PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of agingLink to Publisher's site
 
Aging (Albany NY). Mar 2012; 4(3): 146–158.
Published online Mar 12, 2012.
PMCID: PMC3348475
The journey of resveratrol from yeast to human
Silvie Timmers,1,2 Johan Auwerx,3 and Patrick Schrauwen1,2
1 Top Institute Food and Nutrition (TIFN), 6700 Wageningen, The Netherlands
2 Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, 6200 Maastricht, The Netherlands.
3 Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
Correspondence to: Patrick Schrauwen, PhD; p.schrauwen/at/maastrichtuniversity.nl
Received March 1, 2012; Accepted March 10, 2012.
Abstract
The natural polyphenolic compound resveratrol was first discovered in the 1940s. In the recent years, this compound received renewed interest as several findings implicated resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction, and regulating longevity in lower organisms. Given the worldwide increase in age-related metabolic diseases the beneficial effects of resveratrol on metabolism and healthy aging in humans are currently a topic of intense investigation.
Keywords: Resveratrol, SIRT1, sirtuins, calorie restriction, aging, metabolic diseases
Resveratrol (3,5,4'-trihydroxystilbene) was first isolated from the roots of white hellebore (Veratum grandiflorum O. Loes) in 1940 [1], and later, in 1963 from the roots of Polygonum Cupsidatum, a plant used in traditional Chinese and Japanese medicine [2]. However, the first real interest in this compound came when in 1992 resveratrol was postulated to explain some of the cardio-protective effects of red wine [3] and was suggested to be an important factor in the French Paradox, a term coined to describe the observation that the French population has a very low incidence of cardiovascular disease, despite a diet high in saturated fat [4]. Five years later, in 1997, Jang and colleagues reported resveratrol to work as a chemo-preventive agent, by the ability to inhibit carcinogenesis at multiple stages [5]. Meanwhile, also anti-inflammatory and anti-oxidant properties were identified for resveratrol (see reference [6, 7] for review). Interest in resveratrol peaked after 2003, when Howitz and colleagues [8] identified resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction [9, 10] and regulating longevity in lower organisms, by extending lifespan in yeast [8], worms [11], flies (although some controversy remains for this organism [12, 13]) and in short-lived fish [14]. Although there are a considerable amount of data supporting the role for resveratrol in SIRT1-mediated lifespan extension, recent data by Burnett et al. [15], however, suggest that SIRT1 may not increase longevity in Caenorhabditis elegans and Drosophila melanogaster. Currently the exact role of resveratrol and SIRT1 in longevity is still under debate. What however remains uncontested is that resveratrol does appear to delay or attenuate many age-related chronic diseases in animal models [16]. Given these beneficial effects in animal models, the eventual therapeutic effects of resveratrol merit to be investigated in humans. The first reports of such studies are demonstrating that also in human metabolic diseases, resveratrol may improve overall metabolic health status [17, 18].
Resveratrol is a small polyphenol found in various berries, nuts, and other plant sources [6]. A number of studies have demonstrated that resveratrol and other polyphenols have a very low bioavailability, leading to the concern that many of the beneficial health effects observed in either cells or biochemical assays, may not be achievable in humans due to rapid metabolism [19]. So, one important question - though difficult to answer - is “what dose of resveratrol should be used?”.
The bioavailability and pharmacokinetics of resveratrol has been extensively studied in humans as well as experimental animals. In humans, resveratrol is rapidly taken up after oral consumption of a low dose, with the plasma resveratrol concentration peaking about 30 minutes after consumption [19]. Up to 70% of the ingested resveratrol has been found to be bioavailable in humans based on the levels appearing in the plasma [20], with similar levels being reported for rats (~50%) [21]. Both in rats and humans, resveratrol is suggested to undergo an enterohepatic cycle of metabolism. That is, after being taken up quickly by the enterocytes, resveratrol is metabolized to glucuronide and sulfate conjugates, which are secreted back to the intestine where they may be deconjugated and reabsorbed or excreted in the faeces [20, 21]. The enterohepatic cycle thus reduces the concentration of the free compound reaching the different target tissues in the body. In that respect, the low concentration of resveratrol in the blood is likely explained by the enterohepatic cycle, together with rapid metabolism in the liver. The glucuronide and sulfate conjugates, including disulfates and mixed sulfate-glucuronides, are the major metabolites being formed, apart from dihydroresveratrol [22].
