Resveratrol Review

 Resveratrol

Resveratrol is a grape vine phenolic compound found in seventy two plant species. It was first discovered in 1939 and is classified as a stilbene because of its structure and termed a phytoalexin because of its protective effects against infections in plants. (1)

Resveratrol was named after Veratrum grandiflorum when it was isolated from the root of that vine. It is found in nature both in the cis- and trans- form, where the cis-form predominates. The trans form of Resveratrol that has been shown to display a much broader spectrum of pharmacological activity than the cis isomer. (2)

As a supplement, Resveratrol is extracted from Polygonum cuspidatum, also known as Japanese knotweed, or the Itadori plant.

 Research with Resveratrol has expanded over the last two decades to the point where two international conferences have been conducted over its diverse effects in animals and humans. This has attracted the attention of the worldwide medical community. (4)

Resveratrol has been suggested to have cardioprotective effects and improve metabolic function based on compelling in vitro and animal studies. (5, 6, 7)

A number of human clinical intervention trials have been initiated as a result of Resveratrol's promising preclinical results. However, human data is still scarce and many claims have been made about Resveratrol, making it a controversial subject. (9)

It is unclear whether Resveratrol's biological effects can be attributed to its antioxidant, calorie restriction mimetic, antinflammatory or other effects, and independent research is now exploring each pathway. (10, 11, 12)

Resveratrol is also found in red wine, and it has been suggested that it plays a role in the 'French Paradox' effect where consumption of red wine seems to improve cardiovascular outcomes in the French population despite a high fat diet. In fact the 'French paradox' itself drew the attention of researchers to Resveratrol in the first place when researchers took a deeper look into the precise components of red wine. (13)

Two French investigators, Renaud and de Lorgeril proposed that moderate wine consumption explained the discrepancy where the ratio of cardiovascular mortality was found to be two to three times lower in France than in the U.S., England and Sweden. (13)

This was later confirmed in a Copenhagen study of 2,826 men where moderate wine intake was associated with lower cardiovascular and cerebrovascular diseases. (14)

The active polyphenols in red wine include anthocyanins, which give it its color, flavanols, like quercetin, phenolic acids, such as gallic acid and the stilbene, Resveratrol. (15)

Each of these wine compounds is being researched extensively, but a special emphasis is being placed on Resveratrol.

Resveratrol and Aging

Resveratrol is the first molecule that consistently slows aging across the board in unrelated species - yeast, roundworms, fish and fruitflies – and this effect has been noted in different laboratories.

The most recent lifespan extension effects of Resveratrol is on the short-lived fish, Nothobranchius Guentheri. Nothobranchius Guentheri is considered to be a promising vertebrate model to study aging. Resveratrol increased mean and  maximum lifespan of the fish treat by 17.34% and 17.66% compared to the fish in the control group  (16)

The first lifespan study with Resveratrol was conducted in 2003 in yeast resulting in a 70% increase in yeast lifespan. (17)

Resveratrol also increases the lifespan of fruitflies and the metazoan worms, C. elegans. (18)

Human Implications

Diverse cultures, such as the Japanese and Mediterranean populations eat and drink greater amounts of Resveratrol, for example, from wine and foods higher in polyphenols. No conclusions should be drawn as to whether Resveratrol affects human lifespan, but Resveratrol appears to support healthy lipid and glucose management in preliminary human trials. (19, 20)

References:

1.Drugs Exp Clin Res. 1999;25(2-3):57-63. Stilbene compounds: from the grapevine to wine. Bavaresco L1, Fregoni C, Cantù E, Trevisan M.

Stilbenes are natural compounds occurring in a number of plant families, including Vitaceae and (within this family) Vitis vinifera L., which is the most important species grown worldwide for grape and wine production. Stilbenes (resveratrol and viniferins) are present in grapevine as constitutive compounds of the woody organs (roots, canes, stems) and as induced substances (in leaves and fruit) acting as phytoalexins in the mechanisms of grape resistance against certain pathogens.Resveratrol (3, 5, 4'-trihydroxystilbene) was also detected in wine and it was thought to be the active principle of red wines that were shown to reduce heart diseases. This paper reviews data, obtained by the Viticulture Institute of the Catholic University at Piacenza and taken from the literature, on some aspects of stilbene physiology in grapevine and on their relation to resveratrol wine levels. Constitutive stilbene contents of woody organs are reported, as well as the possible role of cluster stems as a source of resveratrol for wine. The accumulation of stilbenes in grape berries infected by grey mould (Botrytis cinerea Pers.) has been investigated and the effects of environmental factors on resveratrol grape and wine levels will be discussed. An unidentified new hydroxystilbene was detected in wine.

PMID:10370866

2.Altern Med Rev. 2010 Jul;15(2):152-8. Resveratrol. Monograph.

PMID:20807000

3. Resveratrol. Monograph, Journal of Biological Chemistry.

4.PLoS One. 2011;6(6):e19881. What is new for an old molecule? Systematic review and recommendations on the use ofresveratrol.Vang O1, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM.

Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsing?r, Denmark.

METHODOLOGY:

Literature search in databases as PUBMED and ISI Web of Science in combination with manual search was used to answer the following five questions: (1)Can resveratrol be recommended in the prevention or treatment of human diseases?; (2)Are there observed "side effects" caused by the intake of resveratrol in humans?; (3)What is the relevant dose of resveratrol?; (4)What valid data are available regarding an effect in various species of experimental animals?; (5)Which relevant (overall) mechanisms of action of resveratrol have been documented?

