Resveratrol

What Is It?

Resveratrol is a polyphenolic compound produced by plants upon exposure to harmful stimuli including mechanical stress, ionizing radiation, and/or infection by bacteria or fungi$^{1}$. It exists in 70+ plant species and is commonly found in grapes and some wines. Initially, resveratrol gained traction in scientific studies due to its association with the potential benefits of wine consumption, as well as its presence in plant roots used in traditional Chinese and Japanese medicine$^{1}$. More recently, resveratrol has been studied for its potential anti-aging effects, as well as its role in cancer prevention and treatment via its antioxidant and anti-tumor functions$^{1,2}$.

What Are Its Other Names?

There are currently 92 different resveratrol compounds found in foods and plants. Resveratrol has both a cis and trans isomer (alternative forms of the same compound), as exposure to UV radiation converts the compound into its trans form, and is therefore referred to as trans-resveratrol in some instances. Resveratrol is less commonly referred to as 3,4',5-Trihydroxystilbene, as well as by its IUPAC name, 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol.

What Foods Have It?

What Are Its Main Benefits?

Anti-aging effects

Resveratrol has garnered attention for its potential ability to promote longevity and prevent aging on a cellular level. Various studies conducted in yeast, mice, and fruit flies have demonstrated anti-aging effects. Resveratrol is able to activate a family of proteins called sirtuins, which are known for suppressing oxidative stress (the build-up of harmful free radicals that cause cell and tissue damage), thereby potentially slowing/preventing aging$^{6}$.

Antioxidant and anti-inflammatory properties

One of the most well-known benefits of resveratrol is its potential as an antioxidant$^{7,8}$. Resveratrol is able to infiltrate multiple cellular pathways that promote oxidative stress via the activation of signalling cascades (intracellular chemical messages) as well as the direct activation of transcription factors (small proteins that manipulate the expression of genes)$^{7,8}$. Studies also suggest that resveratrol might be anti-inflammatory, as the compound has demonstrated an ability to reduce pro-inflammatory cytokine production (molecules that trigger inflammatory immune responses) and increase anti-inflammatory cytokines, while also decreasing the activation of pro-inflammatory transcription factors$^{9}$. Such qualities have been linked to increasing cell longevity mainly due to a reduction in cell stress, inflammation, and oxidation$^{7-9}$.

Age-related disease

Resveratrol’s antioxidant and anti-inflammatory properties might be useful in preventing degeneration in age-related disease$^{1,10}$. Various animal and cell culture studies have analyzed resveratrol’s potential impact in cardiovascular disease. Resveratrol-treated cells were able to downregulate production of proteins that induce inflammation (such as pro-inflammatory cytokines and matrix metalloproteases) when exposed to inflammatory cholesterols. These cells also reduced their free radical levels and inhibited the activity of NADPH oxidase, an enzyme that produces reactive oxygen species$^{10,11}$. Furthermore, resveratrol might increase neuron formation while preventing neuronal support cell death, thereby making it a potential preventative agent for neurodegenerative diseases$^{12,13}$. It is important to note that these studies were completed in cells/animal models rather than in humans.

Anticancer and anti-tumor functions

Resveratrol’s anticancer effects include preventing tumor growth and/or tumorigenesis via various mechanisms. A study using ovarian cancer cells demonstrated that resveratrol decreased cell proliferation while increasing apoptosis$^{14}$. A mouse study demonstrated that resveratrol treatments prevented both liver metastases and ovarian cancer growth$^{15}$.

What Are Its Main Drawbacks?

