Resveratrol: Studies, Genetic Interactions, and Bioavailability

Key takeaways:
~ Resveratrol is a polyphenol with antioxidant and anti-inflammatory properties.
~ Studies show benefits from resveratrol for cardiovascular health, metabolic health, bone health, and cognitive function.
~ Resveratrol is absorbed well, but fairly quickly metabolized in the liver.

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Resveratrol: Health Benefits and Mechanisms

Resveratrol, a polyphenol found in a variety of plants, has made headlines for its many health benefits.

Resveratrol is found in grape skins and red wine, and it was initially proposed that resveratrol might provide health benefits from drinking red wine. About five decades ago, researchers began looking at resveratrol both for its association with reducing heart disease and for its chemoprotective properties. The initial thought was that resveratrol from wine explained the “French paradox,” which is the low rate of heart disease in French people who also eat a diet high in saturated fat.

There’s currently a bit of controversy about resveratrol — some claim that the research studies have been overblown and the actual benefits are small, while others take it by the spoonful every day for longevity and healthspan.

Luckily, there is a lot of research on resveratrol upon which to base your opinions. Let’s take a look at what the research studies and clinical trial data show:

Cardiovascular Health:

Resveratrol has been associated in many studies with improved cardiovascular health, including reduced risk of heart attack and stroke. Studies show that it has a positive influence on blood pressure, endothelial function, insulin resistance, and inflammation – all of which are important in heart health.[ref]

Endothelial function: In obese adults with borderline high blood pressure, 270 mg of resveratrol improved flow-mediated dilation (FMD), which is a biomarker of endothelial function and cardiovascular health.[ref]

Stroke protection: A recent study showed that resveratrol may help protect against strokes caused by varicella zoster. The varicella zoster virus (chickenpox, shingles) has been shown to increase the risk of stroke fourfold when the virus is located on the intraocular part of the trigeminal nerve (shingles in and around the eye)[ref]

Hypertension exacerbated by microplastics: A recent animal study created a model of hypertension by exacerbating kidney dysfunction by feeding the animals microplastics in their drinking water. The results showed that resveratrol significantly reduced the hypertension by modulating nitric oxide levels.[ref]

Metabolic Effects:

Clinical trials show that resveratrol can lower blood glucose and glycated hemoglobin levels, increase insulin sensitivity, and potentially protect pancreatic cells

Diabetes: In a randomized, double-blind placebo-controlled study of diabetic patients, resveratrol decreased HOMA-IR and insulin levels. The participants took 200 mg of resveratrol per day. In addition: “More than two-fold down regulation in miRNA-34a, miRNA-375, miRNA-21, miRNA-192 and up regulation in miRNA-126 and miRNA-132 expression was noted in patients receiving resveratrol as compared to placebo. “[ref]

Related article: Genetic susceptibility to diabetes

Metabolic syndrome: A small study in obese men taking 150 mg/day of resveratrol (vs. a placebo) showed improvements in HOMA-IR and blood pressure[ref]

PCOS: Stacking resveratrol with myoinositol was shown in a placebo-controlled clinical trial to be effective in reducing serum testosterone and ovarian volume. It also reduced weight. The clinical trial included 1,000 mg of resveratrol and 1,000 mg of myoinositol twice daily for 12 weeks and was superior to metformin.[ref]

Related article: PCOS – root causes and genetic pathways

Antioxidant and Anti-inflammatory Properties:

Resveratrol is an antioxidant that helps eliminate reactive oxygen species (ROS) and protects the body from external stimuli. Importantly, it also has anti-inflammatory properties in the brain, which is beneficial for cognitive function and the prevention of neurodegenerative diseases.

Alzheimer’s Disease: For mild to moderate Alzheimer’s disease, a small, year-long study involving <1g/day of resveratrol showed that it attenuated declines in mini-mental status examination (MMSE) scores. Neuroinflammation markers improved significantly.[ref]

Related article: APOE type and Alzheimer’s disease risk

Inflammation in smokers: A randomized, double- blind, cross-over trial trial in 50 smokers showed that 500mg/day of resveratrol reduced CRP, a marker for inflammation, as well as triglyceride levels.[ref]

Periodontitis: In a placebo-controlled trial involving patients with periodontitis, 500 mg/day of resveratrol for 8 weeks improved all symptoms of periodontitis including bleeding and probe depth.[ref]

Related article: Gingivitis and periodontal disease genes

Anti-cancer Potential:

Animal studies show that resveratrol can inhibit carcinogenesis. These studies are great for showing the mechanism, but they don’t always translate to a clinical effect in humans.

Cell studies show that resveratrol may have anti-tumor and anti-angiogenic effects in certain types of cancer.