CONCLUSIONS/SIGNIFICANCE:

The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research inresveratrol regarding its mechanism of action and its safety and toxicology in human subjects.

PMID:21698226

5.Altern Med Rev. 2010 Sep;15(3):245-63. A review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part 1. Kelly G1.

The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that the sirtuins are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Responses of this system to environmental factors, as well as its role in health and disease, are currently incompletely characterized and at most partially understood. This article reviews the mammalian sirtuin system, discusses the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarizes research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. Polyphenols, especially resveratrol, influence sirtuins. Existing evidence on these nutritional compounds, as they relate to the sirtuin system, is reviewed. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer, are discussed.

PMID:21155626 

6.Resveratrol activity on guinea pig isolated trachea from normal and albumin-sensitized animals. Ragazzi E, Froldi G, Fassina G. Pharmacol Res Commun. 1988 Dec;20 Suppl 5:79-82.

PMID:2907791

7.Plasma and tissue resveratrol concentrations and pharmacological activity. Bertelli A, Bertelli AA, Gozzini A, Giovannini L. Drugs Exp Clin Res. 1998;24(3):133-8.

PMID:9825229

8.Anticancer Res. 2004 Sep-Oct;24(5A):2783-840. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Aggarwal BB1, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y.

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

PMID:15517885

9.Pharmacol Res. 2014 Dec;90:88-115. Resveratrol and cardiovascular health--promising therapeutic or hopeless illusion? Tang PC1, Ng YF2, Ho S1, Gyda M3, Chan SW4.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural polyphenolic compound that exists in Polygonum cuspidatum, grapes, peanuts and berries, as well as their manufactured products, especially red wine. Resveratrol is a pharmacologically active compound that interacts with multiple targets in a variety of cardiovascular disease models to exert protective effects or induce a reduction in cardiovascular risks parameters. This review attempts to primarily serve to summarize the current research findings regarding the putative cardioprotective effects of resveratrol and the molecular pathways underlying these effects. One intent is to hopefully provide a relatively comprehensive resource for clues that may prompt ideas for additional mechanistic studies which might further elucidate and strengthen the role of the stilbene family of compounds in cardiovascular disease and cardioprotection. Model systems that incorporate a significant functional association with tissues outside of the cardiovascular system proper, such as adipose (cell culture, obesity models) and pancreatic (diabetes) tissues, were reviewed, and the molecular pathways and/or targets related to these models and influenced by resveratrol are discussed. Because the body of work encompassing the stilbenes and other phytochemicals in the context of longevity and the ability to presumably mitigate a plethora of afflictions is replete with conflicting information and controversy, especially so with respect to the human response, we tried to remain as neutral as possible in compiling and presenting the more current data with minimal commentary, permitting the reader free reign to extract the knowledge most helpful to their own investigations.

10.Biochim Biophys Acta. 2015 Jun;1852(6):1114-1123. The molecular targets of resveratrol. Kulkarni SS1, Cantó C2.

Resveratrol has emerged in recent years as a compound conferring strong protection against metabolic, cardiovascular and other age-related complications, including neurodegeneration and cancer. This has generated the notion that resveratroltreatment acts as a calorie-restriction mimetic, based on the many overlapping health benefits observed upon both interventions in diverse organisms, including yeast, worms, flies and rodents. Though studied for over a decade, the molecular mechanisms governing the therapeutic properties of resveratrol still remain elusive. Elucidating how resveratrolexerts its effects would provide not only new insights in its fundamental biological actions but also new avenues for the design and development of more potent drugs to efficiently manage metabolic disorders. In this review we will cover the most recent advances in the field, with special focus on the metabolic actions of resveratrol and the potential role of SIRT1 and AMPK. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

11.Endocr Metab Immune Disord Drug Targets. 2015 Mar 16. Resveratrol targets in inflammation. Inoue H1, Nakata R.

Resveratrol, a constituent of grapes and various other plants, has been an attractive compound for biomedical studies because moderate long-term drinking of red wine is associated with a reduced risk of lifestyle-related diseases, such as cardiovascular diseases and cancer. Resveratrol is as a phytoalexin, cyclooxygenase (COX) suppressor, and an activator of peroxisome proliferator-activated receptor (PPAR) and SIRT1. As a major phytoalexin, resveratrol is produced by plants in response to various environmental stresses, such as pathogens and ultraviolet (UV) radiation, and promotes resistance to these stresses. A similar active ingredient, salicylic acid (SA), is also produced by plants. Aspirin, acetylated SA, is a major nonsteroidal anti-inflammatory drug (NSAID) because it inhibits COX activity in humans. The jasmonic acid (JA) pathway in plants and the COX pathway in humans are both defense systems against environmental stresses and involve lipid mediators derived from phospholipids. We can hypothesize that there is a molecular basis for the mutually beneficial relationship between plants and humans, which is important for understanding the mode of action of resveratrol in inflammation. Here we provide a review of the studies on resveratrol, especially with respect to the role of COX and PPAR in inflammation.

PMID:25772176

12.Free Radic Res. 2000 Jul;33(1):105-14. Resveratrol inhibition of lipid peroxidation. Tadolini B1, Juliano C, Piu L, Franconi F, Cabrini L.

