Conceived and designed the experiments: OV. Analyzed the data: OV NA CAB JAB KB AC DKD DD CG H-YL Q-YM PM NN JMP TR YS Y-JS T. Szekeres T. Szkudelski TW JMW. Wrote the paper: OV. Evaluation of the cancer preventive effect: NA KB H-YL NN JMP YS T. Szekeres. Evaluation of the CHD preventive effect: DKD PM JMW. Evaluation of the obesity/diabetes effect: CAB T. Szkudelski. Evaluation of the anti-aging/anti-inflammatory effect: JAB AC Q-YM. Evaluation of the neuroprotective effect: CG TR. Metabolism and pharmacokinetic of resveratrol: DD TW.
OV is a scientific consultant for Fluxome Science A/S. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
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 Helsingør, Denmark.
Literature search in databases as PubMed and ISI Web of Science in combination with manual search was used to answer the following five questions: 1Can resveratrol be recommended in the prevention or treatment of human diseases?; 2Are there observed “side effects” caused by the intake of resveratrol in humans?; 3What is the relevant dose of resveratrol?; 4What valid data are available regarding an effect in various species of experimental animals?; 5Which relevant (overall) mechanisms of action of resveratrol have been documented?
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 in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.
Resveratrol (Resv) is a simple molecule that has taken the spotlight since the first scientific paper described a possible preventive effect on cancer in mice
A number of long-term clinical studies in humans have recently been initiated or is under planning and ideally in 2–5 years, we will know much more about the biological effects of Resv in humans. But before these data are available, the prediction of biological effects of Resv in humans have to rely primarily on data obtained in experimental animals and from
The aim of the recent conference, Resveratrol2010,
The task of the working group discussion was to formulate a number of scientifically based recommendations for 1the human use of resveratrol and 2research on resveratrol for the coming years based on scientific literature and data made available during the previous 2½ days of the conference. As Resv has been suggested to promote health in relation to various diseases or sufferings, the participating scientists covered a broad range of research on the biological effects of Resv, which included the following subjects, 1resveratrol and cancer; 2resveratrol and heart disease; 3neuroprotective activity of resveratrol; 4effect of resveratrol on longevity; 5effect of resveratrol on inflammation; 6effect of resveratrol on obesity and diabetes; 7metabolism and stability of resveratrol and 8production and commercial use of resveratrol.
The final recommendations to the use of resveratrol are given in
Can resveratrol be recommended in the prevention or treatment of human diseases? |
• There are not yet unequivocal scientific data for the effect of resveratrol as a disease preventative substance in humans nor for human life extension. |
• There is not yet sufficient evidence for a therapeutic effect of resveratrol in humans, either alone or in combination with other natural compounds or formulations. |
Are there observed “side effects” caused by the intake of resveratrol in humans? |
• There are no valid data on the toxicity of chronic intake of resveratrol in humans. |
• A short term human study (29 days) indicated frequent gastrointestinal discomfort/diarrhea only at high doses (2.5 g or 5 g per day). Only minor and inconsistent side effects have been observed in other short-term or acute studies. |
What is the relevant dose of resveratrol? |
• A relevant or optimal dose for resveratrol has yet to be established by human studies and will almost certainly vary depending on the effect being studied. |
• Doses in the range of hundreds of mg to several g per day have been proposed based on animal studies, but more human studies are needed to confirm these estimates. |
• Chronic human intake above the concentrations contained in natural food should be considered experimental until long-term human studies have been performed. |
What valid data are available regarding an effect in various species of experimental animals? |
• There is sufficient evidence for a chemopreventive effect of resveratrol on the development of cancer in skin of mice. There are promising results on the prevention of colon cancer in animals. The effects of resveratrol on other cancer types than skin cancer need to be investigated more in detail prior to recommending clinical trials. |
• There is sufficient evidence to suggest resveratrol reduces the incidence of hypertension, heart failure, ischemia heart disease in experimental animal models. |
• There is sufficient evidence to suggest resveratrol improves insulin sensitivity, reduces blood glucose levels, and reduces high fat diet-induced obesity in rodents. |
• Resveratrol showed neuroprotective effects in experimental animal models of injury or degeneration. |
• Resveratrol is well tolerated in rats and no toxicological effects are observed up to 700–1000 mg/kg bw/day. |
Which relevant (overall) mechanisms of action of resveratrol have been documented? |
• Modulation of cell proliferation and apoptosis |
• Modulation of angiogenesis |
• Inhibition of metastasis |
• Modulation of redox status |
• Suppression of adipogenesis and stimulation of adipocyte lipolysis |
• Stimulation of osteogenesis |
• Modulation of mitochondria activity |
• Suppression of inflammation |
• Modulation of DNA damage |
