Resveratrol is a chemical compound that is a member of a family of polyphenols called viniferins. The compound was first isolated from the roots of Veratrum grandiflorum (white hellebore). The chemical name for resveratrol is trans-3,4,5'-trihydroxystilbene (or also 3,4',5-stilbenetriol). Resveratrol is also a phytoalexin ("defender of the plant"). Phytoalexins are antimicrobial substances synthesized de novo by plants that accumulate rapidly at areas of pathogen infection. Resveratrol is produced in plants via the action of the enzyme stilbene synthase not only in response to pathogen invasion but also in response to ozone exposure, heavy metals, sunlight, and changes in climate. Resveratrol exists in nature in both the trans- and cis-stereoisomeric forms with heat and ultraviolet radiation inducing the trans– to cis– isomerization. Both the cis– and the tans– forms of resveratrol exhibit the same level of biological activity. However, in studies on the biological effects of resveratrol it is the trans– form that is most used.
Structure of Resveratrol
The range of action of resveratrol is broad. This compound has been shown to exert anti-inflammatory, anti-carcinogenic, anti-tumorigenic, and anti-aging effect. In addition, resveratrol inhibits platelet aggregation, a process required for blood coagulation, and as such plays a significant role in the cardioprotective activities of the compound. Resveratrol also acts as a phytoestrogen. Phytoestrogens are plant-derived compounds that can either mimic or inhibit the female sex hormone, estrogen.
Most recently resveratrol has been shown to ameliorate metabolic defects that occur as a consequence of normal aging processes. These "age restricting" effects on metabolism exerted by resveratrol are the result of its ability to inhibit a class of enzymes known as phosphodiesterases. These enzymes normally degrade the intracellular "second messenger" cAMP. Therefore, the action of resveratrol results in elevated cAMP levels with concomitant increases in events downstream of this signaling molecule. One important effect is the prevention of diet-induced obesity, increased lipid oxidation due to enhanced mitochondrial function, and increased glucose tolerance.
There are multiple intracellular targets of resveratrol which lead to alterations in cell growth, inflammation, apoptosis (programmed cell death), angiogenesis (the growth of new blood vessels), and metastasis and invasion of cancer cells. Perhaps the most striking effect of resveratrol is the ability of this compound to induce the processes that result in longevity in various model organisms (and presumably humans). The longevity-inducing effects of resveratrol are similar to those that result from calorie restriction. Many of the activities of resveratrol are of an anti-oxidant nature. However, increasing evidence demonstrates that resveratrol also exhibits pro-oxidant activities that result in oxidative DNA damage leading to apoptosis and cell death. This latter activity is related to the potential anti-cancer mechanisms of resveratrol (see below).back to the top
Resveratrol and related types of polyphenols are antioxidants that are enriched in grapes and red wines. The Vitis vinifera (common grape vine), Vitis labrusca (Fox grape), and Vitis rotundifolia (muscadine) grapes contain high concentrations of resveratrol. Vitis vinfera is commonly found in the Mediterranean region, central Europe, and southwestern Asia from Morocco and Spain north to southern Germany and east to northern Iran. Vitis labrusca is native to the eastern United States and is the source of Concord grapes, as well as Catawba grapes, Niagara grapes, and Delaware grapes. Vitis rotundifolia is native to the southeastern United States and is cultivated for wine, juice and jelly production.
Resveratrol is also found in other fruits such as strawberries, raspberries, blueberries, mulberries, cranberries, bilberries, lingo berries, sparkle-berries, jackfruit, deer berries, and partridge berries. Resveratrol is also found in the leaves and flowers of many other plants including peanut root, eucalyptus, spruce, lily, butterfly orchid, corn lily, white hellebore, Scots pine, Eastern white pine, and Japanese knotweed.
Fungal infections in grape plants occur with higher frequency in areas of cool climate. Thus, grapes grown in regions of cool climate have high concentrations of resveratrol. However, since ultraviolet radiation from the sun also induces the synthesis of resveratrol, grapes grown in equatorial regions also have high concentrations of resveratrol. Red wines of differing origins contain from 0–18 micrograms per milliliter (μg/ml) of trans-resveratrol with the level of cis-resveratrol ranging from 0–5μg/ml. Muscadine grapes can contain up to 40 times more resveratrol than common grapes. Examples of the differences in resveratrol content in red wines can be seen in a comparison of Brazilian red wines which contain 18μg/ml, Australian Pinot Noir with 13μg/ml, and Swiss reds that contain only 2–3μg/ml. In addition, depending upon the location the same kind of grapevine yields significantly different levels of resveratrol in the wines produced. The Cabernet Sauvignon wines produced in Trentino, Italy contain up to 7μg/ml, whereas the same wines from Napa Valley in California yield only 0.09μg/ml.