To define the molecular mechanism(s) of resveratrol inhibition of lipid peroxidation we have utilized model systems that allow us to study the different reactions involved in this complex process. Resveratrol proved (a) to inhibit more efficiently than either Trolox or ascorbate the Fe2+ catalyzed lipid hydroperoxide-dependent peroxidation of sonicated phosphatidylcholine liposomes; (b) to be less effective than Trolox in inhibiting lipid peroxidation initiated by the water soluble AAPH peroxyl radicals; (c) when exogenously added to liposomes, to be more potent than alpha-tocopherol and Trolox, in the inhibition of peroxidation initiated by the lipid soluble AMVN peroxyl radicals; (d) when incorporated within liposomes, to be a less potent chain-breaking antioxidant than alpha-tocopherol; (e) to be a weaker antiradical than alpha-tocopherol in the reduction of the stable radical DPPH*. Resveratrol reduced Fe3+ but its reduction rate was much slower than that observed in the presence of either ascorbate or Trolox. However, at the concentration inhibiting iron catalyzed lipid peroxidation, resveratrol did not significantly reduce Fe3+, contrary to ascorbate. In their complex, our data indicate that resveratrol inhibits lipid peroxidation mainly by scavenging lipid peroxyl radicals within the membrane, like alpha-tocopherol. Although it is less effective, its capacity of spontaneously entering the lipid environment confers on it great antioxidant potential.

PMID:10826926 

13.Lancet. 1992 Jun 20;339(8808):1523-6. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Renaud S1, de Lorgeril M.

In most countries, high intake of saturated fat is positively related to high mortality from coronary heart disease (CHD). However, the situation in France is paradoxical in that there is high intake of saturated fat but low mortality from CHD. Thisparadox may be attributable in part to high wine consumption. Epidemiological studies indicate that consumption of alcohol at the level of intake in France (20-30 g per day) can reduce risk of CHD by at least 40%. Alcohol is believed to protect from CHD by preventing atherosclerosis through the action of high-density-lipoprotein cholesterol, but serum concentrations of this factor are no higher in France than in other countries. Re-examination of previous results suggests that, in the main, moderate alcohol intake does not prevent CHD through an effect on atherosclerosis, but rather through a haemostatic mechanism. Data from Caerphilly, Wales, show that platelet aggregation, which is related to CHD, is inhibited significantly by alcohol at levels of intake associated with reduced risk of CHD. Inhibition of platelet reactivity by wine (alcohol) may be one explanation for protection from CHD in France, since pilot studies have shown that platelet reactivity is lower in France than in Scotland.

14.BMJ. 1996 Mar 23;312(7033):736-41. Alcohol consumption, serum low density lipoprotein cholesterol concentration, and risk of ischaemic heart disease: six year follow up in the Copenhagen male study. Hein HO1, Suadicani P, Gyntelberg

To investigate the interplay between use of alcohol, concentration of low density lipoprotein cholesterol, and risk of ischaemic heart disease.

Prospective study with controlling for several relevant confounders, including concentrations of other lipid fractions.

Copenhagen male study, Denmark.

2826 men aged 53-74 years without overt ischaemic heart disease.

Incidence of ischaemic heart disease during a six year follow up period.

RESULTS:

172 men (6.1%) had a first ischaemic heart disease event. There was an overall inverse association between alcohol intake and risk of ischaemic heart disease. The association was highly dependent on concentration of low density lipoprotein cholesterol. In men with a high concentration (> or = 5.25 mmol/l) cumulative incidence rates of ischaemic heart disease were 16.4% for abstainers, 8.7% for those who drank 1-21 beverages a week, and 4.4% for those who drank 22 or more beverages a week. With abstainers as reference and after adjustment for confounders, corresponding relative risks (95% confidence interval) were 0.4 (0.2 to 1.0; P<0.05) and 0.2 (0.1 to 0.8; P<0.01). In men with a concentration <3.63 mmol/l use of alcohol was not associated with risk. The attributable risk (95% confidence interval) of ischaemic heart disease among men with concentrations > or = 3.63 mmol/l who abstained from drinking alcohol was 43% (10% to 64%).

In middle aged and elderly men the inverse association between alcohol consumption and risk of ischaemic heart disease is highly dependent on the concentration of low density lipoprotein cholesterol. These results support the suggestion that use of alcohol may in part explain the French paradox.

15.J Agric Food Chem. 2005 Mar 23;53(6):2015-21. Dietary wine phenolics catechin, quercetin, and resveratrol efficiently protect hypercholesterolemic hamsters against aortic fatty streak accumulation.

Auger C1, Teissedre PL, Gérain P, Lequeux N, Bornet A, Serisier S, Besan?on P, Caporiccio B, Cristol JP, Rouanet JM.