Despite the many promising properties of resveratrol, a drawback is its interactions with various enzymes$^{16}$. In specific patient populations, resveratrol may lead to severe adverse events. For instance, a clinical trial in patients with multiple myeloma was terminated after 63% of patients on resveratrol monotherapy, and 100% using both resveratrol and bortezomib developed renal failure$^{17}$. One of these adverse events led to death$^{17}$. However, the authors of this study stated that the resveratrol dosage they had used was proven safe in many other studies, including one in patients with metastatic colorectal cancer$^{17}$. It is possible that renal failure was only seen in multiple myeloma patients as many of these patients already have renal damage$^{17}$. Moreover, it is important to note that resveratrol might inhibit certain liver enzymes responsible for metabolizing drugs, which could lead to elevated drug concentrations$^{18,19}$. Another significant drawback is the lack of conclusive evidence regarding the efficacy of resveratrol in humans. Although studies suggest that resveratrol may have anti-inflammatory, antioxidant, and anti-aging effects$^{19-21}$, the majority of research concerning specific diseases and functions of the nutrient have been conducted in cell cultures or in mice, with limited clinical trials confirming these properties in humans. In addition, resveratrol has low bioavailability and potency; this means that despite promising preclinical studies, it may be difficult to observe the same effects in patients as the nutrient might be metabolized before reaching bioactive concentrations$^{22}$.

How Does It Work?

Resveratrol has been proposed to exert its potential anti-cancer effects through the following mechanisms: suppressing oxidative stress and inflammation$^{21}$, influencing the expression of sirtuins$^{24,25}$, and inducing apoptosis$^{26}$.

What Are Its Mechanisms of Action?

1. Suppressing Oxidative Stress and Inflammation: Resveratrol activates a key transcription factor called FoxO1 either directly or via the activation of intracellular signalling pathways (PTEN and AMPK)$^{21}$. FoxO1 leads to production of proteins (such as CAT, SOD, and HO-1) that prevent harmful oxidative stress and the build-up of reactive oxidative species (which cause oxidative damage)$^{21}$. At the same time, resveratrol is able to activate transcription factors (Nrf2 and TFEB) that regulate the production of antioxidants$^{20,21,23}$.
2. Sirtuin: Sirtuins (SIRTs) are a family of proteins that perform various functions related to suppressing both oxidative stress and aging processes$^{6}$. Various mouse studies in which mice had increased expression of different SIRT (sirtuin-family) proteins demonstrated increased organ function, cognition, and lower levels of oxidative stress$^{6}$. The proposed mechanism of action includes resveratrol inhibiting SIRT5 while concurrently activating SIRT1 and SIRT4$^{24,25}$.
3. Apoptosis: Apoptosis refers to programmed cell death, a process that eliminates cells which are no longer viable or have sustained irreversible damage. Resveratrol could potentially mediate apoptosis via upregulation of SIRT1$^{26}$. This leads to the production of apoptosis-modulating proteins including Bax$^{26}$.

What Are Typical Doses and Durations?

Dosage Clinical trials analyzing the anticancer effects of resveratrol have used varying dosages of the supplement. Trials used between 5mg – 5600mg/day, with both doses being well-tolerated in their respective studies. However, some trials reported potentially adverse side-effects or no changes in their condition when taking 5000mg of resveratrol daily. Most trials used between 1.0 - 5.0g of resveratrol in their studies. Such dosages were typically spread out throughout the day using multiple capsules. It appears that trials for colorectal and prostate cancer used over 1.0g of resveratrol for their studies, whereas breast cancer trials used less than 1.0g. Duration Furthermore, clinical trials concerning resveratrol administered the nutrient over ranges of 1 day to 19+ months; although, it appears that a 2–5-week period is most commonly used. When administered over a 2–5-week period, resveratrol appears to generate some anticancer effects, however similar effects are observed at greater time periods as well. Despite some of these common doses/durations, the frequency of resveratrol administration may differ drastically based on the severity of disease. For instance, a clinical trial for Stage IV colorectal cancer with liver metastases administered 5000mg of resveratrol daily for 20 days$^{27}$.