So, it is clear that only a small fraction of the ingested resveratrol reaches the body tissues as resveratrol. Furthermore, the amount of resveratrol ingested from dietary sources, such as red wine and juices (rarely exceeding 5 mg/l), often results in plasma levels that are either not detectable or several orders of magnitude below the micromolar concentrations that are employed in vitro (~32 nM – 100 μM) [23]. For example, administration of about 25 mg resveratrol results in plasma concentrations of the free form that range from 1 to 5 ng/ml [24] and administration of higher doses (up to 5 g) increased the plasma resveratrol concentration to about 500 ng/ ml [25].
The low doses of resveratrol observed in the plasma after ingestion are worrisome, as the concentrations used in vitro are not reached. However, one must bear in mind that resveratrol is lipophilic, meaning that it mixes very well with lipids including membranes and lipoproteins. Therefore, the tissue resveratrol levels may in fact be higher than what is suggested based on plasma levels. However, some of the biological effects of resveratrol are also observed at a very low concentration [26, 27], bringing forward the idea that resveratrol exerts its major effects on the intestinal tissue, affecting the rest of the body through secondary effects that are indispensible of the plasma levels reached by the compound [6].
In rodent models, the doses employed normally range from as low as 0.1 mg/kg up to 1,000 mg/kg, with even higher or lower doses occasionally being used [6]. Moreover, resveratrol has been show to exert biphasic effects [28]. That is, resveratrol employed at low doses (~ 5 mg/kg/d) has been shown to cause weight gain in mice on a high-fat diet [29], whereas at high doses (~ 400/mg/kg/d), there is marked weight loss [10]. Also, cardioprotective effects of resveratrol that are observed at 2.5 or 5 mg/kg/d are reversed when the dose is increased to 25 or 50 mg/kg/d [30]. These results may suggest that resveratrol acts via multiple target pathways, and as such, calculating the effective in vivo concentration of resveratrol or designing new studies based on current literature is challenging. Further experiments are necessary to show whether resveratrol or its metabolites accumulate sufficiently in tissues to account for the widespread acclaimed role of resveratrol in the treatment of various diseases. But even if the optimal dose for rodent experiments is determined, the question still remains how to extrapolate to a human equivalent dose. Direct extrapolation by body weight is often used as a guideline, however, as proposed by others, body surface area might be a better option [31].
The exact mechanisms through which resveratrol exerts a wide range of beneficial effects across species and disease models is currently still unclear [6]. Similar to most other polyphenols, resveratrol is suggested to possess intrinsic anti-oxidant capacity, but it is also implicated to induce the expression of a number of anti-oxidant enzymes, with probably both mechanisms contributing to an overall reduction in oxidative stress [32]. Resveratrol further interacts with a large number of receptors, kinases, and other enzymes that could plausibly make a major contribution to its biological effects.
In 2003 Howitz and colleagues proposed that resveratrol is capable of increasing the deacetylase activity of Sirtuin 1 (SIRT1), a genetic modulator that is part of the health-promoting pathway that is activated by calorie restriction [8]. It has already been known since the 1930s that a severe lowering of calorie intake dramatically slows the rate of ageing in mammals and lowers the onset of numerous age-related diseases, including cancer, cardiovascular disease, diabetes and neurodegeneration [33, 34].
Sirtuins are a conserved family of NAD+-dependent deacetylases (class III histone deacetylases) that were named after the founding member, the Saccharomyces cerevisiae silent information regulator 2 (Sir 2) protein [35]. A number of subsequent studies showed that resveratrol induced SIRT1 activity in several species (for review see [36]). Furthermore, resveratrol mimics numerous aspects of calorie restriction in all eukaryotes tested to date [8-11, 14, 29, 37] and in most of them, the effect appears dependent on SIRT1 [8, 10, 11]. In line with being an activator of SIRT1, several studies [8, 9, 11, 14], however not all [29], reported that resveratrol increased lifespan. Resveratrol was also shown to increase energy expenditure in mice [9, 10], through increased SIRT1 activation, and during conditions of high fat availability, resveratrol was capable of preventing diet-induced obesity and the onset of obesity-related metabolic diseases, so ultimately protecting mice against the lifespan curbing effects associated with high calorie intake. The molecular mechanism underlying these beneficial effects seem to depend on the resveratrol-induced increase in mitochondrial content, which is explained by increased signalling through the SIRT1/ PGC1α axis [10].