Brain: A glioma cell line treated with resveratrol showed that LRIG1 was upregulated. LRIG1 is a protein that affects cell proliferation and apoptosis, both of which are important for reducing growth.[ref] Meningioma cells also show inhibition by resveratrol.[ref]

Blood: In lymphoma and leukemia, resveratrol has been shown in multiple studies to have an antiproliferative effect. It acts on several different pathways to decrease proliferation in B cell leukemia and Burkitt’s lymphoma.[ref] However, there are no placebo-controlled clinical trials involving resveratrol for leukemia, so talk with your doctor for guidance.

Bone health:

Osteoporosis: A clinical trial involving older women found that 75mg/2x/day of resveratrol improved bone mineral density and T-scores. There was more of a beneficial effect in women with poor initial bone health biomarker status.[ref]

Knee pain: A clinical trial using 40 mg/day for six months showed no improvement in knee pain due to arthritis. Both the resveratrol and placebo groups had improvements in knee pain.[ref] Note that 40mg/day is quite low compared to doses in other studies.

Cognitive function:

Memory in older adults: A placebo-controlled clinical trial in older adults showed that resveratrol (200 mg/day) improved word recall and short-term memory. It also had beneficial effects on functional connectivity in the brain.[ref]

Mechanism of action:

Resveratrol is a polyphenol that is chemically classified as a stilbenoid, which is a class of organic compounds produced by plants.

Resveratrol inhibits COX1 and COX2 enzymes, which are involved in the production of inflammatory lipid mediators from arachidonic acid. This is likely one way that it can help to prevent cancer.[ref][ref] Aspirin is another example of a COX inhibitor with chemopreventive properties.

Resveratrol also inhibits pro-inflammatory cytokines, including TNF-alpha and IL-1B, by downregulating NF-κB in an mTOR-dependent manner[ref]

Sirtuins are a family of proteins that can turn other genes on and off in response to various stimuli. In the immune response, SIRT1 may help modulate the response and keep it under control. Resveratrol has been shown to activate SIRT1, which is then beneficial in multiple ways — keeping the immune response in check as well as positively affecting healthspan.[ref]

Some studies show that resveratrol protects against DNA damage and breaks in the DNA during replication. This would be one way that resveratrol is chemoprotective and anti-aging.[ref]

Absorption and Metabolism of Resveratrol:

Resveratrol in nature can be found in two forms: trans-resveratrol and cis-resveratrol. Trans-resveratrol is the biologically active form. Poor bioavailability and rapid metabolism are two drawbacks of resveratrol and the reason that higher doses seem to have more of an effect than low doses found in wine or grapes.

Absorption and excretion: About 80% of ingested resveratrol is absorbed in the intestines and about 60% of the absorbed resveratrol then gets excreted in the urine.[ref]

Metabolism: After consumption, resveratrol can be detected in the bloodstream within 30 minutes and reaches peak levels at 60 minutes. It is metabolized in the liver fairly quickly.[ref] The metabolites of resveratrol have also been shown to have beneficial anti-inflammatory effects.[ref]

Resveratrol at 1,000 mg/day has been shown to inhibit CYP3A4, CYP2D6, and CYP2C9. It also induces CYP1A2.[ref] This is important because taking higher doses of resveratrol could interact with most prescription medications. Be sure to talk to your doctor or pharmacist before taking resveratrol in conjunction with other medications.

Related articles: CYP3A4, CYP2D6, CYP2C9

Resveratrol has been shown to slightly increase GST and UGT1A1 levels, but this was mainly in people who had low baseline activity.[ref] GSTs and UGT1A1 are phase II detoxification genes that are important in eliminating toxicants from the body. Increasing activity in these enzymes is likely contributing to the positive benefits of resveratrol.

Related articles: GST genes, UGT genes

Temperature: Trans-resveratrol is less stable at both low and high temperatures. So you may not want to store it in the freezer or cook with it. [ref]

Light: Trans-resveratrol is converted to the lower bioavailability cis form when exposed to UV radiation.[ref] Thus, resveratrol should be kept in a dark place, away from light.

Dosages, Side Effects, and Safety:

The resveratrol dosages used safely in clinical trials range from 150 mg to 1,000 mg/day. In cancer studies, dosages of 2.5g/day and 5g/day have been used for 29 days. However, at 2.5g and above, there were reports of abdominal pain, flatulence, and nausea.[ref] Note that resveratrol can interact with the gut microbiome, so some people may get bloating or transient intestinal issues at dosages less than 2.5g.

One thing to consider is that the optimal dose for chemotherapeutical effects is likely way higher than the optimal dose for anti-inflammatory or heart health effects. Another consideration is individual genetic variants in the CYP genes, which likely affect how long resveratrol stays in your system. A final consideration is that different brands of supplements have different purities of the resveratrol, so a lower amount with one brand may be similar to a higher amount with another brand.

Combining with piperine: Studies show that piperine added to resveratrol prevents glucuronidation and causes peak plasma levels to be significantly higher.[ref] Piperine is the bioactive compound found in black pepper.

Medication interactions: Again, check with your doctor or pharmacist if you are on any medications before taking resveratrol supplements. Warfarin levels, for example, are altered with resveratrol.[ref]