The effects of the phenolic compounds catechin (Cat), quercetin (Qer), and resveratrol (Res) present in red wine on early atherosclerosis were studied in hamsters. Hamsters (n = 32) were divided into 4 groups of 8 and fed an atherogenic diet for 12 weeks. They received by force-feeding 7.14 mL/(kg of body wt.day) Cat, Qer, or Res in water [2.856 mg/(kg of body wt.day) for Cat and 0.1428 mg/(kg of body wt.dday) for Qer and Res], mimicking a moderate consumption of alcohol-free redwine (equivalent to that supplied by the consumption of about two glasses of red wine per meal for a 70 kg human), or water as control. Plasma cholesterol concentration was lower in groups that consumed phenolics than in controls. The increase in plasma apolipoprotein (Apo) A1 concentration was mainly due to Cat (26%) and Qer (22%) and to a lesser extent, but nonsignificantly, Res (19%). Apo-B was not affected. Plasma antioxidant capacity was not improved, and there was no sparing effect on plasma vitamins A and E. Plasma iron and copper concentrations were not modified nor were liver super oxide dismutase and catalase activities. A sparing effect of Qer on liver glutathione peroxidase activity appeared, whereas Cat and Res exhibited a smaller effect. Aortic fatty streak area was significantly reduced in the groups receiving Cat (84%) or Qer (80%) or Res (76%) in comparison with the controls. These findings demonstrate that catechin, quercetin, and resveratrol at nutritional doses prevent the development of atherosclerosis through several indirect mechanisms.

PMID:15769129 

16.Rejuvenation Res. 2015 Jan 8. Resveratrol attenuates oxidative stress and extends lifespan in the annual fish Nothobranchius Guentheri. Liu T1, Qi H, Ma L, Liu Z, Fu H, Zhu W, Song T, Yang B, Li G.

Resveratrol is a natural polyphenol derived mainly from skin of grapes and red wine. Resveratrol prolongs lifespan in several invertebrates, but this function is not found in mice. Our recently published paper demonstrated that resveratrol prolonged longevity of the annual fish Nothobranchius guentheri, a promising vertebrate model for anti-aging research. However, the anti-aging process by resveratrol remains largely unexplored, and little is known about its effects on oxidative stress. In this paper, by long term supplementation of resveratrol from sexual maturity, we detected the survivorship, and oxidative stress at three different developmental stages in vivo. Fish of 112 were fed with resveratrol in the concentration of 200μg/g food and fish of 111 without resveratrol from 16 weeks of age until to the end of their lives. The mean and maximum lifespan of the fish treated with resveratrol was extended by 17.34% and 17.66% compared to the fish in control group. The markers of oxidative stress, such as the level of reactive oxygen species, the activities of antioxidant enzymes and the degree of oxidative damage, were detected at 6-, 9- and 12-month-old respectively. The results presented that levels of ROS and oxidative damage displayed increased trend and activities of antioxidant enzymes appeared decreased trend with age. Resveratroltreatment significantly attenuated the increase of ROS level and oxidative damage, up-regulated the decrease of antioxidant enzyme activities induced by aging. Our results demonstrated that resveratrol decreased oxidative stress and extendedlifespan in this short-lived fish.

PMID:25569124

17.Nature. 2003 Sep 11;425(6954):191-6. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.

Howitz KT1, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B,Sinclair DA.

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeastSaccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast,resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

18.Nature. 2004 Aug 5;430(7000):686-9. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Wood JG1, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D.

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.

19.Mol Nutr Food Res. 2015 Jan;59(1):147-59. Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. Hausenblas HA1, Schoulda JA, Smoliga JM.

The red wine polyphenol, resveratrol, is highly effective in treating type 2 diabetes mellitus (T2DM) in animal models, but there is no consensus regarding its efficacy in humans. We conducted a systematic review, which included searches in nine scholarly databases and six clinical trial registries, and identified randomized controlled clinical trials whereby resveratrolwas used as an adjunct to pharmaceutical interventions in T2DM. Meta-analysis on clinical parameters was performed for available data. Of 764 articles originally identified, data from six unique datasets, examining a total of 196 T2DM patients (104 resveratrol, 92 control/placebo) ultimately met inclusion criteria. Statistically significant (p < 0.05) positive effects, indicating that resveratrol supplementation was more effective than placebo/control, were identified for systolic blood pressure, hemoglobin A1c, and creatinine, but not for fasting glucose, homeostatic model assessment of insulin resistance, diastolic blood pressure, insulin, triglycerides, LDL, or HDL cholesterol. No major adverse events were reported and side effects of resveratrol were not different than placebo/control. Though limitations in sample size and treatment duration preclude definitive changes in clinical practice, significant improvements in multiple cardiometabolic biomarkers and an excellent safety profile support resveratrol as a leading candidate as an adjunct to pharmacological management of T2DM.

20.Nutr Rev. 2013 Dec;71(12):822-35. Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Sahebkar A1.

A systematic review and meta-analysis of available evidence was conducted to obtain a conclusive result on the lipid-modulating effects of resveratrol. Seven randomized controlled trials with a total of 282 subjects (141 in each group) met the eligibility criteria. Overall, resveratrol supplementation had no significant effect on any of the lipid parameters assessed: total cholesterol (weighted mean difference [WMD] -8.70; 95% confidence interval [95% CI] -21.54-4.14; P?=?0.18), low-density lipoprotein cholesterol (WMD -3.22; 95% CI -12.56-6.12); P?=?0.50), high-density lipoprotein cholesterol (WMD -0.26; 95% CI -4.25-3.73; P?=?0.90), and triglycerides (WMD -4.30; 95% CI -20.22-11.63; P?=?0.60). These results were robust in sensitivity analysis and were not dependent on the resveratrol dose, the duration of supplementation, or the cardiovascular risk status of the population studied. While future large-scale, well-designed trials are warranted, the current evidence suggests that mechanisms other than hypolipidemic effects account for the established cardioprotective properties of resveratrol.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 Resveratrol

Resveratrol is a grape vine phenolic compound found in seventy two plant species. It was first discovered in 1939 and is classified as a stilbene because of its structure and termed a phytoalexin because of its protective effects against infections in plants. (1)

Resveratrol was named after Veratrum grandiflorum when it was isolated from the root of that vine. It is found in nature both in the cis- and trans- form, where the cis-form predominates. The trans form of Resveratrol that has been shown to display a much broader spectrum of pharmacological activity than the cis isomer. (2)

As a supplement, Resveratrol is extracted from Polygonum cuspidatum, also known as Japanese knotweed, or the Itadori plant.

