Resveratrol

I’ve been looking at the data for a number of nutrients and ingredients involved in the antioxidant story but it was clearly apparent EFSA would not allow any antioxidant claims following their mass rejection of 169 dossiers in early 2010. It made me think again about how such componentry might be of benefit in nutrition. Take resveratrol for example which has been linked solidly with the “red wine effect” and is claimed to have a number of cardiovascular benefits (Hegsted and Ausman, 1988; Renaud and de Lorgeril, 1992) because of its power as an antioxidant. It is also linked to reducing cancer, diabetes and inflammation.

There have been numerous research articles studying these benefits but EFSA would naturally prefer many more studies – human intervention studies to be precise before such claims can be made. In fact, a very recent study suggests it might not have any benefit at all – an urban myth indeed.

A number of studies have linked the phytochemical to the benefits attributed to following a Mediterranean diet.

What Is Resveratrol?

Resveratrol (3,5,4-trihydroxy-trans-stilbene) is a phytoalexin, a molecule which is produced as a stress response to fight off both fungal (Hain et al., 1990), and irradiation in a wide range of plants, at least 80, and distributed throughout  30 genera and 12 families. First found in a hellebore species (Veratrum grandiflorum O. Loes) in 1940,  it is present in a number of popular foods such as peanuts, chocolate, a number of red fruits – mulberry  and white and red grapes. It is certainly found in red wine but not white because the skins containing resveratrol are removed during the production of white wine. Grape culture has a great deal of bearing on the production of resveratrol and the level in grape skin is between 50 to 100 µg/g (Jeandet et al., 1991).

Critically, the extraction of resveratrol into a wine is one of the more important aspects of processing and wines themselves have been extensively surveyed over the years giving an idea of both how much is generated by the grape and then released into the wine (Goldberg et al., 1995). There is a concentration effect which is influenced by yeast fermentation and by steeping. The levels in red wine are between 0.2 and 3.0 mg/l (Frankel et al., 1995; Goldberg et al., 1995; Romero-Perez et al., 1996) depending on grape variety and processing. A survey of Spanish white and rose wines has also been conducted (Romero-Perez et al., 1996) but the levels are not as significant.  It needs to be borne in mind that there may not be enough resveratrol in wine for an ‘in vivo’ effect and there are other components present such as a vast range of potent polyphenols which have benefit. The anthocyanin content in grape skin and red wine is also believed to influence the claimed cancer-protective effects.

I’m partial to Cabernet Sauvignon varieties in wine for their rich fruitiness and strong colour but it is also one of the highest producers of resveratrol as a grape (Jeandet et al., 1992), followed by Pinot Noir. Resveratrol is a little more complex because there are four isomeric forms, a cis- and trans- form of resveratrol and a cis- and trans- form of piceid which is one of its variants. When discussing resveratrol it needs to be borne in mind that these isomers will also be present in differing amounts in wine and have differing nutritional benefits. The isomers are derived from the conversion of p-coumaryl-Co A using three malonyl-CoA units, catalysed by stilbene synthase (Jeandet et al., 2002). The enzyme is part of a multiple gene family and is induced by stressors such as mould and UV light (Preisig-Muller et al., 1999).

Early Studies

The benefit aspect of the story began back in the 90s when a vast number of plant extracts were screened for their potential inhibition of cyclooxygenase (COX). This enzyme catalyses the conversion of arachidonic acid to prostaglandins and leukotrienes which have a variety of roles, mainly as promoters of inflammation, and which are also linked to stimulating tumour cell growth and reducing the immune system’s surveillance or monitoring. COX also converts certain chemicals into carcinogens. Resveratrol was first identified as a COX inhibitor following the screening of an extract of Cassia quinquangulata Rich. (Leguminosae) from Peru. A bioassay –guided fractionation yielded resveratrol. The inhibition of platelet aggregation, of blood coagulation and of arachidonic acid production was reported (Pace-Asciak et al., 1995).

Resveratrol is found ‘in vitro’ to be a potent antioxidant (Teguo et al., 1998; Stivala et al.,  2001). Dietary resveratrol also has a hyperlipidaemic activity.  At 50 parts per million (ppm) it suppressed blood serum lipid peroxidase levels in rats and dose-dependently suppressed serum triglyceride, VLDL (very low density lipoprotein) and low density lipoprotein (LDL) cholesterol levels (Miura et al., 2003).

Resveratrol And Heart Health

Resveratrol amongst many clinical benefits has been associated with improvements in heart health. ‘In vitro’ studies demonstrated inhibition of xanthine oxidase  (XO, EC 1.2.3.2.) and monoamine oxidase A (MAO, EC 1.4.3.4) but not the B form (Zhou et al., 2001).  It was also linked to the activation of nitric oxide synthase (Wallerath et al., 2002) and  blood vessel vasodilation (Chen and Pace-Asciak, 1996), and leukocyte activation.  Part of that mechanism on NO synthase activation was recently explored in a catecholamine release study of rat medulla linked to Ca²⁺/Na²⁺ ion transport (Woo et al., 2008).