Polycystic Ovarian Syndrome and Cancer

Various clinical trials have analyzed the impacts of resveratrol on polycystic ovary syndrome (PCOS). In general, clinical trials in which PCOS patients received up to 1500mg of resveratrol demonstrated beneficial effects. Common outcomes after taking resveratrol included improved sex hormone mediation and reduced menstrual irregularities. More research is needed to fully understand potential links between PCOS and cancer. A study in the Lancet concluded that women with PCOS had increased prevalence of endometrial carcinoma$^{28}$. Such an effect is likely due to the build of endometrial tissue as a result of excess estrogen coupled with anovulation (when an egg is not released during the menstrual cycle) and a lack of secretory endometrium. In addition, the study mentions that type 2 diabetes and obesity are risk factors for endometrial carcinoma and are also commonly seen in PCOS patients$^{28}$. Limited studies have analyzed PCOS in the context of ovarian cancer. Given that PCOS is often characterized by infertility and anovulation, it is difficult to conclude that the syndrome is associated with an increase in ovarian cancer$^{29}$.

Summary of Data

Resveratrol for Cancer A total of 9 human clinical studies or randomized controlled trials were identified from PubMed that investigated resveratrol as a means of preventing or treating cancer. A summary of the results for each cancer type is as follows:

📄 Detailed Resveratrol human clinical trial study notes analyzed by Anticancer.ca

Resveratrol for Polycystic Ovarian Syndrome A further 5 human clinical studies or randomized control trials were identified from PubMed that considered resveratrol as a means of ameliorating Polycystic Ovarian Syndrome. A summary of the results for these studies is as follows:

📄 Detailed Resveratrol (for PCOS) human clinical trial study notes analyzed by Anticancer.ca