• Modulation of xenobiotic metabolism |
• Modulation of glutamate metabolism |
• Estrogenic activity/anti-estrogenic activity |
1 | Published evidence today is not sufficiently strong to justify recommendation for the chronic administration of resveratrol to human beings, beyond the dose which can be obtained from dietary sources. |
2 | Animal data are promising and indicate the need for further human clinical trials. |
1 | Clinical studies should be initiated, especially with focus on the effect of resveratrol on the development of cancers in colon and skin |
2 | Clinical studies should be initiated to test the potential cardio-vascular benefit of resveratrol |
3 | Elucidating the biological effects of resveratrol metabolites |
4 | Biodistribution and degradation of resveratrol |
5 | Preparation of a resveratrol reference (international standard) product for analytical purposes |
6 | Standardized formulations for clinical studies |
7 | Combinatory effects of resveratrol with other compounds. This include development of relevant models |
8 | Interaction of resveratrol with drug metabolism (especially cytochrome P450 metabolism) |
9 | Identification/development of relevant biomarkers, relevant for the disease-prevention rather than disease treatment, depending on the relevant disease |
10 | Effect of resveratrol on inflammation as general condition relevant for several lifestyle diseases |
11 | Long term preclinical studies in nonhuman primates may be appropriate to determine the effect of resveratrol on diet-induced metabolic disorders, such as development of insulin resistance |
To generate a scientifically valid foundation for the formulation of these recommendations, a systematic search was performed in MEDLINE (
The identified publications were used to answer the following five questions: 1Can resveratrol be recommended in the prevention or treatment of human diseases?; 2Are there observed side effects caused by intake of resveratrol in humans?; 3What is the relevant dose of resveratrol?; 4What valid data are available regarding an effect in various species of experimental animals?; 5Which relevant (overall) mechanisms of action of resveratrol have been documented?
The term “resveratrol” is found in title, abstract or MESH word in 5425 or 3650 publications following searching on ISI Web of Science or PubMed, respectively. The substantially higher number of hits found in ISI Web of Science was due to abstracts or papers with focus on identification of sources of Resv. All the publications relevant for this systematic review were present in both data bases and the refinement of the search using PubMed is indicated in
The literature search was performed to identify all relevant articles focusing on resveratrol and chemoprevention (A), effect of resveratrol on cardio vascular disease (B), effect of resveratrol obesity and diabetes (C), neuroprotective effect of resveratrol (D) and the anti-inflammatory effect of resveratrol (E). In all five groups, articles with non-english language, review articles and articles showing data from
A major challenge for scientists investigating Resv is to prove that it has the health promoting effects, which have been suggested based on the
Most of the available clinical studies with Resv in humans focus on bioavailability, pharmacokinetics and metabolism of Resv
Two clinical studies were described by Elliott
The tissue distribution of Resv and its metabolites was estimated in a study where twenty colon cancer patients received 0.5 g or 1.0 g Resv daily for eight days before surgical resection
Several clinical trials of oral Resv as a pure compound or using Resv-rich products (grapes and grape juice) are under way. In total, 24 clinical studies are listed at the homepage
Based on the limited number of human studies, the working group has concluded that there is not at the moment enough available and scientifically valid data on the effect of Resv to conclusively state whether it could be a disease preventive substance in humans or could be used for human life extension (
Based on animal studies, Resv is generally well tolerated, and only very few short-term or acute exposure experiments in humans have been performed. When eight healthy subjects were exposed to 2000 mg Resv twice/day for eight days, six of eight subjects had mild episodic diarrhea/loose stool, typically in the beginning of the eight days treatment period, and one of the subjects developed a temporary rash and headache
According to Elliott
It is difficult to estimate the normal human consumption of Resv as the intake of red wine (verified main source of Resv) differs greatly in the population and the content of Resv varies (mean 1.9±1.7 mg/L)
Only a single experiment has tested Resv in a classical chronic exposure experiments, i.e. at least 24 months in rats or 18 months in mice
In mice (C57BL/6 p53−/−) oral administration of Resv (1000, 2000, 3000, 4000 or 5000 mg/kg bw/day) showed an increased death rate caused by impaction of Resv in the gastrointestinal tract
Elliott
Several experiments have shown that Resv does not have genotoxic activity, based on the Ames test
Reproductive toxicity was evaluated in rats and the maternal ‘no observed adverse effect level’ (NOAEL) was estimated at 300 mg/kg bw/day and the developmental NOAEL was estimated at 300 mg/kg bw/day, but no experimental details were given
Several examples of self reported side effects of Resv intake may be found on various homepages from the internet, but there is no comprehensive evaluation of these self reported side effects.
