Resveratrol: Benefits, Side Effects, and Research
Resveratrol is a naturally occurring polyphenol commonly found in peanuts, grapes, and some berries. Many benefits have been ascribed to it, including enhanced mitochondrial function, protection from obesity and obesity-related diseases, suppression of inflammation, cancer cell growth, and cardiovascular disease [1-3].
However, clinical trials have produced mixed results . When taken orally, evidence indicates that its bioavailability is relatively low, as it is rapidly metabolized and eliminated from the body.
A history of research
Caloric restriction has been shown to increase longevity across species . Meanwhile, national overconsumption of calories has worsened the obesity epidemic . This situation has prompted researchers to search for compounds that trigger the caloric restriction response. Studies on the effects of calorie restriction in yeast led to the discovery that the enzyme SIR2 was a key player in how the body responds to caloric restriction . Sirtuins are NAD-dependent deacetylases that are associated with longevity.
Following this discovery, many molecules were screened to discover activators of SIRT1, the human version of SIR2, and resveratrol was singled out as being potentially effective . Resveratrol is a naturally occurring compound present in several plant species, one of which is grapes. Red wine sales skyrocketed.
Resveratrol was first characterized as a cyclooxygenase (Cox) inhibitor and a potentially chemoprotective molecule . Cox inhibitors are used to reduce inflammation and pain and treat certain cancers. Since its discovery as a calorie restriction mimetic resveratrol has been shown to have beneficial effects in cardiovascular disease , metabolic disease , cancer , and neurodegeneration .
Depending on the system in question and which mechanisms are most active, resveratrol can improve health in a variety of ways. Resveratrol’s systemic effects are rooted in a handful of mechanisms, including direct antioxidant activity, cyclooxygenase 2 (Cox-2) inhibition, Sirt1 activation, F1-ATPase inhibition, estrogen receptor inhibition, effects on biotransformation enzymes, inhibition of proliferation and induction of apoptosis, inhibition of tumor invasion and angiogenesis, and anti-inflammatory effects.
Resveratrol and cardiovascular disease
Resveratrol has been shown to inhibit vascular cell adhesion molecule (VCAM) expression in tissue culture . VCAM is expressed on the surface of the vascular endothelium (the innermost layer of cells in blood vessels) in response to oxidative stress. The expression of these proteins on the surface of endothelial cells provides an anchoring and entry point for inflammatory white blood cells.
These cells migrate across the endothelium into the middle layer of the artery, where they can become foam cells. Foam cells make up the bulk of arterial plaque . This suggests that resveratrol supplementation may prevent or slow the onset of atherosclerosis by preventing the invasion of the artery by immune cells .
Resveratrol inhibits vascular smooth muscle cell proliferation. Hypertension increases mechanical stress on arterial walls. The body responds to this by promoting the proliferation of vascular smooth muscle cells, which line the middle layer of the artery. This can cause the artery to thicken and become less distensible, leading to chronic hypertension and its consequences. Resveratrol has been snown to inhibit the proliferation of VSMCs in tissue cultures and in the body [16,17].
Resveratrol upregulates nitric oxide synthetase. The endothelium of the artery contains an enzyme that catalyzes the production of nitric oxide (NO). NO induces relaxation of the arterial tree. Dysregulation of NO homeostasis can contribute to increased blood pressure. In cultured endothelial cells, resveratrol has been shown to stimulate endothelial nitric oxide synthetase. This suggests that resveratrol may increase nitric oxide synthesis .
Resveratrol has been shown to inhibit platelet activation and aggregation. These processes are central to clot formation, which is potentially the most dangerous risk factor in cardiovascular disease .
Resveratrol, diabetes, and obesity
More than one-third of United States adults suffer impairments in glucose metabolism. These impairments include insulin resistance, defects in insulin secretion, impaired insulin receptor signaling, inability to use fat for energy, associated disturbances in lipid profiles, and increased pro-inflammatory cytokines [20,21]. Resveratrol improves insulin sensitivity, glucose tolerance, and lipid profiles in obese or metabolically abnormal people . Resveratrol has been shown to lower fasting glucose and insulin concentrations, improve HbA1c, increase HDL, and reduce LDL cholesterol and hypertension . Resveratrol was found to improve the activity of metabolic sensors, including SIRT1 and AMP-activated protein kinase (AMPK) .
Resveratrol and neurodegeneration
Resveratrol has been shown to reduce oxidative stress in nerve tissue, decrease neuroinflammation, clear β-amyloid and α-synuclein plaques, and improve mood and performance on cognitive tests.
Age-related deficits in hypothalamic function result in poor memory. Resveratrol supplementation in rats has been shown to encourage the formation of new synaptic connections and supporting circulatory adaptations in old rats. In tandem, improvements in memory, learning, and mood also occurred . Studies of human supplementation with resveratrol show similar cognitive improvements .
The accumulation of β-amyloid plaques in Alzheimer’s disease  and α-synuclein in Parkinson’s disease  are strongly associated with cognitive decline and function in these diseases. In rodent studies, resveratrol has been shown to slow or reverse the accumulation of these aggregates, promote cell survival, and reduce neuroinflammation. Microglia, cells in the brain that perform immune surveillance when activated, were found to be inhibited by resveratrol [28,29].
