Dr. Patrick's excellent description does not include the Vitamin D Receptor benefits
- Resveratrol improves health (Vitamin D receptor, etc.)
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Table of contents
- Resveratrol's effects on human health and disease
- Neurological health and Alzheimer’s disease
- Physiological responses and molecular mechanisms associated with resveratrol intake
Resveratrol is a natural compound found primarily in the skin of red grapes and the root of Polygonum cuspidatum (also known as Japanese knotweed). It is also present to a lesser degree in peanuts and blueberries. Resveratrol protects the plants in which it is present from fungal attack and the damaging effects of ultraviolet radiation.
Originally extracted in the 1940s, resveratrol attracted little interest in terms of human health until 1992 when research suggested that it could mediate some of the cardioprotective effects of red wine. Since then, numerous studies have demonstrated resveratrol's ability to slow or prevent various illnesses, including cancer and cardiovascular disease, as well as extend the lifespan of organisms ranging from yeast to vertebrates. These protective effects are likely due to resveratrol's anti-inflammatory and antioxidant properties and its capacity to activate sirtuin 1, or SIRT1, a type of enzyme that plays a role in aging and longevity.
Resveratrol's effects on human health and disease
Metabolic and cardiovascular health and markers of inflammation
Resveratrol elicits beneficial health effects when used as a treatment for metabolic diseases such as obesity, glucose intolerance, insulin resistance, hypertension, and fatty liver disease.
In a small clinical trial involving 11 obese people, 150 milligrams of resveratrol treatment for 30 days promoted calorie restriction-like effects. The study participants' systolic blood pressure decreased by ~5mm Hg and they experienced improved circulating glucose, insulin, and triglyceride concentrations compared to when they took a placebo. Multiple studies in people who have type 2 diabetes demonstrate that resveratrol treatment of ~1 gram per day significantly decreases systolic blood pressure, fasting blood glucose, hemoglobin A1c (a measure of long-term blood glucose control), and circulating insulin, while improving insulin sensitivity and increasing high-density lipoprotein levels, when compared to baseline levels and placebo groups.   
Resveratrol activates SIRT1 and AMPK while suppressing mTOR, which may lead to improved healthspan via mechanisms that overlap with caloric restriction.
Patients characterized as having non-alcoholic fatty liver disease who took a resveratrol supplement of either 300 or 500 milligrams per day for three months exhibited decreased serum LDL levels, decreased hepatic steatosis, decreased inflammation markers such as NF-κB, and improved insulin sensitivity. 
In a study involving 75 patients undergoing statin treatment for primary cardiovascular disease prevention, those who took a 350 milligram resveratrol-enriched grape extract daily for six months saw a decrease in multiple cardiovascular risk markers, compared to their baseline measurements. The participants' low-density lipoprotein cholesterol (LDLc) decreased by 4.5 percent, oxidized LDL decreased by 20 percent, and apolipoprotein B decreased by 9.8 percent. After the six-month treatment period, the patients received double the original dose for another six months, which resulted in a decrease of inflammatory markers such as tumor necrosis factor-α and interleukin-6 while increasing the anti-inflammatory marker interleukin-10. Furthermore, in patients who had experienced a heart attack, 10 milligrams of daily resveratrol for three months resulted in a significant decrease in LDLc and improved both left ventricle diastolic function and endothelial function – overall measures of heart health.
Resveratrol treatment also elicits positive outcomes in healthy people by decreasing oxidative and inflammatory stress. Specifically, a six-week course of an extract of Polygonum cuspidatum containing 40 milligrams of resveratrol decreased reactive oxygen species and suppressed the expression of JNK-1 and IKKβ, both of which are mediators of inflammation that reduce pro-inflammatory markers TNF-α and IL-6.
Studies in animals show similar beneficial effects. When non-human primates were fed a high-fat diet and given daily resveratrol for two-years (80 milligrams per day for the first year, then 480 milligrams per day for the second year) they exhibited increased SIRT1 expression, decreased inflammation due to diminished levels of NF-κB, decreased adipocyte (fat cell) size, and improved insulin sensitivity in visceral adipose tissue. In a similar study in non-human primates that were fed a diet high in refined sugar (sucrose) and fat for two years, the animals experienced a 40 percent increase in arterial stiffness and inflammation. However, when fed the same diet but also given 80 milligrams of resveratrol per day the first year, then 480 milligrams per day the second year, the primates were protected from arterial wall stiffness and inflammation.