More recently, some studies have questioned the direct activation of SIRT1 by resveratrol [38, 39]. That is, both reports showed that measuring SIRT1 activity by means of the non-physiological fluorescent “Fluor de Lys” substrate assay could lead to artificial results [38, 39]. Furthermore several reports demonstrate that resveratrol can also activate AMPK [9, 40-42], which reconciles with the positive effect on the mitochondrial respiratory chain that has been reported [43]. Hawley et al. [44] reported that resveratrol-induced AMPK activation in isogenic cell lines, stably expressing AMPK complexes containing AMP-insensitive γ2 subunit variants (R531G), derives from an AMP/ATP imbalance as a consequence of interference with mitochondrial respiration. Although the idea was put forward that the resveratrol-induced AMPK activation was dependent on SIRT1 [45], the use of mouse embryonic fibroblast cells from SIRT1 knock-out mice unequivocally demonstrated that SIRT1 is dispensable for resveratrol-induced AMPK activation [40, 46]. On the contrary, resveratrol cannot activate SIRT1 in the absence of functional AMPK [46, 47]. So, the current working mechanism of resveratrol that evolved from all these reports is that SIRT1 functions as the downstream mediator of AMPK, instead of being a direct molecular target of resveratrol. Canto et al. [48] have shown in that respect that the AMPK induced increase in NAD+ levels, as a consequence of increased fatty acid oxidation, leads to SIRT1 activation.
Currently, activation of AMPK seems to be a major target of resveratrol's actions, providing a plausible explanation for a large part of the health benefits observed in reports published to date. However, fully defining the targets of resveratrol that are biologically relevant is an enormous task, made more difficult by the question whether effects are either direct or indirect. This issue is discussed further in [6, 7].
In rodent models of diet-induced obesity, a high dose of resveratrol (400 mg/kg/d) improves insulin sensitivity and lowers body weight [10], which has increased the interest and the speculation about its potential use as an anti-diabetic agent in humans. However, applying a lower dose of resveratrol (~ 22.5 mg/kg/d) appeared insufficient to produce weight loss, although it still improved glucose tolerance [9]. In fact, low doses of resveratrol are shown to prolong survival in obese mice while simultaneously increasing body weight [29]. One observation that is made, is that animals supplemented with a high dose of resveratrol are capable of increasing their energy expenditure, based on their ability to increase their running distance or tolerate cold longer compared to their untreated controls. However, whether these observations underlie the reduction in body weight is not clear, as voluntary exercise is actually lower in the resveratrol-treated group and body temperature is not detectably changed under basal conditions [10]. Nevertheless, recent work has shown that a one-year intervention with resveratrol at a dose of 200 mg/kg/d seems to cause an increase in basal metabolic rate and total daily energy expenditure in the non-human primate Microcebus murinus [49, 50]; indicating that resveratrol might have the potency to enhance energy expenditure thereby promoting weight loss.
In 2007 already, a cross-sectional study found that supplemental resveratrol is taken by 2/3 of people who routinely consume multiple dietary supplements, and this number may be increasing as studies describing resveratrol's health effects have reached the lay public through ample coverage in popular media. Because of the increasing public interest, and the favourable health effects in lower organisms, there is urgent need for studies examining the therapeutic potential of resveratrol in humans, especially since the prevalence of chronic metabolic diseases is reaching epidemic proportions worldwide.
