Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a g ...

s, such as

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...

. Sources of resveratrol in food include the skin of

grape A grape is a fruit, botanically a berry, of the deciduous woody vines of the flowering plant genus '' Vitis''. Grapes are a non- climacteric type of fruit, generally occurring in clusters. The cultivation of grapes began perhaps 8,000 years a ...

blueberries Blueberries are a widely distributed and widespread group of perennial flowering plants with blue or purple berries. They are classified in the section ''Cyanococcus'' within the genus ''Vaccinium''. ''Vaccinium'' also includes cranberries, b ...

, raspberries,

mulberries ''Morus'', a genus of flowering plants in the family Moraceae, consists of diverse species of deciduous trees commonly known as mulberries, growing wild and under cultivation in many temperate world regions. Generally, the genus has 64 identif ...

, and

peanut The peanut (''Arachis hypogaea''), also known as the groundnut, goober (US), pindar (US) or monkey nut (UK), is a legume crop grown mainly for its edible seeds. It is widely grown in the tropics and subtropics, important to both small an ...

s. Although commonly used as a

dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...

and studied in laboratory models of human diseases, there is no high-quality evidence that resveratrol improves lifespan or has a substantial effect on any human disease.

Research

Resveratrol has been studied for its potential therapeutic use, with little evidence of anti-disease effects or health benefits in humans.

Cardiovascular disease

There is no evidence of benefit from resveratrol in people who already have heart disease. A 2018

meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...

found no effect on systolic or diastolic blood pressure; a sub-analysis revealed a 2 mmHg decrease in systolic pressure only from resveratrol doses of 300 mg per day, and only in diabetic people. A 2014 Chinese meta-analysis found no effect on systolic or diastolic blood pressure; a sub-analysis found an 11.90 mmHg reduction in systolic blood pressure from resveratrol doses of 150 mg per day.

Cancer

, there is no evidence of an effect of resveratrol on cancer in humans.

Metabolic syndrome

There is no conclusive evidence for an effect of resveratrol on human metabolic syndrome. One 2015 review found little evidence for use of resveratrol to treat

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

. A 2015 meta-analysis found little evidence for an effect of resveratrol on diabetes biomarkers. One review found limited evidence that resveratrol lowered fasting plasma glucose in people with diabetes. Two reviews indicated that resveratrol supplementation may reduce

body weight Human body weight is a person's mass or weight. Strictly speaking, body weight is the measurement of weight without items located on the person. Practically though, body weight may be measured with clothes on, but without shoes or heavy accessor ...

and body mass index, but not fat mass or total blood cholesterol. A 2018 review found that resveratrol supplementation may reduce biomarkers of

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

, TNF-α and C-reactive protein.

Lifespan

There is insufficient evidence to indicate that consuming resveratrol has an effect on human lifespan.

Cognition

Resveratrol has been assessed for a possible effect on

cognition Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, though ...

, but with mixed evidence for an effect. One review concluded that resveratrol had no effect on neurological function, but reported that supplementation improved recognition and mood, although there were inconsistencies in study designs and results.

Diabetes

Although animal experiments have found some evidence that resveratrol may help improve insulin sensitivity and so potentially help manage diabetes, subsequent research on people is limited and does not support the use of resveratrol for this purpose.

Other

There is no significant evidence that resveratrol affects vascular endothelial function, neuroinflammation,

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

, skin infections or

aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

skin. A 2019 review of human studies found mixed effects of resveratrol on certain bone biomarkers, such as increases in blood and bone

alkaline phosphatase The enzyme alkaline phosphatase (EC 3.1.3.1, alkaline phosphomonoesterase; phosphomonoesterase; glycerophosphatase; alkaline phosphohydrolase; alkaline phenyl phosphatase; orthophosphoric-monoester phosphohydrolase (alkaline optimum), systematic ...

, while reporting no effect on other biomarkers, such as

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

and

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...

Pharmacology

Pharmacodynamics

Resveratrol has been identified as a pan-assay interference compound, which produces positive results in many different laboratory assays. Its ability for varied interactions may be due to direct effects on

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

s. As of 2015, many specific biological targets for resveratrol had been identified, including NQO2 (alone and in interaction with AKT1), GSTP1,

estrogen receptor beta Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...

, CBR1, and integrin αVβ. It was unclear at that time if any or all of these were responsible for the observed effects in cells and model organisms.

Pharmacokinetics

The viability of an oral delivery method is unlikely due to the low aqueous solubility of the molecule. The bioavailability of resveratrol is about 0.5% due to extensive hepatic

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

and sulfation. Glucuronidation occurs in the intestine as well as in the liver, whereas sulfonation not only occurs in the liver but in the intestine and by microbial gut activity. Due to rapid metabolism, the

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

of resveratrol is short (about 8–14 minutes), but the half-life of the sulphate and glucoronide metabolites is above 9 hours.