Also, although the major difference between red wines and white wines is that in the production process the grape skins are removed in the making of white wines, there are still antioxidant compounds in white wines. However, the level of resveratrol in white wines is low. The major antioxidant compounds in white wines are tyrosol and hydroxytyrosol both of which can induce the anti-aging pathways that are activated by resveratrol.
Of potential clinical significance is the difference in bioavailability of resveratrol obtained from different preparations of grape products. Whereas, the resveratrol content of grape juice can be very high, the concentration of trans-resveratrol found in the blood after grape juice consumption is negligible. This latter fact is related to the absence of ethanol (alcohol) in grape juices and other non-wine sources of resveratrol. When resveratrol is conjugated to compounds that increase its water solubility and thus, presumably its bioavailability, high levels of resveratrol are still not observed in the blood. This is due to the fact that most of the conjugated compound is excreted in the urine.
It is also important to note that there are hundreds of antioxidant compounds in the skin and seeds of grapes and that resveratrol is not the only beneficial polyphenolic compound. The polyphenolic antioxidant compounds in grape skins and seeds consist of the flavonoids and the nonflavonoids. Resveratrol belongs to the nonflavonoid class which also includes the hydroxycinnamates (caffeic, caftaric, and coutaric acids), and the hydroxybenzoates. The polyphenolic flavonoids consist of the flavonols (quercetin and myricetin), flavanols or flavan-3-ols (catechin and epicatechin), and anthocyanins. These compounds are discussed in more detail in the Antioxidants page.back to the top
Resveratrol consumption is associated with a reduced risk of cardiovascular, cerebrovascular, and peripheral vascular disease. The cardioprotective effects of resveratrol are exerted at relatively low doses in the range of 2.5–5.6 milligrams per kilogram of body weight per day (mg/kg/day). The beneficial effects of resveratrol on the vascular system are many. One major effect of resveratrol in the blood is the prevention of oxidation of low density lipoproteins (LDLs, the so-called "bad" cholesterol). Oxidized LDLs contribute significantly to the development of athersclerosis (plaques in the vessels). Additionally, resveratrol exhibits an ability to reduce platelet and monocyte (a type of white blood cell) adhesion to the walls of blood vessels. When platelets and monocytes adhere to vessel walls they induce the coagulation of blood which forms a clot. The clot can break off the vessel wall and flow to an area of constriction in the vessel where the clot cannot pass. The clot then occludes the vessel so blood does not flow leading to death of the tissue surrounding the vessel. These types of events are called embolisms and they can lead to heart failure, death of regions in the brain as well as lung impairment.back to the top
Calorie restriction has been shown to promote longevity in many different organisms from the simple round worm to rats and mice. In studies on the effects of calorie restriction it has been shown that life spans can be increased by as much as 40%. The pathway to longevity, induced by calorie restriction, involves the activation of the function of a protein encoded by a gene called SIRT1.
SIRT1 or sirtuin 1 is the homolog of the yeast (S. cerevisiae) Sir2 gene (Sir refers to Silent mating type Information Regulator). SIRT1 is a member of the sirtuin family of proteins (seven members in humans; SIRT1 through SIRT7) that are characterized by a sirtuin core domain and grouped into four classes. The yeast sirtuin proteins are known to regulate life-span extension, epigenetic gene silencing and suppress recombination of ribosomal DNA (rDNA).