Based on the available data, which mostly originate from studies of very short duration, the working group formulated the following conclusions (
There are no valid data on the toxicity of chronic intake of resveratrol in human subjects.
A short term human study (29 days) indicated frequent gastrointestinal discomfort/diarrhea only at high doses (2.5 g or 5 g per day). Only minor and inconsistent side effects have been observed in other short-term or acute studies.
Resveratrol has been proposed to be active in the prevention of various life style diseases such as cancer, coronary heart diseases and type 2 diabetes. Different mechanisms are likely involved besides the modulation of inflammation as a unifying mechanism. Because of different mechanisms and targets one must assume that the optimal dose will depend on the particular disease.
As indicated above, only a few human studies have been performed, showing down-regulation of cancer biomarkers by 2.5 g Resv/day for 28 days
Several human studies have investigated the effects of Resv containing food items. The exposure to Resv is likely in all cases less than 4 mg. Human acute or sub chronic (two weeks) intake of red wine, dealcoholized red wine or red grape juice did not show effect on Tumor necrosis factor (TNF) α, Interleukin (IL)-2 or IL-4 levels, indicating no anti-inflammatory response of the wine but the presence of Resv in the wine was not proven
Resveratrol is found to reduce the risk of colon cancer development in experimental animals (see below) using doses in the range of 0.2 to 8 mg/kg in rats and 2.4 to 60 mg/kg in mice. Applying the dose translations factors described by Reagan-Shaw
Enhanced insulin sensitivity by Resv was observed in experimental animals when exposed to 2.5–400 mg/kg in mice and 1–100 mg/kg in rats (see below). The corresponding HED are 12–1945 mg (based on mouse data) or 10–973 mg/day for a 60 kg person.
The relevant effective dose of Resv needs to be established in humans in relation to the different diseases that it may counteract and the working group concludes (
A relevant or optimal dose for resveratrol has yet to be established by human studies and will almost certainly vary depending on the effect being studied.
Doses in the range of hundreds of mg to several g per day have been proposed based on animal studies, but more human studies are needed to confirm these estimates.
Chronic human intake above the concentrations contained in natural food should be considered experimental until long-term human studies have been performed.
The initial paper by Jang
To test the effect of Resv on breast cancer, four studies used mice where Resv showed a reducing effect in three experiments
Resveratrol reduced chemically-induced liver cancer in rats
To study the effect of Resv on colon cancer development in animals, four studies focus on chemically-induced colon cancer in rats or mice
Resveratrol showed a chemopreventive effect on development of prostate cancer using rat or mice strains prone to spontaneously developing prostate cancer
Risk reduction of cardiovascular events is one of the most well-known health promoting effects of Resv. It has been shown that Resv may modulate various aspects of cardio-vascular diseases, including atherosclerosis, hypertension, ischemia reperfusion injury and heart failure.
Resveratrol reduced hypertension in various models (
Several studies (five have been identified) showed a preventive effect of Resv on myocardial infarction induced by surgery. All studies showed a reduced infarct size effect and one experiment even at the low dose of 1 mg Resv/kg bw/day for four weeks
Animal studies focusing on the effect of Resv on obesity and diabetes are shown in
The effect of Resv on insulin sensitivity has been the subject in nine studies using rats or mice in which insulin sensitivity was reduced by high fat diets, using animal strains prone to developing insulin resistance or by chemically induced diabetes (treatment with streptozotocin). Nearly all experiments showed a reduced insulin level or increased insulin sensitivity using doses covering 2.5–400 mg/kg bw/day and exposure time covering 1–6 months
Ten studies have been identified which investigated the effect of Resv on blood glucose levels, using genetically obese mice or rats, dietary induced obesity or chemically induced diabetes by STZ or alloxan
Several animal studies have indicated that Resv has a neuroprotective effect (
Inflammatory response is a well known mechanism of the diseases described above such as cancer, coronary-heart disease, diabetes and neurodegeneration. Resveratrol is shown to modulate the inflammatory response induced by various stimuli. Fourteen studies have investigated the effect of exposure of one week or more to Resv on various inflammatory markers in rats. The same number of studies has been identified using mice as an experimental model. Generally, Resv in nearly all models counteracted the increased levels of pro inflammatory biochemical markers, such as TNFα, IL-1β, IL-6 in nearly all models. Beside these cytokines, MCP-1, COX-2 and iNOS was most often found to be down-regulated by Resv when stimulated by the pro-inflammatory treatment. The estimates of inflammation were often performed as a part of a study with another aim, i.e. testing a chemopreventive effect, or the effect of Resv on diabetes or cardiovascular disease. Therefore, different inducers of the inflammatory status have been used; Resv reduced inflammation in several models such as obesity-induced
Besides the animal experiments described above which focused on chronic or near-chronic exposures, a long list of papers exist that analyze the effect of Resv after an acute exposure on biomarkers relevant for prevention of cancer, coronary-heart disease and diabetes. These articles are not included in the present review.