Metabolism

Resveratrol is extensively metabolized in the body, with the liver and intestines as the major sites of its metabolism. Liver metabolites are products of phase II (conjugation) enzymes, which are themselves induced by resveratrol in vitro.

Chemistry

Resveratrol (3,5,4'-trihydroxystilbene) is a stilbenoid, a derivative of stilbene. It exists as two geometric isomers: ''cis-'' (''Z'') and ''trans-'' (''E''), with the ''trans''-isomer shown in the top image. Resveratrol exists conjugated to glucose. The ''trans-'' form can undergo photoisomerization to the ''cis-'' form when exposed to

ultraviolet Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation ...

irradiation. Rasveratrol isomerization

UV irradiation to cis-resveratrol induces further photochemical reaction, producing a fluorescent molecule named "Resveratrone". ''Trans''-resveratrol in the powder form was found to be stable under "accelerated stability" conditions of 75% humidity and 40 °C in the presence of air. The ''trans'' isomer is also stabilized by the presence of transport proteins. Resveratrol content also was stable in the skins of grapes and

pomace Pomace ( ), or marc (; from French ''marc'' ), is the solid remains of grapes, olives, or other fruit after pressing for juice or oil. It contains the skins, pulp, seeds, and stems of the fruit. Grape pomace has traditionally been used to pro ...

taken after fermentation and stored for a long period. ^lH- and ¹³C-NMR data for the four most common forms of resveratrols are reported in literature.

Biosynthesis

Resveratrol is produced in plants via the enzyme resveratrol synthase ( stilbene synthase). Its immediate precursor is a tetraketide derived from malonyl CoA and 4-coumaroyl CoA. The latter is derived from

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...

Biotransformation

The grapevine fungal

Botrytis cinerea ''Botrytis cinerea'' is a necrotrophic fungus that affects many plant species, although its most notable hosts may be wine grapes. In viticulture, it is commonly known as "botrytis bunch rot"; in horticulture, it is usually called "grey mould" or ...

'' is able to oxidise resveratrol into metabolites showing attenuated antifungal activities. Those include the resveratrol dimers restrytisol A, B, and C, resveratrol trans-dehydrodimer, leachinol F, and

pallidol Pallidol is a resveratrol dimer. It can be found in ''red wine Red wine is a type of wine made from dark-colored grape varieties. The color of the wine can range from intense violet, typical of young wines, through to brick red for mature wi ...

. The soil bacterium '' Bacillus cereus'' can be used to transform resveratrol into piceid (resveratrol 3-O-beta-D-

glucoside A glucoside is a glycoside that is derived from glucose. Glucosides are common in plants, but rare in animals. Glucose is produced when a glucoside is hydrolysed by purely chemical means, or decomposed by fermentation or enzymes. The name was ...

Adverse effects

Only a few human studies have been done to determine the

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...

s of resveratrol, all of them preliminary with small participant numbers. Adverse effects resulted mainly from long-term use (weeks or longer) and daily doses of 1000 mg or higher, causing

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

stomach pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...

, flatulence, and

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

. A review of 136 patients in seven studies who were given more than 500 mg for a month showed 25 cases of diarrhea, 8 cases of abdominal pain, 7 cases of nausea, and 5 cases of flatulence. In a year-long preliminary

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

in people with

, the most frequent adverse effects were nausea and weight loss. A 2018 review of resveratrol effects on blood pressure found that some people had increased frequency of bowel movements and loose stools.

Occurrences

Plants

Resveratrol is a phytoalexin, a class of compounds produced by many plants when they are infected by pathogens or physically harmed by cutting, crushing, or ultraviolet radiation. Plants that synthesize resveratrol include knotweeds,

pine A pine is any conifer tree or shrub in the genus ''Pinus'' () of the family (biology), family Pinaceae. ''Pinus'' is the sole genus in the subfamily Pinoideae. The World Flora Online created by the Royal Botanic Gardens, Kew and Missouri Botanic ...

trees including Scots pine and

Eastern white pine ''Pinus strobus'', commonly called the eastern white pine, northern white pine, white pine, Weymouth pine (British), and soft pine is a large pine native to eastern North America. It occurs from Newfoundland, Canada west through the Great Lake ...

, grape vines, raspberries, mulberries, peanut plants, cocoa bushes, and '' Vaccinium'' shrubs that produce berries, including blueberries, cranberries, and bilberries.

Foods

The levels of resveratrol found in food varies considerably, even in the same food from season to season and batch to batch.

Wine and grape juice

Resveratrol concentrations in red wines average trans-resveratrol/L (), ranging from nondetectable levels to 14.3 mg/L (62.7 μM) ''trans''-resveratrol. Levels of ''cis''-resveratrol follow the same trend as ''trans''-resveratrol. In general, wines made from grapes of the Pinot noir and St. Laurent varieties showed the highest level of ''trans''-resveratrol, though no wine or region can yet be said to produce wines with significantly higher concentrations than any other wine or region. Champagne and vinegar also contain appreciable levels of resveratrol. Red wine contains between 0.2 and 5.8 mg/L, depending on the grape variety. White wine has much less because red wine is fermented with the skins, allowing the wine to extract the resveratrol, whereas white wine is fermented after the skin has been removed. The composition of wine is different from that of grapes since the extraction of resveratrol from grapes depends on the duration of the skin contact, and the resveratrol 3-glucosides are in part hydrolysed, yielding both ''trans''- and ''cis''-resveratrol.

