experiment, resveratrol suppressed the ischemia/reperfusion-induced ventricular arrhythmias in Langendorff-perfused rat hearts. In the current clamp study of the experiment, resveratrol prolonged the action potential duration (APD(50) and APD(90)) and suppressed the upstroke velocity of the action potential (V(max)). In the voltage clamp study, resveratrol inhibited sodium inward current (I(Na)) in a concentration-dependent manner and negative-shifted the voltage-dependent inactivation curve. Resveratrol also reduced the calcium inward current (I(Ca), 51.2+/-13.3% at 100 microM). Furthermore, the transient (I(to)) and sustained (I(ss)) outward potassium currents were decreased 60.2+/-5.7% and 42.3+/-5.2% after exposure to resveratrol (100 microM), respectively. The inward rectifier potassium current (I(K1)) was also reduced 24.2+/-7.0% in the presence of resveratrol (100 microM). In the isolated heart perfusion model, resveratrol (100 microM) prolonged AV nodal refractory period, the Wenckebach cycle length and the conduction through AV node and His-Purkinje system. In conclusion, resveratrol increased the cardiac effective refractory period mainly through inhibiting the ionic channels including I(Na), I(to) and I(ss) which could contribute to the conversion of ischemia/reperfusion-induced lethal arrhythmias. - Induction of cell apoptosis in 3T3-L1 pre-adipocytes by flavonoids is associated with their antioxidant activity
Obesity is biologically characterized at the cellular level by an increase in the number and size of adipocytes differentiated from fibroblastic pre-adipocytes in adipose tissue. In this study, we focused on the relationship between the influence of flavonoids on cell population growth and their antioxidant activity. The results showed that the inhibition of flavonoids (naringenin, rutin, hesperidin, resveratrol, naringin and quercetin) on 3T3-L1 pre-adipocytes was 28.3, 8.1, 11.1, 33.2, 5.6 and 71.5%, respectively. In oxygen radical absorbance capacity (ORAC) assay, quercetin had the highest ORAC(ROO) value among the six flavonoids tested. Apoptosis assays showed that quercetin increased apoptotic cells in time- and dose-dependent manner. Treatment of cells with quercetin decreased the mitochondrial membrane potential in the courses of time and dose. The cell apoptosis/necrosis assay showed that quercetin increased the number of apoptotic cells, but not necrotic cells. Quercetin treatment of cells caused a significant time- and dose-dependent increase in the caspase-3 activity. Western analysis indicated that treatment of quercetin markedly down-regulated PARP and Bcl-2 proteins, and activated caspase-3, Bax, and Bak proteins. These results indicate that quercetin efficiently inhibits cell population growth and induction of apoptosis in 3T3-L1 pre-adipocytes. - Anti-leukemia effect of resveratrol
Resveratrol is a phytoalexin naturally present in fruits, medicinal plants and wines. It has a diversity of biological activities. While its role in the protection against coronary heart disease (CHD) in people with moderate wine consumption, remains unclear, resveratrol preferentially inhibits the growth of leukemia cells in culture. Potential mechanisms for its anti-leukemia effect include induction of leukemia cell differentiation, apoptosis, and cell cycle arrest at S-phase; and inhibition of DNA synthesis by inhibiting ribonucleotide reductase or DNA polymerase. Preliminary results suggest that resveratrol also inhibits the viability of freshly isolated leukemia cells, especially promyelocytic leukemia cells. Because of its low in vivo toxicity, resveratrol deserves further investigation as an anti-leukemia agent. - The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease
A number of lines of evidence suggest that red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease (CHD) mortality. This protection over and above that due to ethanol itself may be explained by phenolic components with which red wines are richly endowed. We have studied the effects of the trihydroxy stilbene trans-resveratrol on human platelet aggregation and on the synthesis of three eicosanoids from arachidonate by platelets, i.e. thromboxane B2 (TxB2), hydroxyheptadecatrienoate (HHT) and 12-hydroxyeicosatetraenoate (12-HETE). These effects were compared with the actions of other wine phenolics (quercetin, catechin and epicatechin) and antioxidants (alpha-tocopherol, hydroquinone and butylated hydroxytoluene). trans-Resveratrol and quercetin demonstrated a dose-dependent inhibition of both thrombin-induced and ADP-induced platelet aggregation, whereas ethanol inhibited only thrombin-induced aggregation. The other compounds tested were inactive. trans-Resveratrol also inhibited the synthesis of TxB2, HHT, and to a lesser extent 12-HETE, from arachidonate in a dose-dependent manner. Quercetin inhibited only 12-HETE synthesis, and hydroquinone caused slight inhibition of TxB2 synthesis, the remaining compounds being ineffective. De-alcoholized red wines inhibited platelet aggregation; their ability to inhibit the synthesis of TxB2 but not that of 12-HETE from labelled arachidonate by washed human platelets was proportional to their trans-resveratrol concentration. These results are consistent with the notion that trans-resveratrol may contribute to the presumed protective role of red wine against atherosclerosis and CHD. - Molecular mechanism of the chemopreventive effect of resveratrol