To date, the number of published clinical trials that have examined the effect of resveratrol on insulin sensitivity are still limited and several trials are currently still ongoing (see Table Table11 for an overview of all published peer-reviewed clinical trials on resveratrol). However, none of the peer-reviewed human clinical trials have addressed the ability of resveratrol to serve as a weight loss compound. In 2009 a clinical study Elliott et al. [51] reported for the first time the effect of resveratrol on type 2 diabetes patients at doses of 2.5 and 5 g/day for 28 days. The levels of fasting and postprandial glucose and insulin serum levels were statistically significantly decreased at the dose of 5g/day, but few experimental details were provided in that work. In 2011, Brasnyo et al. [52] found that a four-week intervention with resveratrol in type 2 diabetic men significantly improved insulin sensitivity. Thus, supplementing trans-resveratrol twice daily at a dose of 5 mg decreased insulin resistance (computed by the homeostatic model assessment of insulin resistance HOMA-IR), lowered blood glucose levels and delayed the glucose peak following a standardized meal in type 2 diabetic men (n=10) compared with placebo (n=9) [52]. The authors suggested that a decreased oxidative stress might underlie these effects, as significant reductions in 24 h urinary creatinine-normalized ortho-tyrosine concentrations and an increased Akt phosphorylation in blood platelets was observed after the fours weeks of supplementation. Ghamin et al. [53] reported on the other hand that fasting glucose, insulin or HOMA-IR scores remained unchanged following a six-week supplementation of 40 mg resveratrol (in P. cuspidatum extract) in healthy volunteers. In that respect it might be noteworthy to mention that also normal healthy mice on a chow-diet fail to improve their insulin sensitivity upon resveratrol supplementation [10], arguing that resveratrol might only be effective under metabolic stress conditions such as obesity or diabetes. Recently, a small pilot study was carried out that showed the potential of resveratrol treatment to improve glucose tolerance, insulin sensitivity and vascular function [17]. For this intervention the authors chose to study the effects of resveratrol in subjects with impaired glucose tolerance that have definite but not yet severe metabolic dysregulation, and therefore may be most amenable to intervention. After four weeks of resveratrol supplementation with a daily dose of 1, 1.5 or 2g, post meal plasma glucose was lowered in IGT subjects at doses between 1 and 2 g/day, whereas the insulin response remained unchanged [17]. Furthermore, a trend towards an improved post meal endothelial function was reported.
Table 1
Table 1
Summary of peer reviewed published clinical trials*
We also investigated the metabolic effects of resveratrol in obese men [54] and were able to support the notion that resveratrol might have a similar mechanism of action in obese humans as in high-fat fed animals. Supplementation with resveratrol for 30 days induced health effects that were comparable to the effects of calorie restriction. Resveratrol reduced sleeping and resting metabolic rate in the absence of body weight changes. Furthermore, skeletal muscle mitochondrial function and fat oxidative capacity improved and fasting plasma glucose and insulin values were decreased by resveratrol. Gene set enrichment analysis revealed that resveratrol activated similar pathways in humans compared to mice, as mitochondrial pathways related to ATP production and oxidative phosphorylation were upregulated and inflammatory pathways were downregulated. In accordance to the rodent data, we confirmed that resveratrol supplementation induced an increase in skeletal muscle SIRT1 protein levels. These results are especially encouraging since Rutanen et al. showed that low SIRT1 expression could contribute to the disturbance in energy balance, that is already present in offspring of type 2 diabetes, by reducing mitochondrial function [55].
Though limited data is available on resveratrol's efficacy in chronic metabolic diseases in humans, the clinical trials that are available show much promise that resveratrol might be applied to improve general health status and prevent chronic disease in humans. However, further research is warranted to increase our understanding of the physiological responses of resveratrol before widespread use in humans can be promoted. Future research should aim to explore the relationship between dose – bioavailability- and efficacy and further define the pleiotrophic mechanisms of actions in humans. Furthermore, chronic studies are an absolute must, as it is still unclear if resveratrol supplementation on the longer term is beneficial for overall health status.
Footnotes
The authors of this manuscript have no conflict of interest to declare.
  • Takaoka MJ. Of the phenolic substances of white hellebore (Veratrum grandiflorum Loes. fil.) J. Faculty Sci. Hokkaido Imperial University. 1940;3:1–16.