Neurological health and Alzheimer’s disease
Resveratrol treatment has been shown to reduce neuronal inflammation and improve cognitive performance by mitigating reactive oxygen species, inhibiting pro-inflammatory molecules such as cyclooxygenase-1, or COX1, and inhibiting beta-amyloid plaque formation and aggregation, a hallmark of Alzheimer's disease.
In a study of healthy adults aged 50-75 years, 200 milligrams of resveratrol taken per day for 26 weeks improved the participants' ability to complete memory tasks. Resveratrol has also shown promise in a phase 2 clinical trial for the treatment of Alzheimer's disease. Specifically, 56 patients diagnosed with Alzheimer's disease were treated with 500 milligrams of resveratrol once daily with a dose-escalation by 500 milligram increments every 13 weeks, ending with 1000 milligrams twice daily. The patients saw improvements in mental examination status scores, reduced cerebrospinal fluid amyloid-beta levels – a biomarker of Alzheimer's disease – and lowered cerebrospinal fluid matrix metalloproteinase 9, a mediator of neuroinflammation. Although this study demonstrated that resveratrol treatment may improve parameters associated with Alzheimer's disease, larger and longer studies are needed to determine whether resveratrol can promote cognitive and functional improvement.
Whether resveratrol may be beneficial for the treatment of cancer in humans is not currently known; however, numerous in vivo rodent studies have shown the potential of resveratrol for the treatment of pancreatic, prostate, colorectal, liver and breast cancer.  Before resveratrol can be considered a viable option for cancer therapy, more human studies are needed.
The use of resveratrol in cancer prevention might be more promising than cancer treatment, however. Two clinical studies in which healthy subjects received varying doses of resveratrol found that doses of 1 gram and 2.5 grams reduced IGF-1 (insulin-like growth factor 1), which is associated with tumor formation and metastasis. Furthermore, resveratrol treatment increased a variety of carcinogen-detoxifying enzymes, such as glutathione S-transferase and glucuronosyltransferase.  
Calorie restriction extends lifespan in multiple species, an effect that may be mediated in part by sirtuins, enzymes that play key roles in healthspan and longevity. Resveratrol, a potent activator of SIRT1, may mimic the effects of calorie restriction. In multiple species such as yeast, worms, and fish, resveratrol treatment has been shown to increase longevity . In healthy mammals, studies have yet to confirm that resveratrol supplementation extends lifespan. However, studies have shown that resveratrol supplementation can increase the lifespan of metabolically compromised animals. In particular, in a study in which mice were fed a high-fat diet supplemented with resveratrol, the mice had a 31 percent reduced risk of death and displayed a physiology similar to mice fed a standard chow diet without resveratrol.
Physiological responses and molecular mechanisms associated with resveratrol intake
Resveratrol's protective effects against age-related diseases are thought in large part to be mediated through sirtuins. Resveratrol has been shown to bind to sirtuins, altering their affinity for NAD+ and their protein substrates, thereby increasing sirtuins' activity. As such, resveratrol and other sirtuin-activating compounds present a promising therapeutic strategy to ameliorate age-related diseases and extend healthspan.
Learn more about sirtuins in this overview article.
Autophagy is an adaptive response mechanism that is activated upon cellular stress to remove unnecessary or dysfunctional cellular components as well as mobilize stored energy reserves. Calorie restriction is a potent driver of autophagy through the activation of SIRT1.  While resveratrol directly activates sirtuins, it also induces autophagy independent of SIRT1 by inhibiting the activity of mTOR – mammalian target of rapamycin – which is a key regulator of autophagy. Resveratrol's autophagy-inducing capacity likely has implications for both aging and cancer.
Learn more about autophagy in this overview article.