SIRT1 is an NAD+-dependent deacetylase that modulates the activities of proteins that are in pathways downstream of the beneficial effects of calorie restriction. SIRT1 catalyzes a reaction where hydrolysis of NAD+ is coupled to the deacetylation of acetylated lysines in target proteins. These target proteins include histones, transcription factors and transcription factor co-regulators. The NAD+ is hydrolyzed to nicotinamide (which is a strong inhibitor of SIRT1 activity) and O-acetyl-ADP ribose.back to the top
Phytochemicals, such as resveratrol, are deemed useful as potential anti-cancer/therapeutic agents if they can restore normal growth control to cancerous cells by modulating aberrant signaling pathways and/or by inducing apoptosis (a cellular process of programmed cell death) and by targeting the biochemical and physiological pathways that are involved in tumor development. The potential for resveratrol to act as an anti-cancer agent was first published in 1997. Since then the compound has been shown to have relatively low toxicity while exhibiting the capacity to target multiple signaling proteins that promote cancer cell survival and tumor growth. Although it is not important to know or understand the function of each of the genes/proteins indicated in the Table below, the purpose of the Table is to demonstrate the broad range of activities of resveratrol in treating cancer.
|Cancer Type||Genes and Pathways Targeted||Effect(s)|
|Breast||p53, PTEN, p27, p21, p70S6K, pS6RP, Src-Stat3, Akt, Bcl2, NF-κB, calpain, MMP-9, cyclin D, Cdk4, ribonucleotide reductase, CYP1A1, telomerase; nitric oxide (NO) production, reactive oxygen species (ROS)||apoptosis, growth arrest, cell migration|
|Prostate||Caspases-3 and -9, p53, p21, p27, Bax, Bak, Bid, Bad, MKP5, PI3K, Akt, cyclins B/D1/E, Cdk1/4, Bcl2, Src-Stat3, ROS||apoptosis, cell viability, proliferation rate, cell-cycle arrest|
|Colon||AMPK, cathepsin D, caspase-2, cytochrome c, ATF3, Cdk7, p34Cdc2; ROS||apoptosis, cell growth|
|Pancreatic||MIC-1, cytochrome c, caspase-3, Src-Stat3, NF-κB||apoptosis, cell growth|
|Ovarian||Cdc2, ATM/ATR, chk1/2, Cdc25C, H2A.X, Akt, HIF-1a, VEGF||autophagocytic death, cell-cycle arrest|
|Thyroid||p53, c-fos, c-jun, p21||apoptosis|
|Multiple myeloma||c-fms, CD14, CD11a, 1,25(OH)2D3 nuclear receptor (VDR), Bax, Apaf-1, Cathepsin K, RANK, NFATc1, NF-κB (nuclear translocation), Bcl2, Bcl-x(L), XIAP, Mcl-1, MMP-2, MMP-9||apoptosis|
|Leukemia||NO||apoptosis, cell growth|
|B-cell lymphoma||p27, p53, CD69, BCL6, Myc, Akt, p70S6K||apoptosis, cell-cycle arrest, glycolysis|
|Squamous cell carcinoma||p21, p27, Cyclins A/E/D1/D2 Cdk2/4/6, pRb, MEK1, pERK1/2, c-Jun, AP-1, HIF-1α, VEGF, Akt, E2F1-5, DP1/2||cell-cycle arrest|
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Principal pathways involved in glucose homeostasis and insulin sensitivity are affected by SIRT1 activity. In skeletal muscle, a major site of insulin-induced glucose uptake, SIRT1 and AMPK work in concert to increase the rate of fatty acid oxidation in periods of decreased nutrient availability.
The effects of resveratrol have been shown to increase mitochondrial content, ameliorate insulin resistance and prolong survival in laboratory mice fed a high-fat diet. Recent studies on the action of SIRT1 agonists have demonstrated that compounds that activate SIRT1, but that are structurally unrelated to resveratrol, also improve insulin sensitivity in adipose tissue, liver and skeletal muscle resulting in lower plasma glucose. The actions of these compounds in laboratory studies indicate the potential efficacy of a therapeutic approach to type 2 diabetes that includes activators of SIRT1 activity.back to the top
Park, S-J, Ahmad, F, Philp, A, Baar, K, Williams, T, Luo, H, Ke, H, Rehmann, H, Taussig, R, Brown, AL, Kim, MK, Beaven, MA, Burgin, AB, Manganiello, V, and Chung, JH. 2012. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148(3):421-433
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Knutson, MD and Leeuwenburgh, C 2008. Resveratrol and novel potent activators of SIRT1: effects on aging and age-related diseases. Nutrition Reviews 66(10):591-596
Lekli, I, Ray, D and Das, DK 2010. Longevity nutrients resveratrol, wines and grapes. Genes Nutr. 5:55-60
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