In fat metabolism, it also appears to block oxidation of LDL-cholesterol and reduce cholesterol synthesis.

In 2012, a study presented at the 24th Scientific meeting of International Society of Hypertension related how resveratrol supplementation improved the circulatory function of 28 obese, mildly hypertensive adults (DSM, 2012). In a double blind, placebo controlled study these subjects were given 75 mg of DSM’s resVida ^® resveratrol per day for 6 weeks. The vasodilator function was monitored because a poor vasodilator response is an early biomarker for reduced cardiovascular function, linked to obesity and high blood pressure. Those taking the resveratrol had a 23% increase in vasodilator compared to placebo and the extent of improvement was greatest in those with initially poor vasodilation.

Reducing Cancer Incidence

The mechanisms for its cancer protective effects have also been surveyed (Dong, 2003) following initial studies (Jang et al., 1997) into componentry in grapes.  There are a few initial studies with animals. One study looked at resveratrol suppression of regrowth of ovarian tumours following some chemotherapy (Tan et al., 2016). Here, the resveratrol inhibited the uptake of glucose by these cancer cells which is the energy molecule of choice for fast metabolising cells like this.

Human trials are inconclusive. Read the American Cancer Society web-site which is sceptical at the moment because better  randomized clinical trials are needed to support recent findings. The link to ovarian cancer is interesting – some researchers think this material can affect oestrogen (estrogen) levels as well as other sex hormones.

Diabetes Control With Resveratrol Supplementation

Resveratrol supplementation was also shown to improve glycaemic control in patients with type 2 diabetes mellitus (T2DM) (Bhatt et al., 2012). in this study, 62 subjects with T2DM were randomised into control and intervention groups. The control group received only the oral hypoglcaemic supplements whilst those in the intervention group received 250mg of resveratrol per day alongside the same dosage of hypoglycaemic agents. The study, over 3 months, demonstrated that supplementation significantly improved mean haemoglobin A(1c), systolic blood pressure, total cholesterol and total protein levels in these patients. It was reasoned that oral supplementation could be an effective control for glycaemia and possibly serve as a potential adjuvant for treating and managing diabetes.

Alzheimer’s Disease

Resveratrol has a potential therapeutic effect in reducing the risk of nerve damage and degeneration. At the moment it is being explored for a role in reducing the damage produced by Alzheimer’s Disease (AD) and even reducing its risk of development (Brady et al., 2016). AD is one of the main causes of progressive dementia.

It is thought that resveratrol helps with the breakdown of the amyloid precursor protein (APP) which gradually builds up in AD patients to a point where it stops the brain functioning properly. It is also thought to help with removal of the  neurotoxic amyloid beta (Aβ) peptides. These too are implicated in the development of AD.

Controversy

Anecdotes abound about people in Sardinian mountain villages and Tuscany who have extremely long lives – past 100 years of age because they drink lots of red wine full of resveratrol. 

The most recent study suggested resveratrol had no benefits at all especially in lowering the prevalence of cancer, cardiovascular disease or inflammation (Semba et al., 2014). A prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study (“Aging in the Chianti Region”) as its known looked at the senior population, 783 people in total, from two villages. All these people were 65 years or older and they followed them over 11 years between 1998 and 2009. The villager’s urine was analysed for various resveratrol metabolites. It was reasoned that given the villagers did not take supplements, any by-products were purely from consumed wine and food. Over 9 years, 268 participants (34%) died with 174 (27%) developing cardiovascular disease in follow-up , and of the 734 villagers who were free of cancer at the start of the study, 34 went on to develop it during follow-up. Statistically resveratrol supplementation had no impact on those disease states which it is claimed to lower.

The most concerning and perhaps most controversial research on the clinical benefits of resveratrol relates to the work of Dipak K. Das, Ph.D. He was a professor in the Department of Surgery at the University of Connecticut and a director the Cardiovascular Research Center. The researcher was guilty of serious research misconduct. He had fabricated and  falsified results on 145 counts and some of this work related to the many benefits of resveratrol. From 2014, all the journals had retracted his papers.