Resveratrol has been shown to reduce the undercurrent of mitochondrial dysfunction and oxidative stress, which leads to numerous neurological disorders [30,31].
A study of older overweight adults taking both resveratrol (200mg/day) and quercetin (320mg/day) supplements for 26 weeks resulted in significant improvements in memory .
Resveratrol and longevity
Resveratrol increases lifespan in yeast by 70% . In worms, fruit flies, and vertebrate fish, resveratrol also significantly extends lifespan [33,34]. However, in mice, the situation becomes more nuanced. Resveratrol has been shown to increase the lifespan of mice on calorie-rich diets to the point that their average life expectancy matched that of normally fed mice . At present, there are no epidemiological studies that link resveratrol, an activator of human SIRT1, with extended maximal lifespan in humans. There is also no study that measures lifetime consumption of resveratrol .
Resveratrol and cancer
Resveratrol is a phytoalexin, a substance produced by certain plant species at sites of pathogen infestation . It functions by inhibiting the growth of bacteria or fungi, which has raised the question of how resveratrol might affect eukaryotic cell growth and proliferation. Resveratrol has been found to inhibit growth and proliferation in several human cancer cell lines, including breast, colon, liver, pancreatic, prostate, skin, thyroid, white blood cells and lungs [37-39]. In total, resveratrol has been shown to inhibit the initiation, promotion, and progression of cancer.
In rodent models, resveratrol prevents the induction or initiation of cancer cells in several ways, including direct and indirect scavenging of reactive oxygen species, blocking the action of enzymes that convert carcinogens to their active forms, and by selectively downregulating DNA repair processes and anti-apoptotic signaling in cancer cells.
For carcinogens to cause cancer, they must be activated by enzymes in the body, such as cytochrome p450. Resveratrol inhibits cytochrome p450, thus nullifying the activation of carcinogenic compounds . Resveratrol was shown to downregulate proteins essential for normal DNA repair processes in cancer cells, such as DNA ligase I, which rejoins broken parts of DNA . Resveratrol’s antioxidant activity aids in the scavenging of reactive oxygen species, and it has been shown to reduce inflammation  and promote cell-cycle arrest and apoptosis .
Finally, resveratrol slows the progression of cancer through multiple mechanisms, including the inhibition of new blood vessel growth , inhibition of matrix metalloproteinases [39,45], and inhibition of the processes that enable the invasion and spread of cancer in the body [46,47].
The clinical utility of resveratrol as a cancer therapeutic in humans has been difficult to assess due to resveratrol’s low bioavailability. One study examining the effects of resveratrol in colon cancer found a month-long regimen of 4g to 8g of resveratrol a day modestly reduced cell proliferation with minimal side effects .
New micronized and liposomal formulations of resveratrol have yielded more useful results. Micronized formulations increase bioavailability by breaking the product into a finer particulate with more surface area. Using the more bioavailable version of resveratrol delivery, researchers found there was an increase in the death rate of colorectal cancer cells .
Another study, using the resveratrol formulation as a treatment for the blood cancer multiple myeloma, found numerous side effects, including kidney failure. However, kidney failure is very common in multiple myeloma, and it is not clear if these complications were due to resveratrol or a natural result of the disease .
New formulations that utilize nanocarrier technology promise more targeted delivery with high bioavailability. These formulations include the use of liposomes, polymeric nanoparticles, ethosomes, phytosomes, and nanotubes. Some of these applications are topical, and others are oral. Targeted delivery greatly reduces off-target effects and toxicity while requiring less resveratrol .
Safety of resveratrol
Animal studies suggest that resveratrol can be consumed in doses as high as 600 mg/kg in dogs with minimal safety concerns. That translates to approximately 45g/day for a 150-pound individual .
Significant side effects in humans appear to be rare, although few clinical trials have attempted to determine what the limits for resveratrol consumption are . Some studies have indicated a risk of mild to moderate gastrointestinal side effects, including nausea, flatulence, and abdominal pain, in people consuming more than 1g a day. A small study found that 5 grams a day resulted in no serious side effects .
Pregnancy, lactation, and resveratrol
No studies have established safe upper limits for resveratrol consumption in pregnant and lactating women; however, women are cautioned against the consumption of red wine as a source of resveratrol.
Estrogen and resveratrol
Resveratrol is an estrogen-like compound that has been shown to function as both a blocker of the estrogen receptor and an estrogen mimic in different studies. Women with a history of estrogen-driven cancers are cautioned against resveratrol consumption until studies yield a clearer consensus as to what effects resveratrol has on them.
Anticoagulant drugs significantly increase the risk of bruising and bleeding. Resveratrol is known to inhibit platelet aggregation in vitro; therefore, resveratrol combined with anticoagulant drugs of any kind could potentially result in uncontrolled bleeding .
While resveratrol’s inhibition of cytochrome P450 suppresses carcinogen activation, P450 is also used to metabolize many drugs. This suggests that resveratrol intake could increase the potency and risk of toxicity of these drugs .
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