Resveratrol as an insect antifeedant and its role in xenohormesis
Humans have evolved the ability to eat a wide range of plants. During both normal development and under conditions of stress, these plants produce a variety of compounds broadly referred to as phytochemicals. Examples include flavonols, anthocyanins, and resveratrol. In plants, these compounds may act as attractants for pollinators or serve as antioxidants or antifeedants – substances that adversely affect insects or animals, including humans, that feed on the plants.
In humans, phytochemicals can activate cellular stress response pathways which confer protective effects. This biological phenomenon, known as xenohormesis, switches on protective mechanisms that not only protect our cells from the phytochemicals themselves but also provide protection against the potential deterioration of our environment as well as the presence of damaging factors that we are exposed to on a daily basis such as air pollution or overexposure to UV radiation. Why animals, including humans, should respond with a stress response to compounds with otherwise low systemic toxicity has been the source of some speculation. One school of thought suggests that humans and animals use signals of plant stress, the unifying condition by which the production of many beneficial xenohormetic compounds are boosted, as signs that the environment may be demanding enhanced fitness.
The protective effects of resveratrol on humans may be mediated through a variety of cellular stress response pathways such as the activation of SIRT1, AMP-activated protein kinase (AMPK), and cyclic-AMP phosphodiesterase. SIRT1– a highly conserved enzyme that utilizes NAD+ – is linked to anti-inflammatory activity, metabolic adaptations, and neurological protection. AMPK is a fuel-sensing enzyme that can activate numerous pathways involved in catabolism – the breakdown of complex molecules such as fatty acids. AMPK can also inhibit mTOR, leading to the downregulation of cellular growth pathways.  Cyclic-AMP phosphodiesterase is an enzyme that breaks down cAMP – an intracellular signaling molecule – which increases cellular NAD+ levels. Resveratrol has been shown to inhibit cyclic-AMP phosphodiesterase, leading to an increase in NAD+ and SIRT1.  The activation of these cellular stress response pathways may in part mediate some of the beneficial effects as seen with calorie restriction.
Resveratrol as a calorie restriction mimetic
Calorie restriction has widely been shown to increase lifespan across a wide range of organisms from bacteria to primates. With its ability to activate SIRT1 – the gene that likely mediates many of the positive benefits of calorie restriction – resveratrol is thought to be a calorie restriction mimetic.
A study in which mice were fed an obesogenic diet and treated with resveratrol found that the animals not only lived longer compared to mice that didn't receive resveratrol, but they experienced physiological changes typically seen with calorie restriction, such as reduced IGF-1 and increased AMPK activity.
In a study in which mice were fed a standard chow diet to test resveratrol's ability to mimic caloric restriction, resveratrol supplementation did not increase lifespan in the mice. However, the mice that received resveratrol exhibited changes in gene expression that mimicked calorie restriction and demonstrated improved overall health as reflected by reduced incidence of osteoporosis, cataracts, vascular dysfunction, and declines in motor coordination.
Exercise performance enhancement from resveratrol
Although resveratrol has been shown to elicit beneficial effects on metabolic and neurological parameters, studies investigating the effects of resveratrol on exercise training are contradictory. One study involved 27 men between the ages of 60 and 72 years who participated in an 8-week training program with two days of cycling and one day of Crossfit. Each of the men took a 250 milligram resveratrol supplement daily. The resveratrol supplement blunted the positive effects of exercise training on blood pressure, blood cholesterol, and maximal oxygen uptake observed with exercise alone. However, a similar study involved 30 men and women between the ages of 65 and 80 years who participated in a 12-week resistance and aerobic training plan three days a week and took a 500 milligram supplement of resveratrol per day. At the end of the training program, the participants experienced an increase in mitochondrial density, muscle fibers, and maximal oxygen consumption compared to exercise training alone. Another study in which 22 year old men who engaged in four weeks of high-intensity interval training three days a week and supplemented with 150 milligrams of resveratrol per day, the lowest dose of the studies mentioned so far, did not promote increases in the men's aerobic or anaerobic capacity, exercise substrate utilization, or muscle fiber-specific adaptations compared to exercise alone.
The type of exercise, intensity, and the dose of resveratrol may contribute to these contradictory results. More studies are needed to determine how resveratrol supplementation affects exercise performance.
