Recommendations on relevant research to be performed in the near future It clearly follows from the recommendations for the use of Resv that evidence for the effect of Resv in humans is lacking. Table 7 shows the research in the field of Resv considered of highest priority. These recommendations naturally do not give space for a full list of relevant research projects, but only the most relevant from the point of view of the scientific working group of the Resveratrol2010 conference. The clinical studies with focus on cancer prevention might have a high priority, and as the most clear results have been shown in animal models of cancer in skin and colon these targets are the most relevant points of initiation. Furthermore, investigation of the effect of Resv on metabolic disorders evaluated in preclinical studies in nonhuman primates also has a high priority. Relevant clinical studies should be done soon and address the preventive effect of Resv on coronary heart disease. However, long term studies in animal models are still needed in order to evaluate the chronic effect of Resv to identify a probable NOAEL in human. Since chronic low grade inflammation is reduced by resveratrol and is a general characteristic of several of the life style disease, the effect of Resv on inflammatory biomarkers should be investigated in the coming clinical studies. 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 biomark- ers need to be identified, developed and verified to analyze the long term disease prevention (Table 7). 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 pre- clinical 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 in vivo, which is very relevant to forecast the biological effect of Resv in humans. Several Resv metabolites have been identified but the biological activity of these metabolites formed in humans and experimental animals needs to be elucidated fully. Lastly, the combinatory effect of Resv with other bioactive compounds has only been studied in few cases in experimental animals or in vitro. These studies should be amplified, as the outcomes of the combinations are not only additive but also synergistic or even antagonistic. The effect of Resv on the metabolism of these compounds have to be addressed as well, e.g. regulation of Cytochrome P450 enzymes and activities. Conclusions The scientific literature cannot yet justify recommendation for the chronic administration of resveratrol to human beings, as stated in Table 6. Humans are receiving resveratrol frequently in red wine, berries, peanuts etc. but these levels are low, less than 4 mg. Before having data from chronic exposure to higher levels of Recommendations on the Use of Resveratrol resveratrol or more chronic studies with experimental animals, intake of resveratrol at higher doses should be considered experimental. 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. Supporting Information Table S1 Overview of the effect of resveratrol on cancer development in experimental animals. To identify papers investigating the cancer preventive potential of resveratrol, a literature search using the terms ‘‘resveratrol’’ in combination with ‘‘cancer’’, ‘‘carcinogenesis’’ or ‘‘chemoprevention’’ up to Septem- ber 2010 was performed. In total, 1191 papers were identified, but only 41 papers were found to investigate the effect of resveratrol in animal model systems. (DOCX) Table S2 Overview of the effect of resveratrol on coronary heart disease models in experimental animals. To identify papers investigating the effect of resveratrol on coronary heart diseases, a literature search using the terms ‘‘resveratrol’’ in combination with ‘‘hypertension’’, ‘‘heart failure’’, ‘‘myocardial infarct’’, ‘‘cardiac arrest’’, ‘‘ischemia heart disease’’, ‘‘stroke’’ or ‘‘serum lipids’’ up to September 2010 was done. 118 papers were found, but only 26 papers showed data from non acute animal experiments. (DOCX) Table S3 Overview of experiments focusing on the effect of resveratrol on obesity and diabetes in experi- mental animals. In total, 218 articles were identified, but only 19 animal studies were found to investigate the non-acute effects of resveratrol. The search terms ‘‘resveratrol’’ were used in combination with ‘‘metabolic syndrome’’, ‘‘obesity’’, ‘‘diabetes’’, ‘‘insulin sensitivity’’, ‘‘plasma glucose’’ or ‘‘visceral fat’’ in a literature search including papers published up to September 2010. (DOCX) Table S4 Overview of the neuroprotective effect by resveratrol was in focus of 163 papers, of which 40 papers concerned animal with acute exposure and sub- and chronic exposure. The search terms ‘‘resveratrol’’ was used in combination with ‘‘neuroprotection’’ or ‘‘neuroprotective’’ including papers published up to September 2010. (DOCX) Table S5 Overview of the effect of resveratrol on inflammatory markers in experimental animals. To identify papers investigating the effect of resveratrol on inflam- matory markers, a literature search using the terms ‘‘resveratrol’’ in combination with ‘‘inflammation’’ or ‘‘inflammatory’’ was done, including papers published up to September 2010. In total, 559 papers were identified, whereas only 31 papers included sub- chronic and chronic exposures of resveratrol to experimental animals. (DOCX) Acknowledgments Associate Professor Louise Dalgaard, Roskilde University, is acknowledged for critical comments during the process of writing this article. PLoS ONE | www.plosone.org 8 June 2011 | Volume 6 | Issue 6 | e19881