Chemoprevention is a promising approach to control human cancer. Resveratrol has been shown to have a potent chemopreventive effect in multiple carcinogenesis models. However, the precise mechanism explaining its anti-carcinogenic effect is not clear. This review summarizes recent studies from our laboratory on the mechanisms of resveratrol's effects. In JB6 cells, resveratrol was found to induce apoptosis and inhibit tumor promoter-induced cell transformation. We also found that resveratrol-induced activation of p53 and resveratrol-induced apoptosis occurred through a p53-dependent pathway. The MAP kinases, ERKs, JNKs, or p38 kinases, are involved in resveratrol-induced activation of p53 and apoptosis. - p53: at the crossroad between cancer and ageing
The p53 tumour suppressor plays an undisputed role in cancer. p53's tumour suppressive activity stems from its ability to respond to a variety of stresses to trigger cell cycle arrest, apoptosis or senescence, thereby protecting against malignant transformation. An increasing body of evidence suggests that p53 also drives organismal ageing. Although genetic models with altered p53 function display age-related phenotypes and thus provide in vivo evidence that p53 contributes to the ageing process, p53's role in organismal ageing remains controversial. Anti-cancer therapies that target p53 and reactivate or enhance its activity are considered good alternatives for treating various neoplasms. Therefore, it is important to determine whether these clinical approaches compromise tissue homeostasis and contribute to ageing. This review presents a number of models with altered p53 function and discusses how these models implicate p53 as part of a molecular network that integrates tumour suppression and ageing. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. - SIRT1 promotes DNA repair activity and deacetylation of Ku70
Human SIRT1 controls various physiological responses including cell fate, stress, and aging, through deacetylation of its specific substrate protein. In processing DNA damage signaling, SIRT1 attenuates a cellular apoptotic response by deacetylation of p53 tumor suppressor. The present study shows that, upon exposure to radiation, SIRT1 could enhance DNA repair capacity and deacetylation of repair protein Ku70. Ectopically over-expressed SIRT1 resulted in the increase of repair of DNA strand breakages produced by radiation. On the other hand, repression of endogenous SIRT1 expression by SIRT1 siRNA led to the decrease of this repair activity, indicating that SIRT1 can regulate DNA repair capacity of cells with DNA strand breaks. In addition, we found that SIRT1 physically complexed with repair protein Ku70, leading to subsequent deacetylation. The dominant-negative SIRT1, a catalytically inactive form, did not induce deacetylation of Ku70 protein as well as increase of DNA repair capacity. These observations suggest that SIRT1 modulates DNA repair activity, which could be regulated by the acetylation status of repair protein Ku70 following DNA damage. - Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase
A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells. - Cancer-Specific Functions of SIRT1 Enable Human Epithelial Cancer Cell Growth and Survival
SIRT1 is a conserved NAD-dependent deacetylase that regulates life span in accord with nutritional provision. In mammalian cells, SIRT1 also down-regulates stress-induced p53 and FoxO pathways for apoptosis, thus favoring survival under stress. The functioning of SIRT1 under normal, nonstressed conditions of cell growth is unknown. Here we have asked if SIRT1 has the capacity to influence cell viability in the absence of applied stress. For this purpose we used synthetic small interfering RNA to silence SIRT1 gene expression by RNA interference (RNAi). We show that the process of RNAi, by itself, does not affect cell growth and is not sufficient to activate a cellular stress response (indicated by lack of activation of endogenous p53). We also show that, in the absence of applied stress, SIRT1 silencing induces growth arrest and/or apoptosis in human epithelial cancer cells. In contrast, normal human epithelial cells and normal human diploid fibroblasts seem to be refractory to SIRT1 silencing. Combined gene knockout with RNAi cosilencing experiments indicate that SIRT1 and Bcl-2 may suppress separable apoptotic pathways in the same cell lineage and that the SIRT1-regulated pathway is independent of p53, Bax, and caspase-2. Alternatively, SIRT1 may suppress apoptosis downstream from these apoptotic factors. In either case, we show that FoxO4 (but not FoxO3) is required as proapoptotic mediator. We further identify caspase-3 and caspase-7 as downstream executioners of SIRT1/FoxO4regulated apoptosis. Our work identifies SIRT1 as a novel target for selective killing of cancer versus noncancer epithelial cells. - CALORIE RESTRICTION, SIRT1 AND METABOLISM: UNDERSTANDING LONGEVITY
Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing. - Molecular links between aging and adipose tissue
White adipose tissue now emerges as a pivotal organ controlling lifespan. Calorie restriction, which so far extends lifespan in all organisms, primarily affects energy stores in adipose tissue. Genetic manipulations aiming at modifying fat mass also impact on the duration of life in several model organisms. We recently proposed that silent information regulator 2 (SIR2) ortholog, sirtuin 1 (SIRT1), the mammalian ortholog of the life-extending yeast gene SIR2, is involved in the molecular mechanisms linking lifespan to adipose tissue. SIRT1 represses peroxisome proliferator-activated receptors gamma transactivation and inhibits lipid accumulation in adipocytes. The effect of adipose tissue reduction on lifespan could be due to the production of adipokines acting on target tissues such as the brain, or due to the indirect prevention of age-related metabolic disorders like type 2 diabetes or atherosclerosis. - Resveratrol in Cardioprotection: A Therapeutic Promise of Alternative Medicine