Resveratrol supplementation and safety (and bioavailability)
Resveratrol exists as a trans and cis isomer – a molecule with the same atoms but in a different arrangement. Trans-resveratrol is believed to be the most predominant and stable of the two forms while also eliciting the major health benefits. Trans-resveratrol should be protected from light as studies have shown that upon a few hours of solar or UV radiation, trans-resveratrol undergoes isomerization into the less active cis-resveratrol form. The majority of resveratrol supplements sold in the US contain the trans form of resveratrol, according to their labeling.
Resveratrol's bioavailability – the amount that is taken up in the gut and delivered to the remainder of the body's tissues – is only about 25 percent due to rapid metabolism and excretion.  Studies have shown that resveratrol metabolism varies in a circadian fashion, with higher bioavailability occurring in the morning. Resveratrol is water insoluble and studies have shown that resveratrol enclosed in a nanocapsule – a shell that encapsulates an inner core – can increase stability and bioavailability. Furthermore, a study in healthy human volunteers found that resveratrol exposure is increased when taken with a moderate fat breakfast (18 grams fat, 70 grams carbohydrate, and 12 grams protein) versus a very high fat breakfast (45 grams of fat, 60 grams of carbohydrates and 30 grams of protein) 
Other studies have shown that resveratrol supplementation in combination with piperine – a natural compound found in black pepper – may potentially increase bioavailability and efficacy by inhibiting enzymes involved in the metabolism of resveratrol. In mice given a single dose of resveratrol at 100 milligrams per kilogram of body weight along with piperine at 10 milligrams per kilogram of body weight resulted in a 1544 percent increase in serum concentration of resveratrol compared to mice only given resveratrol at 100 milligrams per kilogram of body weight.  However, a study in humans found that piperine does not improve bioavailability but may improve efficacy in regard to improved cerebral blood flow, which may benefit cognitive function. Specifically, 23 adults who took 250 milligrams of trans-resveratrol with 20 milligrams of piperine had an increase in cerebral blood flow. Further research is needed to determine whether piperine has the ability to increase bioavailability and efficacy of resveratrol.
A 5-ounce glass of red wine contains approximately 1.8 milligrams of resveratrol while therapeutic doses typically range from approximately 100 milligrams to 1 gram. Human trials of resveratrol supplementation have demonstrated that up to 5 grams of resveratrol per day do not cause toxicity or serious side effects.  A repeat dose study for 29 days in healthy volunteers showed that resveratrol supplementation of up to 5 grams was not toxic; however, doses above 2.5 grams were associated with mild to moderate gastrointestinal distress, such as nausea, flatulence (gas), abdominal discomfort, and diarrhea. Furthermore, in overweight adults who were 70 years of age or older, 2 grams of resveratrol taken daily for 90 days was well tolerated.
While resveratrol supplementation has been reported to have minimal side effects in multiple human trials, supplementation should be considered with caution. Hormetic effects in animal models have elicited adverse cardiovascular outcomes, particularly in rats given more than 25 milligrams per day. Long term toxicology studies in humans (longer than one year) have not been performed.
Studies have also shown that resveratrol supplementation may interfere with the way in which the body metabolizes other drugs. In particular, resveratrol inhibits cytochrome P450 enzymes, or CYPs, which are involved with the metabolism of many drugs such as statins, antiarrhythmic agents, and antihistamines. This inhibition could reduce the metabolic clearance of certain drugs leading to increased bioavailability and risk of toxicity.  
Resveratrol elicits a broad range of physiological responses such as activating anti-inflammatory and antioxidant response pathways and promoting the activation of SIRT1. These responses have translated to functional health improvements when used to treat people diagnosed with various metabolic diseases as well as Alzheimer's disease. Given resveratrol's ability to activate cellular protective mechanisms and act as a calorie restriction mimetic, it has the potential to be used as a preventive supplement. Although resveratrol has proven effective in treating metabolic disease and holds promise as a preventive therapy, more studies are needed to ensure safety for long term use and the proper dose.
Resveratrol benefits health in many ways - Dr. Patrick Sept 2019
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