  • Nonomura S, Kanagawa H, Makimoto A. [Chemical Constituents of Polygonaceous Plants. I. Studies on the Components of Ko-J O-Kon. (Polygonum Cuspidatum Sieb. Et Zucc.)] Yakugaku Zasshi. 1963;83:988–990. [PubMed]
  • Siemann EH, Creasy L.L. Concentration of the phytoalexin resveratrol in wine. Am. J. Eno. Vitic. 1992;43:49–52.
  • Liu BL, Zhang X, Zhang W, Zhen HN. New enlightenment of French Paradox: resveratrol's potential for cancer chemoprevention and anti-cancer therapy. Cancer Biol Ther. 2007;6:1833–1836. [PubMed]
  • Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275:218–220. [PubMed]
  • Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5:493–506. [PubMed]
  • Vang O, 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, et al. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One. 2011;6:e19881. [PMC free article] [PubMed]
  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003:425191–196. [PubMed]
  • Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–342. [PubMed]
  • Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127:1109–1122. [PubMed]
  • Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686–689. [PubMed]
  • Agarwal B, Baur JA. Resveratrol and life extension. Ann N Y Acad Sci. 2011;1215:138–143. [PubMed]
  • Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev. 2007;128(10):546–552. [PubMed]
  • Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol. 2006;16:296–300. [PubMed]
  • Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvari M, Piper MD, Hoddinott M, Sutphin GL, Leko V, McElwee JJ, Vazquez R, Orfila A, Ackerman D, Au C, Vinti G, Riesen M, et al. Absence of effects of Sir2 over-expression on lifespan in C. elegans and drosophila. Nature. 2011;477:482–485. [PMC free article] [PubMed]
  • Canto C, Auwerx J. Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol Rev. 2012;64:166–187. [PubMed]
  • Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N. Pilot Study of Resveratrol in Older Adults With Impaired Glucose Tolerance. J Gerontol A Biol Sci Med Sci. 2012 [PubMed]
  • Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14:612–622. [PubMed]
  • Goldberg DM, Yan J, Soleas GJ. Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin Biochem. 2003;36:79–87. [PubMed]
  • Walle T, Hsieh F, DeLegge MH, Oatis JE, Jr., Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004;32:1377–1382. [PubMed]
  • Marier JF, Vachon P, Gritsas A, Zhang J, Moreau JP, Ducharme MP. Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther. 2002;302:369–373. [PubMed]
  • Wang D, Hang T, Wu C, Liu W. Identification of the major metabolites of resveratrol in rat urine by HPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;829:97–106. [PubMed]
  • Smoliga JM, Vang O, Baur JA. Challenges of translating basic research into therapeutics: resveratrol as an example. J Gerontol A Biol Sci Med Sci. 2011;67:158–167. [PMC free article] [PubMed]
  • Almeida L, Vaz-da-Silva M, Falcao A, Soares E, Costa R, Loureiro AI, Fernandes-Lopes C, Rocha JF, Nunes T, Wright L, Soares-da-Silva P. Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. Mol Nutr Food Res. 2009;1(53 Suppl):S7–15. [PubMed]
  • Boocock DJ, Patel KR, Faust GE, Normolle DP, Marczylo TH, Crowell JA, Brenner DE, Booth TD, Gescher A, Steward WP. Quantitation of trans-resveratrol and detection of its metabolites in human plasma and urine by high performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;848:182–187. [PMC free article] [PubMed]
  • Waite KA, Sinden MR, Eng C. Phytoestrogen exposure elevates PTEN levels. Hum Mol Genet. 2005;14:1457–1463. [PubMed]
