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Herbs and Nutrients That May Assist
Polygonum
Reynoutria japonica, dry root
Providing resveratrol
BCM-95™ Turmeric
Curcuma longa, rhizome
Quercetin
Clinical Applications
- Healthy ageing
- DNA protection
- Oxidative stress
- Mitochondrial function
- Inflammation
- Cardiovascular protection
- Improve glycaemic control
Clinical Overview
Resveratrol Age Well is a formulation specifically designed to aid in the achievement of healthy ageing. The formula is aimed at addressing key areas of biological dysfunction associated with ageing, including DNA damage and mitochondrial dysfunction. Polygonum, providing a rich source of resveratrol, combined with turmeric BCM-95TM extract and quercetin, promotes healthy ageing by modulating the drivers of dysfunction: oxidative stress and inflammation. In addition, the ingredients in Resveratrol Age Well help protect areas that often incur dysfunction during ageing, including the cardiovascular system, the nervous system, and metabolic control.
Background Information
Reynoutria japonica rhizome is used traditionally in Chinese medicine for a variety of complaints from abdominal pain, gallstones, amenorrhea, dysmenorrhoea and vaginal discharge, to sports injuries, rheumatic complaints, skin infections and productive coughs. Polygonum possesses antibiotic, antipyretic, anti-inflammatory, analgesic and hepatoprotective effects. 1 Polygonum rhizome is also used traditionally in Chinese medicine to treat diabetes, and studies in polygonum species have confirmed antidiabetic effects in animal models. 2 Polygonum rhizomes are a rich source of resveratrol. A polyphenol compound, trans-resveratrol (trans-3,5,4’-trihydroxystilbene) functions in plants as a phytoalexin that protects against fungal infections. 3 Also found in grapes, resveratrol is recognised to contribute to the cardioprotective effects of red wine, and has significant anti-inflammatory effects, as will be discussed later.
Resveratrol is also being investigated as a potential chemopreventive agent, as it has been shown to block all three phases of tumour development (initiation, promotion, and progression), and may inhibit the growth of a wide variety of tumour cells, including leukaemic, prostate, breast, and endothelial cells. 3 For example, animal studies suggest that inhibition of DNA synthesis and angiogenesis may contribute to antitumour and antimetastatic activities of resveratrol. 4 Inflammation is closely linked to tumour promotion. 5 The transcription factor nuclear factor- B (NF- B) has major roles in inflammatory and immune responses, regulation of cell proliferation and apoptosis and so is important for tumour development. Resveratrol has chemopreventive activities associated with inhibition of this factor. 6 Resveratrol also inhibits other protein kinases that direct
tumour promotion and progression, and trigger inflammation. 7 Resveratrol has also been demonstrated to reduce CYP450 activation of carcinogens, inhibiting tumour initiation and may additionally upregulate phase II metabolising enzymes that may be involved in the detoxification of carcinogens. 8
Quercetin is another polyphenolic compound, a bioflavonoid found in Ginkgo biloba, red wine, grapefruit, onions, apples and black tea. Quercetin has antioxidant and anti-inflammatory activity; it is an inhibitor of mast cell secretion, inhibiting allergic inflammation; and it may also have cancer-preventing activity. 9 In addition to these properties, quercetin may have activity in conditions characterised by capillary fragility, may enhance immunity and have gastroprotective activities, and may protect against the development of such diabetic complications as cataracts, retinopathy, neuropathy and nephropathy. 10
There is evidence to suggest that the combination of quercetin with resveratrol may increase the bioavailability of resveratrol via inhibition of its sulphation and glucuronidation. Resveratrol and other polyphenolic compounds undergo duodenal and hepatic sulphation and also glucuronidation, and this metabolism might limit its bioavailability. Quercetin is a potent inhibitor of resveratrol sulfotransferase and, to a lesser extent, glucuronosyl transferase, reducing the metabolism of resveratrol via these enzymes; thus, quercetin may improve the bioavailability of resveratrol. 11,12,13