Selected foods

Ounce for ounce, peanuts have about 25% as much resveratrol as red wine.

Peanut The peanut (''Arachis hypogaea''), also known as the groundnut, goober (US), pindar (US) or monkey nut (UK), is a legume crop grown mainly for its edible seeds. It is widely grown in the tropics and subtropics, important to both small an ...

s, especially sprouted peanuts, have a content similar to grapes in a range of 2.3 to 4.5 μg/g before sprouting, and after sprouting, in a range of 11.7 to 25.7 μg/g, depending on peanut

cultivar A cultivar is a type of cultivated plant that people have selected for desired traits and when propagated retain those traits. Methods used to propagate cultivars include: division, root and stem cuttings, offsets, grafting, tissue culture ...

Mulberries ''Morus'', a genus of flowering plants in the family Moraceae, consists of diverse species of deciduous trees commonly known as mulberries, growing wild and under cultivation in many temperate world regions. Generally, the genus has 64 identif ...

(especially the skin) are a source of as much as 50 micrograms of resveratrol per gram dry weight.

History

The first mention of resveratrol was in a Japanese article in 1939 by Michio Takaoka, who isolated it from ''

Veratrum album ''Veratrum album'', the false helleborine, white hellebore, European white hellebore, or white veratrum (syn. ''Veratrum lobelianum'' Bernh.) is a poisonous plant in the family Melanthiaceae. It is native to Europe and parts of western Asia (weste ...

'', variety ''grandiflorum'', and later, in 1963, from the roots of Japanese knotweed. In 2004,

Harvard University Harvard University is a private Ivy League research university in Cambridge, Massachusetts. Founded in 1636 as Harvard College and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of highe ...

professor David Sinclair co-founded Sirtris Pharmaceuticals, the initial product of which was a resveratrol formulation.

Related compounds

Dihydro-resveratrol Dihydro-resveratrol is a dihydrostilbenoid found in wine. It is also a metabolite of trans-resveratrol formed in the intestine by the hydrogenation of the double bond by microflora. It is also a non-cannabinoid estrogenic compound found in cannabi ...

* Epsilon-viniferin,

Pallidol Pallidol is a resveratrol dimer. It can be found in ''red wine Red wine is a type of wine made from dark-colored grape varieties. The color of the wine can range from intense violet, typical of young wines, through to brick red for mature wi ...

and

Quadrangularin A Quadrangularin A is an oligostilbene found in '' Cissus quadrangularis'' and in '' Parthenocissus laetevirens''.Characterization of polyphenol compounds from the roots and stems of Parthenocissus laetevirens by high-performance liquid chromatograp ...

three different resveratrol dimers *

Elafibranor Elafibranor ( INN, code name GFT505) is an experimental medication that is being studied and developed by Genfit for the treatment of cardiometabolic diseases including diabetes, insulin resistance, dyslipidemia, and non-alcoholic fatty liver di ...

, a structurally related compound that acts as a dual PPARα/δ agonist * THSG, a glycoside compound found in He Shou Wu which is very similar to resveratrol. * Trans-diptoindonesin B, a resveratrol trimer * Hopeaphenol, a resveratrol tetramer * Oxyresveratrol, the aglycone of mulberroside A, a compound found in '' Morus alba'', the white mulberry * Piceatannol, an active metabolite of resveratrol found in red wine * Piceid, a resveratrol glucoside * Pterostilbene, a doubly methylated resveratrol * 4'-Methoxy-(E)-resveratrol 3-O-rutinoside, a compound found in the stem bark of '' Boswellia dalzielii''Alemika Taiwo E, Onawunmi Grace O and Olugbade Tiwalade O
Antibacterial phenolics from Boswellia dalzielii.
''Nigerian Journal of Natural Products and Medicines'', 2006 * Rhaponticin a glucoside of the stilbenoid

rhapontigenin Rhapontigenin is a stilbenoid. It can be isolated from '' Vitis coignetiae'' or from ''Gnetum cleistostachyum''. It shows an action on prostate cancer cells. It has been shown to inhibit the human cytochrome P450 1A1, an enzyme implicated in the ...

, found in

rhubarb Rhubarb is the fleshy, edible stalks ( petioles) of species and hybrids (culinary rhubarb) of '' Rheum'' in the family Polygonaceae, which are cooked and used for food. The whole plant – a herbaceous perennial growing from short, thick rhi ...

rhizomes

References

External links

* {{Stilbenes Aromatase inhibitors GPER agonists Phytoalexins Phytoestrogens Stilbenoids