Resveratrol, a polyphenol phytoalexin, possesses diverse biochemical and physiological actions, including estrogenic, antiplatelet, and anti-inflammatory properties. Several recent studies determined the cardioprotective abilities of resveratrol. Both in experiments (acute) and in chronic models, resveratrol attenuates myocardial ischemic reperfusion injury, atherosclerosis, and reduces ventricular arrhythmias. It appears that resveratrol-mediated cardioprotection is achieved through the preconditioning effect (the best yet devised method of cardioprotection), rather than direct protection. Thus, resveratrol likely fulfills the definition of a pharmacological preconditioning compound and gives hope to the therapeutic promise of alternative medicine. - Cardiovascular protective effects of resveratrol
Resveratrol (3,4',5-trihydroxy-trans-stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that at low doses (such as consumed in the common diet) resveratrol may have cardioprotective activity. In this article we describe recent in vitro and in vivo studies in animal models. The results of these studies suggest that resveratrol modulates vascular cell function, inhibits LDL oxidation, suppresses platelet aggregation and reduces myocardial damage during ischemia-reperfusion. Although the reported biological data indicate that resveratrol is a highly promising cardiovascular protective agent, more studies are needed to establish its bioavailability and in vivo cardioprotective effects, particularly in humans. - Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications
Resveratrol is a phytoalexin polyphenolic compound found in various plants, including grapes, berries, and peanuts. Multiple lines of compelling evidence indicate its beneficial effects on neurological, hepatic, and cardiovascular systems. Also one of the most striking biological activities of resveratrol soundly investigated during the late years has been its cancer-chemopreventive potential. In fact, recently it has been demonstrated that this stilbene blocks the multistep process of carcinogenesis at various stages: tumor initiation, promotion, and progression. One of the possible mechanisms for its biological activities involves downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of activated immune cells, or inhibiting such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via its inhibitory effects on nuclear factor (kappa)B (NF-(kappa)B) or the activator protein-1 (AP-1). More recent data provide interesting insights into the effect of this compound on the lifespan of yeast and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. It is worthy to note that the phenolic compound possesses a low bioavailability and rapid clearance from the plasma. As the positive effects of resveratrol on inflammatory response regulation may comprise relevant clinical implications, the purpose of this article is to review its strong anti-inflammatory activity and the plausible mechanisms of these effects. Also, this review is intended to provide the reader an up-date of the bioavailability and pharmacokinetics of resveratrol and its impact on lifespan. - High absorption but very low bioavailability of oral resveratrol in humans
The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 ± 90 ng/ml (about 2 µM) and a plasma half-life of 9.2 ± 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.
SITE MAP
Maagdarmstoornissen: Candida infectie - Prikkelbaredarmsyndroom - Crohn - Colitus Ulcerosa - CVS/ME: Chronische vermoeidheid Syndroom - Diabetische complicaties: Bloeduiker stabilisatie - Neuropathie - Retinopathie - Nefropathie - Hart- en vaatziekten: Cardiomyopathie en Hartfalen - Hoge bloeddruk - Cholesterol verlaging - Aderverkalking (atherosclerose) - Spataderen - Levensverlenging: 100 jaren jong - DHEA - Melatonine - 65+ - Kanker: - Ondersteuningstherapie bij kanker - Bot en gewrichtsaandoeningen: - Artrose - Artritis - Osteoporose - Fibromyalgie: - Fibromyalgie - Urinewegaandoeningen: - Prostaatklachten - Blaasontsteking - Vrouwenklachten: Menopauze - Premenstrueelsyndroom - Overgewicht: - Overgewicht - SLIM - Oogaandoeningen: Staar - Slecht zien Andere artikelen: - HPU - Astma - Multiple Sclerose - Psoriasis - Depressie
Maagdarmstoornissen: Candida infectie - Prikkelbaredarmsyndroom - Crohn - Colitus Ulcerosa - CVS/ME: Chronische vermoeidheid Syndroom - Diabetische complicaties: Bloeduiker stabilisatie - Neuropathie - Retinopathie - Nefropathie - Hart- en vaatziekten: Cardiomyopathie en Hartfalen - Hoge bloeddruk - Cholesterol verlaging - Aderverkalking (atherosclerose) - Spataderen - Levensverlenging: 100 jaren jong - DHEA - Melatonine - 65+ - Kanker: - Ondersteuningstherapie bij kanker - Bot en gewrichtsaandoeningen: - Artrose - Artritis - Osteoporose - Fibromyalgie: - Fibromyalgie - Urinewegaandoeningen: - Prostaatklachten - Blaasontsteking - Vrouwenklachten: Menopauze - Premenstrueelsyndroom - Overgewicht: - Overgewicht - SLIM - Oogaandoeningen: Staar - Slecht zien Andere artikelen: - HPU - Astma - Multiple Sclerose - Psoriasis - Depressie