The working group concluded (
There is sufficient evidence for a chemopreventive effect of resveratrol on the development of skin cancer in mice. There are promising results on the prevention of colon cancer in animals. The effects of resveratrol on other cancer types besides skin cancer need to be investigated more in detail prior to recommending clinical trials.
There is sufficient evidence to suggest that resveratrol reduces the incidence of hypertension, heart failure, ischemia heart disease in experimental animal models.
There is sufficient evidence to suggest that resveratrol improves insulin sensitivity, reduces blood glucose levels, and reduces high fat diet-induced obesity in rodents.
Resveratrol showed neuroprotective effects in experimental animal models of injury or degeneration.
Resveratrol is well tolerated in rats and no toxicological effects are observed up to 700–1000 mg/kg bw/day.
Without going too much into details, and without giving the references, several mechanisms of action of Resv are relevant in relation to its proposed enhancement of human health. A number of mechanisms are relevant for several of the diseases mentioned herein, whereas others are more specific. The working group has identified twelve such mechanisms, as listed in
Suppression of inflammation is a general mechanism relevant for prevention of cancer diseases, coronary heart diseases, diabetes and neurodegeneration, as indicated above. Similarly, modulation of the cellular redox status is closely related to several diseases and linked to the anti-inflammatory effect. Modulation of cell proliferation and apoptosis as well as modulation of angiogenesis, inhibition of metastasis and suppression of DNA damage are relevant especially in cancer diseases. Modulation of xenobiotic metabolism by Resv likely plays a significant role in cancer prevention but may also have an impact on metabolism of drugs used to treat the listed diseases. Modulation of mitochondrial activity seems crucial in obesity/diabetes but may also be relevant for understanding life extension as well as be related to the inhibition of cell proliferation. Suppression of adipogenesis and stimulation of adipocyte lipolysis by Resv is relevant when one consider the effect on obesity and diabetes. Relevant for neuroprotection by Resv is the modulation of glutamate metabolism. Resveratrol also stimulates osteogenesis which indicates an effect on bone biology. Estrogenic activity but also anti-estrogenic activity by Resv has been shown but the clinical significance of these observations is uncertain.
It clearly follows from the recommendations for the use of Resv that evidence for the effect of Resv in humans is lacking.
One of the major challenges in the clinical studies investigating the preventive effect of e.g. Resv is to show the absence or reduced incidence of a specific disease end point. Such intervention studies should then be long term and will therefore be very expensive. To overcome these challenges, new biomarkers need to be identified, developed and verified to analyze the long term disease prevention (
To make preclinical and clinical studies comparable, the working group suggests that a standard Resv formulation should be performed. Such standardized Resv formulation should be made based on very pure Resv preparations. The use of non-pure Resv samples for preclinical or clinical experiments makes their interpretation very difficult. On the other hand, elucidation of the combined effect of Resv together with other dietary or non-dietary compounds should be accelerated as combinatory effects may solve some of the possible draw backs of high doses of resveratrol.
Besides using a standardized Resv formulation for the preclinical and clinical studies a Resv reference should be prepared for analytical purposes, such as analyzing metabolite formation and in the investigation of the bioavailability of Resv.
The bioavailability of Resv is described to some extent but have to be analyzed further to find the biodistribution and the degradation
Lastly, the combinatory effect of Resv with other bioactive compounds has only been studied in few cases in experimental animals or
The scientific literature cannot yet justify recommendation for the chronic administration of resveratrol to human beings, as stated in
In contrast to the lacking data of resveratrol in humans, the animal data are promising and indicate the need for further human clinical trials. Therefore, the working group from the Resveratrol 2010 conference recommends that these human trials will be initiated soon.
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Associate Professor Louise Dalgaard, Roskilde University, is acknowledged for critical comments during the process of writing this article.