  • Pearce VP, Sherrell J, Lou Z, Kopelovich L, Wright WE, Shay JW. Immortalization of epithelial progenitor cells mediated by resveratrol. Oncogene. 2008;27:2365–2374. [PMC free article] [PubMed]
  • Calabrese EJ, Mattson MP, Calabrese V. Resveratrol commonly displays hormesis: occurrence and biomedical significance. Hum Exp Toxicol. 2010;29:980–1015. [PubMed]
  • Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008;8:157–168. [PMC free article] [PubMed]
  • Dudley J, Das S, Mukherjee S, Das DK. Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. J Nutr Biochem. 2009;20:443–452. [PubMed]
  • Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659–661. [PubMed]
  • Halliwell B. Dietary polyphenols: good, bad, or indifferent for your health? Cardiovasc Res. 2007;73:341–347. [PubMed]
  • Barger JL, Walford RL, Weindruch R. The retardation of aging by caloric restriction: its significance in the transgenic era. Exp Gerontol. 2003;38:1343–1351. [PubMed]
  • McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size The Journal of nutrition. 1935;10:63–79. [PubMed]
  • Brachmann CB, Sherman JM, Devine SE, Cameron EE, Pillus L, Boeke JD. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 1995;9:2888–2902. [PubMed]
  • Baur JA. Resveratrol, sirtuins, and the promise of a DR mimetic. Mech Ageing Dev. 2010;131:261–269. [PMC free article] [PubMed]
  • Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One. 2008;3:e2264. [PMC free article] [PubMed]
  • Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005;280:17187–17195. [PubMed]
  • Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, Napper A, Curtis R, DiStefano PS, Fields S, Bedalov A, Kennedy BK. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005;280:17038–17045. [PubMed]
  • Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007;104:7217–7222. [PubMed]
  • Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008;8:347–358. [PubMed]
  • Park CE, Kim MJ, Lee JH, Min BI, Bae H, Choe W, Kim SS, Ha J. Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. Exp Mol Med. 2007;39:222–229. [PubMed]
  • Zini R, Morin C, Bertelli A, Bertelli AA, Tillement JP. Effects of resveratrol on the rat brain respiratory chain. Drugs Exp Clin Res. 1999;25:87–97. [PubMed]
  • Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM, Hardie DG. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 2010;11:554–565. [PMC free article] [PubMed]
  • Suchankova G, Nelson LE, Gerhart-Hines Z, Kelly M, Gauthier MS, Saha AK, Ido Y, Puigserver P, Ruderman NB. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem Biophys Res Commun. 2009;378:836–841. [PMC free article] [PubMed]
  • Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010;59:554–563. [PMC free article] [PubMed]
  • Canto C, Auwerx J. AMP-activated protein kinase and its downstream transcriptional pathways. Cell Mol Life Sci. 2010;67:3407–3423. [PubMed]
  • Canto C, Auwerx J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab. 2009;20:325–331. [PubMed]
  • Dal-Pan A, Blanc S, Aujard F. Resveratrol suppresses body mass gain in a seasonal non-human primate model of obesity. BMC Physiol. 2010;10:11. [PMC free article] [PubMed]
  • Dal-Pan A, Terrien J, Pifferi F, Botalla R, Hardy I, Marchal J, Zahariev A, Chery I, Zizzari P, Perret M, Picq JL, Epelbaum J, Blanc S, Aujard F. Caloric restriction or resveratrol supplementation and ageing in a non-human primate: first-year outcome of the RESTRIKAL study in Microcebus murinus. Age (Dordr) 2011;33:15–31. [PMC free article] [PubMed]
  • Elliott PJ, Walpole S, Morelli L, Lambert PD, Lunsmann W, Westphal CH, Lavu S. Resveratrol/SRT-501. Drugs Fut. 2009;34:291–295.
