Why We Do Not Include Resveratrol in our Protocol

Author: Jeffrey Wacks, MD

Resveratrol is a relatively well-known nutraceutical supplement, used by many Functional Medicine practitioners. Thus, some might find it surprising that it is not included in our protocol. To be clear, we are neutral on resveratrol, meaning we do not necessarily recommend against it and we do not tell patients to stop it if they are already on it or if it was recommended by an outside provider. As an antioxidant, resveratrol does clearly have some benefits. However, it is not something we explicitly recommend for because of some potential concerns that have arisen in the literature. 

Resveratrol is a natural polyphenol compound found in grapes and berries. It has gained much of its popularity due to preclinical/animal research that shows it may increase longevity. Specifically, resveratrol is thought to activate the sirtuin pathway, which is thought to modulate lifespan via multiple mechanisms.¹ However, we discussed in volume 1 of the training manual that in our opinion, animal-based longevity research, particularly in the context of caloric restriction, likely has minimal applicability to humans and we would de-emphasize its importance as an outcome measure in general. 

Positive Effects of Resveratrol

The benefits of resveratrol like stem from its free-radical scavenging antioxidant activity.² Due to its antioxidant activity, resveratrol is thought to have anti-inflammatory, anticancer, cardioprotective, and neuroprotective effects.³ From a metabolic perspective, human trials have shown slight improvements in glycemic control,⁴ hyperlipidemia,⁵ and serum CRP levels.⁶

Negative Effects of Resveratrol

While resveratrol is well-known for its antioxidant properties, there is some evidence that in some contexts, it may behave as a pro-oxidizing agent.⁷ For example, in some conditions, resveratrol can be oxidized to create a 4'-phenoxyl radical, leading to ROS production.⁸ To this point, an interesting study done by Gadacha et al.⁹ looked at the impact of resveratrol administration in rats as a function of the day/night rhythm and showed that when administered during the dark span, resveratrol behaved as an antioxidant, but behaved as a pro-oxidant during the light span. Thus, paradoxically, it is theoretically possible for it to be implicated in the pathology of disease states. 

The other theoretical problem with resveratrol is that it is potentially estrogenic.¹⁰ As discussed in depth in the training manual, estrogen is a very complicated topic. Essentially, estrogen has important physiologic functions and low basal levels in post-menopausal women is associated with dysfunction; however, elevated levels is pre-menopausal women in men is associated with stress and inflammation, and it is likely that chronically elevated estrogen levels (particularly via prolactin) is involved in the etiology of various pathology. Thus, we would be cautious about a supplement that potentially manipulates this dynamic. Additionally, one study in mice showed that resveratrol may inhibit steroidogenesis and the production of progesterone,¹¹ which could also theoretically contribute to issues of hormone imbalance.

Two other studies cast further doubt on resveratrol. A study in 2013 by Gliemann et al.¹² showed that resveratrol supplementation actually blunted the positive effects of exercise training in older men. Specifically, it abolished the reduction in blood pressure and serum lipid levels, altered the balance of prostanoid vasodilators and vasoconstrictors (led to a more artery constricting effect), and blunted the training-induced increase in maximal oxygen uptake. Additionally, Wilson et al.¹³ showed that in hypercholesterolemic rabbits, resveratrol actually promoted atherosclerosis. 

Although we have some concerns about resveratrol, and thus choose to not include it in the protocol, we will continue to reassess as new evidence emerges. At this time, we feel that other antioxidant supplements such as berberine, curcumin, tocotrienol Vitamin E, and N-acetylcysteine have superior evidence. 

References:

1. Bhullar KS, Hubbard BP. Lifespan and healthspan extension by resveratrol. Biochim Biophys Acta. 2015;1852(6):1209-1218. doi:10.1016/j.bbadis.2015.01.012
2. Malhotra A, Bath S, Elbarbry F. An Organ System Approach to Explore the Antioxidative, Anti-Inflammatory, and Cytoprotective Actions of Resveratrol. Oxid Med Cell Longev. 2015;2015:803971. doi:10.1155/2015/803971
3. Salehi B, Mishra AP, Nigam M, et al. Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines. 2018;6(3):91. Published 2018 Sep 9. doi:10.3390/biomedicines6030091
4. García-Martínez BI, Ruiz-Ramos M, Pedraza-Chaverri J, Santiago-Osorio E, Mendoza-Núñez VM. Influence of Age and Dose on the Effect of Resveratrol for Glycemic Control in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis. Molecules. 2022;27(16):5232. Published 2022 Aug 16. doi:10.3390/molecules27165232
5. Akbari M, Tamtaji OR, Lankarani KB, et al. The effects of resveratrol on lipid profiles and liver enzymes in patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Lipids Health Dis. 2020;19(1):25. Published 2020 Feb 17. doi:10.1186/s12944-020-1198-x
6. Haghighatdoost F, Hariri M. Can resveratrol supplement change inflammatory mediators? A systematic review and meta-analysis on randomized clinical trials. Eur J Clin Nutr. 2019;73(3):345-355. doi:10.1038/s41430-018-0253-4
7. de la Lastra CA, Villegas I. Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans. 2007;35(Pt 5):1156-1160. doi:10.1042/BST0351156
8. Li DD, Han RM, Liang R, et al. Hydroxyl radical reaction with trans-resveratrol: initial carbon radical adduct formation followed by rearrangement to phenoxyl radical. J Phys Chem B. 2012;116(24):7154-7161. doi:10.1021/jp3033337
9. Gadacha W, Ben-Attia M, Bonnefont-Rousselot D, Aouani E, Ghanem-Boughanmi N, Touitou Y. Resveratrol opposite effects on rat tissue lipoperoxidation: pro-oxidant during day-time and antioxidant at night. Redox Rep. 2009;14(4):154-158. doi:10.1179/135100009X466131
10. Qasem RJ. The estrogenic activity of resveratrol: a comprehensive review of in vitro and in vivo evidence and the potential for endocrine disruption. Crit Rev Toxicol. 2020;50(5):439-462. doi:10.1080/10408444.2020.1762538
11. Chen YC, Nagpal ML, Stocco DM, Lin T. Effects of genistein, resveratrol, and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor cells. J Endocrinol. 2007;192(3):527-537. doi:10.1677/JOE-06-0087
12. Gliemann L, Schmidt JF, Olesen J, et al. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol. 2013;591(20):5047-5059. doi:10.1113/jphysiol.2013.258061
13. Wilson T, Knight TJ, Beitz DC, Lewis DS, Engen RL. Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits. Life Sciences. 1996 May 31;59(1):PL15-21. doi:10.1016/0024-3205(96)00260-3