 

 Research with Resveratrol has expanded over the last two decades to the point where two international conferences have been conducted over its diverse effects in animals and humans. This has attracted the attention of the worldwide medical community. (4)

Resveratrol has been suggested to have cardioprotective effects and improve metabolic function based on compelling in vitro and animal studies. (5, 6, 7)

A number of human clinical intervention trials have been initiated as a result of Resveratrol's promising preclinical results. However, human data is still scarce and many claims have been made about Resveratrol, making it a controversial subject. (9)

It is unclear whether Resveratrol's biological effects can be attributed to its antioxidant, calorie restriction mimetic, antinflammatory or other effects, and independent research is now exploring each pathway. (10, 11, 12)

Resveratrol is also found in red wine, and it has been suggested that it plays a role in the 'French Paradox' effect where consumption of red wine seems to improve cardiovascular outcomes in the French population despite a high fat diet. In fact the 'French paradox' itself drew the attention of researchers to Resveratrol in the first place when researchers took a deeper look into the precise components of red wine. (13)

Two French investigators, Renaud and de Lorgeril proposed that moderate wine consumption explained the discrepancy where the ratio of cardiovascular mortality was found to be two to three times lower in France than in the U.S., England and Sweden. (13)

This was later confirmed in a Copenhagen study of 2,826 men where moderate wine intake was associated with lower cardiovascular and cerebrovascular diseases. (14)

The active polyphenols in red wine include anthocyanins, which give it its color, flavanols, like quercetin, phenolic acids, such as gallic acid and the stilbene, Resveratrol. (15)

Each of these wine compounds is being researched extensively, but a special emphasis is being placed on Resveratrol.

Resveratrol and Aging

 Resveratrol is the first molecule that consistently slows aging across the board in unrelated species - yeast, roundworms, fish and fruitflies – and this effect has been noted in different laboratories.

The most recent lifespan extension effects of Resveratrol is on the short-lived fish, Nothobranchius Guentheri. Nothobranchius Guentheri is considered to be a promising vertebrate model to study aging. Resveratrol increased mean and  maximum lifespan of the fish treat by 17.34% and 17.66% compared to the fish in the control group  (16)

The first lifespan study with Resveratrol was conducted in 2003 in yeast resulting in a 70% increase in yeast lifespan. (17)

Resveratrol also increases the lifespan of fruitflies and the metazoan worms, C. elegans. (18)

Human Implications

Diverse cultures, such as the Japanese and Mediterranean populations eat and drink greater amounts of Resveratrol, for example, from wine and foods higher in polyphenols. No conclusions should be drawn as to whether Resveratrol affects human lifespan, but Resveratrol appears to support healthy lipid and glucose management in preliminary human trials. (19, 20)

References:

1.Drugs Exp Clin Res. 1999;25(2-3):57-63. Stilbene compounds: from the grapevine to wine. Bavaresco L1, Fregoni C, Cantù E, Trevisan M.

Stilbenes are natural compounds occurring in a number of plant families, including Vitaceae and (within this family) Vitis vinifera L., which is the most important species grown worldwide for grape and wine production. Stilbenes (resveratrol and viniferins) are present in grapevine as constitutive compounds of the woody organs (roots, canes, stems) and as induced substances (in leaves and fruit) acting as phytoalexins in the mechanisms of grape resistance against certain pathogens.Resveratrol (3, 5, 4'-trihydroxystilbene) was also detected in wine and it was thought to be the active principle of red wines that were shown to reduce heart diseases. This paper reviews data, obtained by the Viticulture Institute of the Catholic University at Piacenza and taken from the literature, on some aspects of stilbene physiology in grapevine and on their relation to resveratrol wine levels. Constitutive stilbene contents of woody organs are reported, as well as the possible role of cluster stems as a source of resveratrol for wine. The accumulation of stilbenes in grape berries infected by grey mould (Botrytis cinerea Pers.) has been investigated and the effects of environmental factors on resveratrol grape and wine levels will be discussed. An unidentified new hydroxystilbene was detected in wine.

PMID:10370866

2.Altern Med Rev. 2010 Jul;15(2):152-8. Resveratrol. Monograph.

PMID:20807000

3. Resveratrol. Monograph, Journal of Biological Chemistry.

4.PLoS One. 2011;6(6):e19881. What is new for an old molecule? Systematic review and recommendations on the use ofresveratrol.Vang O1, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM.

Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsing?r, Denmark.

METHODOLOGY:

Literature search in databases as PUBMED and ISI Web of Science in combination with manual search was used to answer the following five questions: (1)Can resveratrol be recommended in the prevention or treatment of human diseases?; (2)Are there observed "side effects" caused by the intake of resveratrol in humans?; (3)What is the relevant dose of resveratrol?; (4)What valid data are available regarding an effect in various species of experimental animals?; (5)Which relevant (overall) mechanisms of action of resveratrol have been documented?