  • Brasnyo P, Molnar GA, Mohas M, Marko L, Laczy B, Cseh J, Mikolas E, Szijarto IA, Merei A, Halmai R, Meszaros LG, Sumegi B, Wittmann I. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011:1–7. [PubMed]
  • Ghanim H, Sia CL, Abuaysheh S, Korzeniewski K, Patnaik P, Marumganti A, Chaudhuri A, Dandona P. An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. J Clin Endocrinol Metab. 2010;95:E1–8. [PubMed]
  • Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, et al. Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans. Cell Metab. 2011;14:612–622. [PubMed]
  • Rutanen J, Yaluri N, Modi S, Pihlajamaki J, Vanttinen M, Itkonen P, Kainulainen S, Yamamoto H, Lagouge M, Sinclair DA, Elliott P, Westphal C, Auwerx J, Laakso M. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes. 2010;59:829–835. [PMC free article] [PubMed]
  • Brown VA, Patel KR, Viskaduraki M, Crowell JA, Perloff M, Booth TD, Vasilinin G, Sen A, Schinas AM, Piccirilli G, Brown K, Steward WP, Gescher AJ, Brenner DE. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 2010;70:9003–9011. [PMC free article] [PubMed]
  • Burkon A, Somoza V. Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides - two novel resveratrol metabolites in human plasma. Mol Nutr Food Res. 2008;52:549–557. [PubMed]
  • la Porte C, Voduc N, Zhang G, Seguin I, Tardiff D, Singhal N, Cameron DW. Steady-State pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin Pharmacokinet. 2010;49:449–454. [PubMed]
  • Meng X, Maliakal P, Lu H, Lee MJ, Yang CS. Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J Agric Food Chem. 2004;52:935–942. [PubMed]
  • Nunes T, Almeida L, Rocha JF, Falcao A, Fernandes-Lopes C, Loureiro AI, Wright L, Vaz-da-Silva M, Soares-da-Silva P. Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects. J Clin Pharmacol. 2009;49:1477–1482. [PubMed]
  • Patel KR, Brown VA, Jones DJ, Britton RG, Hemingway D, Miller AS, West KP, Booth TD, Perloff M, Crowell JA, Brenner DE, Steward WP, Gescher AJ, Brown K. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010;70:7392–7399. [PMC free article] [PubMed]
  • Ortuño J, Covas MI, Farre M, Pujadas M, Fito M, Khymenets O, Andres-Lacueva C, Roset P, Joglar J, RM L-R. Matrix effects on the bioavailability of resveratrol in humans. Food Chem. 2010;120:1123–1130.
  • Gresele P, Pignatelli P, Guglielmini G, Carnevale R, Mezzasoma AM, Ghiselli A, Momi S, Violi F. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr. 2008;138:1602–1608. [PubMed]
  • Urpí-Sardà M, Jáuregui O, Lamuela-Raventós RM, Jaeger W, Miksits M, Covas MI, Andres-Lacueva C. Uptake of diet resveratrol into the human low-density lipoprotein. Identification and quantification of resveratrol metabolites by liquid chromatography coupled with tandem mass spectrometry. Anal Chem. 2005;77:3149–3155. [PubMed]
  • Vitaglione P, Sforza S, Galaverna G, Ghidini C, Caporaso N, Vescovi PP, Fogliano V, Marchelli R. Bioavailability of trans-resveratrol from red wine in humans. Mol Nutr Food Res. 2005;49:495–504. [PubMed]
  • Zamora-Ros R, Urpí-Sardà M, Lamuela-Raventós RM, Estruch R, Vázquez-Agell M, Serrano-Martínez M, Jaeger W, C A-L. Diagnostic performance of urinary resveratrol metabolites as a biomarker of moderate wine consumption. Clin Chem. 2006;52:1373–1380. [PubMed]
  • Ghanim H, Sia CL, Korzeniewski K, Lohano T, Abuaysheh S, Marumganti A, Chaudhuri A, Dandona P. A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J Clin Endocrinol Metab. 2011;96:1409–1414. [PubMed]
  • Kennedy DO, Wightman EL, Reay JL, Lietz G, Okello EJ, Wilde A, Haskell CF. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Am J Clin Nutr. 2010;91:1590–1597. [PubMed]
  • Wong RH, Howe PR, Buckley JD, Coates AM, Kunz I, Berry NM. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis. 2010 [PubMed]
  • Nguyen AV, Martinez M, Stamos MJ, Moyer MP, Planutis K, Hope C, Holcombe RF. Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Manag Res. 2009;1:25–37. [PMC free article] [PubMed]
  • Chow HH, Garland LL, Hsu CH, Vining DR, Chew WM, Miller JA, Perloff M, Crowell JA, Alberts DS. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev Res (Phila) 2010;3:1168–1175. [PMC free article] [PubMed]
  • Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci. 2011;1215:161–169. [PubMed]
  • Smoliga JM, Baur JA, HA H. Resveratrol and health--a comprehensive review of human clinical trials. Mol Nutr Food Res. 2011;55:1129–1141. [PubMed]
Articles from Aging (Albany NY) are provided here courtesy of
Impact Journals, LLC