Product Development

The number of new product launches with resveratrol globally increased from 2000 onwards but almost exploded in 2009 as the resveratrol story developed. According to Innova Market Insights (www.innovadatabase.com), the USA led the way with resveratrol appearing in snacks and confectionary. All products exploited natural ingredient additions such as peanuts, grape skins and cocoa powder or chocolate which have significant levels of resveratrol. The marketing campaigns from 2009 onwards made great play on the antioxidant benefits. DSM’s resVida^® resveratrol is a highly potent form of pure nature-identical trans-resveratrol which has been on the market for over 5 years. It might also be a useful flavour protector, having been shown to reduce oxygen radical damage of the lemon grass note citronellal (Stivala et al., 2001).

In time, further studies should yield a more complete picture of the benefits of resveratrol and the interactions between it, anthocyanins and a host of other plant derived compounds. At the moment, values of antioxidant potential are used to gauge the strength of various compounds but clearly, in the case of tackling cancer, much more sophisticated measures are needed.

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References

Bhatt, J.K., Thomas, S. Namjan, M.J. (2012) Resveratrol supplementation improves glycemic control in type-2 diabetes mellitus. Nutr. Res., 32(7) pp. 537-541

Braidy, N., Jugder, B.E., Poljak, A., Jayasena, T., Mansour, H., Nabavi SM, Sachdev P, Grant R. (2016) Resveratrol as a Potential Therapeutic Candidate for the Treatment and Management of Alzheimer’s Disease. Curr Top Med Chem. 16(17) pp. 1951-60. doi: 10.2174/1568026616666160204121431. PMID: 26845555. (Article)
Chen, C.K., Pace-Asciak, C.R. (1996)  Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta. Gen. Pharmacol. 27  pp. 363–366.
Dong, Z. (2003) Molecular mechanism of the chemopreventive effect of resveratrol. Mutation Res., 523-524 pp. 145-150
DSM. (2012) Resveratrol may support cardiovascular health. A study presented at the 24th Scientific Meeting of the international Society of Hypertension shows that resveratrol may improve circulatory function in obese, hypertensive adults. DSM Nutritionals, press released, Oct. 3
Frankel E. N., Waterhouse A. L., Teissedre P. L. (1995) Principal phenolic phytochemicals in selected California wines and their antioxidant activity in inhibiting oxidation of human low-density lipoproteins. J. Agric. Food Chem. 43  pp. 890-894
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Jeandet, P., Sbaghi, M., Bessis, R. (1992) The production of resveratrol (3, 5, 4′-trihydroxystilbene) by grapevine in vitro cultures, and its application to screening for grey mould resistance. J. Wine Res. 3, pp. 47 – 57
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Preisig-Muller, R.; Schwekendiek, A.; Brehm, I.; Reif, H.-J.; Kindl, H. (1999) Characterization of a pine multigene family containing elicitor-responsive stilbene synthase genes. Plant Mol. Biol. 39, pp. 221-229.
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Romero- Perez, A.I., Lamuela-Raventos, R.M., Waterhouse, A.L. Delatorre-Boronat, M.C. (1996) Levels of cis- and trans-resveratrol and their glucosides in white and rose Vitius vinifera wines from Spain. J. Agric. Food Chem. 44 pp. 2124–2128.
Semba, R.D., Ferrucci, L., Bartali, B., et al. (2014) Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling Adults. JAMA Intern Med. Published online May 12, 2014. doi:10.1001/jamainternmed.2014.1582.
Stivala, L. A., Savio, M., Fedarico, C., Perucca, P., Bianchi, L., Magas, G., Forti, L., Pagnoni, U. M., Albini, A., Prosperi, E., annini, V. (2001) Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol. J. Biol. Chem. 276, pp. 22586-22594

Tan, L., Wang, W., He, G., Kuick, R. D., Gossner, G., Kueck, A. S., Wahl, H., Opipari, A. W. and Liu, J. R. (2016), Resveratrol inhibits ovarian tumor growth in an in vivo mouse model. Cancer. 122: pp. 722–729. doi:10.1002/cncr.29793

Teguo, P. W., Fauconneau, B., Deffieux, G., Huguet, F., Vercauteren, J., Merillon, J.-M. (1998) Isolation, identification, and antioxidant activity of three stilbene glucosides newly extracted from Vitis Vinifera cell cultures. J. Nat. Prod. 61 pp. 655-657
Wallerath, T., Deckert, G., Ternes, T., Anderson, H., Li, H., Witte, K., Forstermann, U. (2002) Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 106  pp. 1652–1658.
Woo, S.-C.,  Na, G.-M., Lim, D-Y. (2008) Resveratrol Inhibits Nicotinic Stimulation-Evoked Catecholamine Release from the Adrenal Medulla. Korean J Physiol. Pharmacol. 12(4) pp. 155–164
Zhou, C.X., Kong, L.D., Ye, W.C., Cheng, C.H., Tan, R.X. (2001) Inhibition of xanthine and monoamine oxidases by stilbenoids from Veratrum taliense. Planta Med. 67  pp. 158–161.