CONCLUSIONS/SIGNIFICANCE:

The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research inresveratrol regarding its mechanism of action and its safety and toxicology in human subjects.

PMID:21698226

5.Altern Med Rev. 2010 Sep;15(3):245-63. A review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part 1. Kelly G1.

The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that the sirtuins are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Responses of this system to environmental factors, as well as its role in health and disease, are currently incompletely characterized and at most partially understood. This article reviews the mammalian sirtuin system, discusses the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarizes research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. Polyphenols, especially resveratrol, influence sirtuins. Existing evidence on these nutritional compounds, as they relate to the sirtuin system, is reviewed. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer, are discussed.

PMID:21155626 

6.Resveratrol activity on guinea pig isolated trachea from normal and albumin-sensitized animals. Ragazzi E, Froldi G, Fassina G. Pharmacol Res Commun. 1988 Dec;20 Suppl 5:79-82.

PMID:2907791

7.Plasma and tissue resveratrol concentrations and pharmacological activity. Bertelli A, Bertelli AA, Gozzini A, Giovannini L. Drugs Exp Clin Res. 1998;24(3):133-8.

PMID:9825229

8.Anticancer Res. 2004 Sep-Oct;24(5A):2783-840. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Aggarwal BB1, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y.

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

PMID:15517885

9.Pharmacol Res. 2014 Dec;90:88-115. Resveratrol and cardiovascular health--promising therapeutic or hopeless illusion? Tang PC1, Ng YF2, Ho S1, Gyda M3, Chan SW4.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural polyphenolic compound that exists in Polygonum cuspidatum, grapes, peanuts and berries, as well as their manufactured products, especially red wine. Resveratrol is a pharmacologically active compound that interacts with multiple targets in a variety of cardiovascular disease models to exert protective effects or induce a reduction in cardiovascular risks parameters. This review attempts to primarily serve to summarize the current research findings regarding the putative cardioprotective effects of resveratrol and the molecular pathways underlying these effects. One intent is to hopefully provide a relatively comprehensive resource for clues that may prompt ideas for additional mechanistic studies which might further elucidate and strengthen the role of the stilbene family of compounds in cardiovascular disease and cardioprotection. Model systems that incorporate a significant functional association with tissues outside of the cardiovascular system proper, such as adipose (cell culture, obesity models) and pancreatic (diabetes) tissues, were reviewed, and the molecular pathways and/or targets related to these models and influenced by resveratrol are discussed. Because the body of work encompassing the stilbenes and other phytochemicals in the context of longevity and the ability to presumably mitigate a plethora of afflictions is replete with conflicting information and controversy, especially so with respect to the human response, we tried to remain as neutral as possible in compiling and presenting the more current data with minimal commentary, permitting the reader free reign to extract the knowledge most helpful to their own investigations.

10.Biochim Biophys Acta. 2015 Jun;1852(6):1114-1123. The molecular targets of resveratrol. Kulkarni SS1, Cantó C2.

Resveratrol has emerged in recent years as a compound conferring strong protection against metabolic, cardiovascular and other age-related complications, including neurodegeneration and cancer. This has generated the notion that resveratroltreatment acts as a calorie-restriction mimetic, based on the many overlapping health benefits observed upon both interventions in diverse organisms, including yeast, worms, flies and rodents. Though studied for over a decade, the molecular mechanisms governing the therapeutic properties of resveratrol still remain elusive. Elucidating how resveratrolexerts its effects would provide not only new insights in its fundamental biological actions but also new avenues for the design and development of more potent drugs to efficiently manage metabolic disorders. In this review we will cover the most recent advances in the field, with special focus on the metabolic actions of resveratrol and the potential role of SIRT1 and AMPK. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

11.Endocr Metab Immune Disord Drug Targets. 2015 Mar 16. Resveratrol targets in inflammation. Inoue H1, Nakata R.

Resveratrol, a constituent of grapes and various other plants, has been an attractive compound for biomedical studies because moderate long-term drinking of red wine is associated with a reduced risk of lifestyle-related diseases, such as cardiovascular diseases and cancer. Resveratrol is as a phytoalexin, cyclooxygenase (COX) suppressor, and an activator of peroxisome proliferator-activated receptor (PPAR) and SIRT1. As a major phytoalexin, resveratrol is produced by plants in response to various environmental stresses, such as pathogens and ultraviolet (UV) radiation, and promotes resistance to these stresses. A similar active ingredient, salicylic acid (SA), is also produced by plants. Aspirin, acetylated SA, is a major nonsteroidal anti-inflammatory drug (NSAID) because it inhibits COX activity in humans. The jasmonic acid (JA) pathway in plants and the COX pathway in humans are both defense systems against environmental stresses and involve lipid mediators derived from phospholipids. We can hypothesize that there is a molecular basis for the mutually beneficial relationship between plants and humans, which is important for understanding the mode of action of resveratrol in inflammation. Here we provide a review of the studies on resveratrol, especially with respect to the role of COX and PPAR in inflammation.

PMID:25772176

12.Free Radic Res. 2000 Jul;33(1):105-14. Resveratrol inhibition of lipid peroxidation. Tadolini B1, Juliano C, Piu L, Franconi F, Cabrini L.