References

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9. Buttari B, Profumo E, Segoni L, D'Arcangelo D, Rossi S, Facchiano F, Saso L, Businaro R, Iuliano L, Riganò R. Resveratrol counteracts inflammation in human M1 and M2 macrophages upon challenge with 7-oxo-cholesterol: potential therapeutic implications in atherosclerosis. Oxid Med Cell Longev. 2014;2014:257543. doi: 10.1155/2014/257543. Epub 2014 May 8. PMID: 24895526; PMCID: PMC4034709
10. Xia N, Daiber A, Förstermann U, Li H. Antioxidant effects of resveratrol in the cardiovascular system. Br J Pharmacol. 2017 Jun;174(12):1633-1646. doi: 10.1111/bph.13492. Epub 2016 May 6. PMID: 27058985; PMCID: PMC5446570.
11. Vasamsetti SB, Karnewar S, Gopoju R, Gollavilli PN, Narra SR, Kumar JM, Kotamraju S. Resveratrol attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of intracellular GSH homeostasis: Relevance in atherosclerosis. Free Radic Biol Med. 2016 Jul;96:392-405. doi: 10.1016/j.freeradbiomed.2016.05.003. Epub 2016 May 5. PMID: 27156686.
12. Torres-Perez M., Tellez-Ballesteros R. I., Ortiz-Lopez L., et al. Resveratrol enhances neuroplastic changes, including hippocampal neurogenesis, and memory in Balb/C mice at six months of age. PLoS One. 2015;10:p. 21.
13. Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature, and reduced glial activation. Scientific Reports. 2015;5:p. 16.
14. Opipari AW Jr, Tan L, Boitano AE, Sorenson DR, Aurora A, Liu JR. Resveratrol-induced autophagocytosis in ovarian cancer cells. Cancer Res. 2004 Jan 15;64(2):696-703. doi: 10.1158/0008-5472.can-03-2404. PMID: 14744787.
15. Liu Y, Tong L, Luo Y, Li X, Chen G, Wang Y. Resveratrol inhibits the proliferation and induces the apoptosis in ovarian cancer cells via inhibiting glycolysis and targeting AMPK/mTOR signaling pathway. J Cell Biochem. 2018;119: 6162–6172. doi:10.1002/jcb.26822. PMID: 29663499
16. Izzo C, Annunziata M, Melara G, Sciorio R, Dallio M, Masarone M, Federico A, Persico M. The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials. Nutrients. 2021 Mar 13;13(3):933. doi: 10.3390/nu13030933. PMID: 33805795; PMCID: PMC7999728.
17. Popat R, Plesner T, Davies F, Cook G, Cook M, Elliott P, Jacobson E, Gumbleton T, Oakervee H, Cavenagh J. A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br J Haematol. 2013 Mar;160(5):714-7. doi: 10.1111/bjh.12154. Epub 2012 Dec 4. PMID: 23205612.
18. Zhou DD, Luo M, Huang SY, Saimaiti A, Shang A, Gan RY, Li HB. Effects and Mechanisms of Resveratrol on Aging and Age-Related Diseases. Oxid Med Cell Longev. 2021 Jul 11;2021:9932218. doi: 10.1155/2021/9932218. PMID: 34336123; PMCID: PMC8289612.
19. Ramírez-Garza SL, Laveriano-Santos EP, Marhuenda-Muñoz M, Storniolo CE, Tresserra-Rimbau A, Vallverdú-Queralt A, Lamuela-Raventós RM. Health Effects of Resveratrol: Results from Human Intervention Trials. Nutrients. 2018 Dec 3;10(12):1892. doi: 10.3390/nu10121892. PMID: 30513922; PMCID: PMC6317057.
20. Meng, X.; Zhou, J.; Zhao, C.-N.; Gan, R.-Y.; Li, H.-B. Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review. Foods 2020, 9, 340. https://doi.org/10.3390/foods9030340
21. Omidian M, Abdolahi M, Daneshzad E, Sedighiyan M, Aghasi M, Abdollahi H, Omidian P, Dabiri S, Mahmoudi M. The Effects of Resveratrol on Oxidative Stress Markers: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Endocr Metab Immune Disord Drug Targets. 2020;20(5):718-727. doi: 10.2174/1871530319666191116112950. PMID: 31738139.
22. Ren B, Kwah MX, Liu C, Ma Z, Shanmugam MK, Ding L, Xiang X, Ho PC, Wang L, Ong PS, Goh BC. Resveratrol for cancer therapy: Challenges and future perspectives. Cancer Lett. 2021 Sep 1;515:63-72. doi: 10.1016/j.canlet.2021.05.001. Epub 2021 May 28. PMID: 34052324.
23. Koushki M, Lakzaei M, Khodabandehloo H, Hosseini H, Meshkani R, Panahi G. Therapeutic effect of resveratrol supplementation on oxidative stress: a systematic review and meta-analysis of randomised controlled trials. Postgrad Med J. 2020 Apr;96(1134):197-205. doi: 10.1136/postgradmedj-2019-136415. Epub 2019 Oct 18. PMID: 31628212.
24. Moraes DS, Moreira DC, Andrade JMO, Santos SHS. Sirtuins, brain and cognition: A review of resveratrol effects. IBRO Rep. 2020 Jun 26;9:46-51. doi: 10.1016/j.ibror.2020.06.004. PMID: 33336103.
25. Gertz M, Nguyen GT, Fischer F, Suenkel B, Schlicker C, Fränzel B, Tomaschewski J, Aladini F, Becker C, Wolters D, Steegborn C. A molecular mechanism for direct sirtuin activation by resveratrol. PLoS One. 2012;7(11):e49761. doi: 10.1371/journal.pone.0049761. Epub 2012 Nov 21. PMID: 23185430.
26. Takashina M, Inoue S, Tomihara K, Tomita K, Hattori K, Zhao QL, Suzuki T, Noguchi M, Ohashi W, Hattori Y. Different effect of resveratrol to induction of apoptosis depending on the type of human cancer cells. Int J Oncol. 2017 Mar;50(3):787-797. doi: 10.3892/ijo.2017.3859. Epub 2017 Jan 24. PMID: 28197625.
27. Howells LM, Berry DP, Elliott PJ, Jacobson EW, Hoffmann E, Hegarty B, et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. J Cancer Prev. 2011;4: 1419–1425. doi:10.1158/1940-6207.capr-11-0148
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• Resveratrol
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• How Does It Work?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Polycystic Ovarian Syndrome and Cancer
• Summary of Data
• References
• About This Article
• Disclaimer