To define the molecular mechanism(s) of resveratrol inhibition of lipid peroxidation we have utilized model systems that allow us to study the different reactions involved in this complex process. Resveratrol proved (a) to inhibit more efficiently than either Trolox or ascorbate the Fe2+ catalyzed lipid hydroperoxide-dependent peroxidation of sonicated phosphatidylcholine liposomes; (b) to be less effective than Trolox in inhibiting lipid peroxidation initiated by the water soluble AAPH peroxyl radicals; (c) when exogenously added to liposomes, to be more potent than alpha-tocopherol and Trolox, in the inhibition of peroxidation initiated by the lipid soluble AMVN peroxyl radicals; (d) when incorporated within liposomes, to be a less potent chain-breaking antioxidant than alpha-tocopherol; (e) to be a weaker antiradical than alpha-tocopherol in the reduction of the stable radical DPPH*. Resveratrol reduced Fe3+ but its reduction rate was much slower than that observed in the presence of either ascorbate or Trolox. However, at the concentration inhibiting iron catalyzed lipid peroxidation, resveratrol did not significantly reduce Fe3+, contrary to ascorbate. In their complex, our data indicate that resveratrol inhibits lipid peroxidation mainly by scavenging lipid peroxyl radicals within the membrane, like alpha-tocopherol. Although it is less effective, its capacity of spontaneously entering the lipid environment confers on it great antioxidant potential.

PMID:10826926 

13.Lancet. 1992 Jun 20;339(8808):1523-6. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Renaud S1, de Lorgeril M.

In most countries, high intake of saturated fat is positively related to high mortality from coronary heart disease (CHD). However, the situation in France is paradoxical in that there is high intake of saturated fat but low mortality from CHD. Thisparadox may be attributable in part to high wine consumption. Epidemiological studies indicate that consumption of alcohol at the level of intake in France (20-30 g per day) can reduce risk of CHD by at least 40%. Alcohol is believed to protect from CHD by preventing atherosclerosis through the action of high-density-lipoprotein cholesterol, but serum concentrations of this factor are no higher in France than in other countries. Re-examination of previous results suggests that, in the main, moderate alcohol intake does not prevent CHD through an effect on atherosclerosis, but rather through a haemostatic mechanism. Data from Caerphilly, Wales, show that platelet aggregation, which is related to CHD, is inhibited significantly by alcohol at levels of intake associated with reduced risk of CHD. Inhibition of platelet reactivity by wine (alcohol) may be one explanation for protection from CHD in France, since pilot studies have shown that platelet reactivity is lower in France than in Scotland.

14.BMJ. 1996 Mar 23;312(7033):736-41. Alcohol consumption, serum low density lipoprotein cholesterol concentration, and risk of ischaemic heart disease: six year follow up in the Copenhagen male study. Hein HO1, Suadicani P, Gyntelberg

To investigate the interplay between use of alcohol, concentration of low density lipoprotein cholesterol, and risk of ischaemic heart disease.

Prospective study with controlling for several relevant confounders, including concentrations of other lipid fractions.

Copenhagen male study, Denmark.

2826 men aged 53-74 years without overt ischaemic heart disease.

Incidence of ischaemic heart disease during a six year follow up period.

RESULTS:

172 men (6.1%) had a first ischaemic heart disease event. There was an overall inverse association between alcohol intake and risk of ischaemic heart disease. The association was highly dependent on concentration of low density lipoprotein cholesterol. In men with a high concentration (> or = 5.25 mmol/l) cumulative incidence rates of ischaemic heart disease were 16.4% for abstainers, 8.7% for those who drank 1-21 beverages a week, and 4.4% for those who drank 22 or more beverages a week. With abstainers as reference and after adjustment for confounders, corresponding relative risks (95% confidence interval) were 0.4 (0.2 to 1.0; P<0.05) and 0.2 (0.1 to 0.8; P<0.01). In men with a concentration <3.63 mmol/l use of alcohol was not associated with risk. The attributable risk (95% confidence interval) of ischaemic heart disease among men with concentrations > or = 3.63 mmol/l who abstained from drinking alcohol was 43% (10% to 64%).

In middle aged and elderly men the inverse association between alcohol consumption and risk of ischaemic heart disease is highly dependent on the concentration of low density lipoprotein cholesterol. These results support the suggestion that use of alcohol may in part explain the French paradox.

15.J Agric Food Chem. 2005 Mar 23;53(6):2015-21. Dietary wine phenolics catechin, quercetin, and resveratrol efficiently protect hypercholesterolemic hamsters against aortic fatty streak accumulation.

Auger C1, Teissedre PL, Gérain P, Lequeux N, Bornet A, Serisier S, Besan?on P, Caporiccio B, Cristol JP, Rouanet JM.

The effects of the phenolic compounds catechin (Cat), quercetin (Qer), and resveratrol (Res) present in red wine on early atherosclerosis were studied in hamsters. Hamsters (n = 32) were divided into 4 groups of 8 and fed an atherogenic diet for 12 weeks. They received by force-feeding 7.14 mL/(kg of body wt.day) Cat, Qer, or Res in water [2.856 mg/(kg of body wt.day) for Cat and 0.1428 mg/(kg of body wt.dday) for Qer and Res], mimicking a moderate consumption of alcohol-free redwine (equivalent to that supplied by the consumption of about two glasses of red wine per meal for a 70 kg human), or water as control. Plasma cholesterol concentration was lower in groups that consumed phenolics than in controls. The increase in plasma apolipoprotein (Apo) A1 concentration was mainly due to Cat (26%) and Qer (22%) and to a lesser extent, but nonsignificantly, Res (19%). Apo-B was not affected. Plasma antioxidant capacity was not improved, and there was no sparing effect on plasma vitamins A and E. Plasma iron and copper concentrations were not modified nor were liver super oxide dismutase and catalase activities. A sparing effect of Qer on liver glutathione peroxidase activity appeared, whereas Cat and Res exhibited a smaller effect. Aortic fatty streak area was significantly reduced in the groups receiving Cat (84%) or Qer (80%) or Res (76%) in comparison with the controls. These findings demonstrate that catechin, quercetin, and resveratrol at nutritional doses prevent the development of atherosclerosis through several indirect mechanisms.

PMID:15769129 

16.Rejuvenation Res. 2015 Jan 8. Resveratrol attenuates oxidative stress and extends lifespan in the annual fish Nothobranchius Guentheri. Liu T1, Qi H, Ma L, Liu Z, Fu H, Zhu W, Song T, Yang B, Li G.

Resveratrol is a natural polyphenol derived mainly from skin of grapes and red wine. Resveratrol prolongs lifespan in several invertebrates, but this function is not found in mice. Our recently published paper demonstrated that resveratrol prolonged longevity of the annual fish Nothobranchius guentheri, a promising vertebrate model for anti-aging research. However, the anti-aging process by resveratrol remains largely unexplored, and little is known about its effects on oxidative stress. In this paper, by long term supplementation of resveratrol from sexual maturity, we detected the survivorship, and oxidative stress at three different developmental stages in vivo. Fish of 112 were fed with resveratrol in the concentration of 200μg/g food and fish of 111 without resveratrol from 16 weeks of age until to the end of their lives. The mean and maximum lifespan of the fish treated with resveratrol was extended by 17.34% and 17.66% compared to the fish in control group. The markers of oxidative stress, such as the level of reactive oxygen species, the activities of antioxidant enzymes and the degree of oxidative damage, were detected at 6-, 9- and 12-month-old respectively. The results presented that levels of ROS and oxidative damage displayed increased trend and activities of antioxidant enzymes appeared decreased trend with age. Resveratroltreatment significantly attenuated the increase of ROS level and oxidative damage, up-regulated the decrease of antioxidant enzyme activities induced by aging. Our results demonstrated that resveratrol decreased oxidative stress and extendedlifespan in this short-lived fish.

PMID:25569124

17.Nature. 2003 Sep 11;425(6954):191-6. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.

Howitz KT1, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B,Sinclair DA.

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeastSaccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast,resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

18.Nature. 2004 Aug 5;430(7000):686-9. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Wood JG1, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D.

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.

19.Mol Nutr Food Res. 2015 Jan;59(1):147-59. Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. Hausenblas HA1, Schoulda JA, Smoliga JM.

The red wine polyphenol, resveratrol, is highly effective in treating type 2 diabetes mellitus (T2DM) in animal models, but there is no consensus regarding its efficacy in humans. We conducted a systematic review, which included searches in nine scholarly databases and six clinical trial registries, and identified randomized controlled clinical trials whereby resveratrolwas used as an adjunct to pharmaceutical interventions in T2DM. Meta-analysis on clinical parameters was performed for available data. Of 764 articles originally identified, data from six unique datasets, examining a total of 196 T2DM patients (104 resveratrol, 92 control/placebo) ultimately met inclusion criteria. Statistically significant (p < 0.05) positive effects, indicating that resveratrol supplementation was more effective than placebo/control, were identified for systolic blood pressure, hemoglobin A1c, and creatinine, but not for fasting glucose, homeostatic model assessment of insulin resistance, diastolic blood pressure, insulin, triglycerides, LDL, or HDL cholesterol. No major adverse events were reported and side effects of resveratrol were not different than placebo/control. Though limitations in sample size and treatment duration preclude definitive changes in clinical practice, significant improvements in multiple cardiometabolic biomarkers and an excellent safety profile support resveratrol as a leading candidate as an adjunct to pharmacological management of T2DM.

20.Nutr Rev. 2013 Dec;71(12):822-35. Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Sahebkar A1.

A systematic review and meta-analysis of available evidence was conducted to obtain a conclusive result on the lipid-modulating effects of resveratrol. Seven randomized controlled trials with a total of 282 subjects (141 in each group) met the eligibility criteria. Overall, resveratrol supplementation had no significant effect on any of the lipid parameters assessed: total cholesterol (weighted mean difference [WMD] -8.70; 95% confidence interval [95% CI] -21.54-4.14; P?=?0.18), low-density lipoprotein cholesterol (WMD -3.22; 95% CI -12.56-6.12); P?=?0.50), high-density lipoprotein cholesterol (WMD -0.26; 95% CI -4.25-3.73; P?=?0.90), and triglycerides (WMD -4.30; 95% CI -20.22-11.63; P?=?0.60). These results were robust in sensitivity analysis and were not dependent on the resveratrol dose, the duration of supplementation, or the cardiovascular risk status of the population studied. While future large-scale, well-designed trials are warranted, the current evidence suggests that mechanisms other than hypolipidemic effects account for the established cardioprotective properties of resveratrol.