Curcuma longa (turmeric) root / rhizome extract has been traditionally used in Ayuvedic and Chinese Medicine as a tonic for the stomach, blood purifier and externally for the treatment of skin diseases and wound healing. Turmeric contains a family of polyphenols called curcuminoids and volatile oils. The curcuminoid, curcumin, has been found to be the active ingredient in turmeric. Research has discovered curcumin to be anti-arthritic, anti-allergic, anti-bacterial, anti-inflammatory and have anti-tumour and anti- oxidant properties. 14
BCM-95 ® curcuminoid complex is a proprietary, 100% natural turmeric extract containing curcuminoids and various volatile compounds of turmeric. It is a standardised turmeric extract that enhances the bioavailability of curcumin. Human studies have shown that, as well as up to 700% enhanced bioavailability, BCM-95 ® gives enhanced retention of curcumin in the blood when compared with a standard turmeric extract (95% curcuminoids). 14
Figure 1: Increased bioavailability and retention of curcumin with a single dose BCM-95 extract (red line) compared to a standard curcumin (purple line). 14
Clinical Applications
Healthy Ageing
In mammals, caloric restriction with a reduction of caloric intake from 25% to 60% of that of control animals fed ad libitum, extends the lifespan, provided that the diet contains sufficient amounts of all essential nutrients. Caloric restriction conserves insulin sensitivity and also reduces sexual maturation and fecundity, allowing for long-term survival through energy sparing. 15 Members of the sirtuin (silent information regulator 2) family are key regulators required for the anti-ageing effects of caloric restriction to take place. Sirtuins are NAD +–dependent deacetylases conserved from simple organisms to humans. In humans, seven sirtuins have been identified (SIRT1–7). SIRT1, the most extensively studied, regulates such processes as glucose and insulin production, fat metabolism, and cell survival. 15, 16
SIRT1 is a nuclear protein (enzyme) that removes an acteyl group from a substrate, most notably SIRT1 deacetylates histones – the spools of DNA. SIRT1 histone deaceylation directly regulates a number of nuclear transcription factors believed to be key components of the biological benefits of calorie restriction. It is thought that SIRT1 activation regulates cellular pathways involved in stress resistance and metabolism; a hormetic like effect. 17
SIRT1 regulates multiple transcription factors for stress adaptation and metabolic function. Deacetylation of FOXO3 results in reducing oxidative stress by up-regulating catalase and MnSOD. FOXO3 also induces cell cycle arrest preventing cellular apoptosis. A combination of increased anti-oxidant defence and preventing apoptosis contributes to FOXO1 ability to promote cellular stress resistance. SIRT1 regulates inflammation by deacetylating proteins at sites critical for NF-ĸB transcriptional activity. PGC-1α is also deacetylated by SIRT1, which upon activation leads to improved mitochondrial bioenergetics and biogenesis. Finally, another key transcription factor deacetylated by SIRT1 is p53. p53 is a tumour suppressor protein and also functions to prevent cellular apoptosis (see figure 2). 18
Emerging human evidence suggests that a lack of SIRT1 activity is involved in a number of chronic diseases associated with ageing including breast cancer, metabolic syndrome, Alzheimer’s disease and chronic obstructive pulmonary disorder. 19,20,21,22 Therefore targeting and increasing SIRT1 activity has become and intense focus recently as a means of preventing and treating diseases of ageing. 23
Figure 2: SIRT1 deacyetlates key mediators of cellular functions associated with chronic disease and ageing. 18
Resveratrol in Healthy Ageing
In search for substances that could mimic the effects of caloric restriction, polyphenols found in high concentrations in red wine were identified as potent activators of sirtuins. Quercetin and resveratrol can both alter SIRT1 activity, with the latter being the most potent. 15 More recent in vitro human studies have confirmed resveratrol increases SIRT1 activity, however there is debate whether this is a direct or indirect activation. 24,25,26 Resveratrol has been demonstrated to extend the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster, fish and mice. In mammalian cells, resveratrol produces SIRT1-dependent effects that are consistent with improved cellular function and general health. 16
Resveratrol has been shown in middle-aged mice, to shift the physiological changes induced by a high- calorie diet towards that of mice on a standard diet, improving their health and significantly increasing their survival. Resveratrol produced changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) activity, increased mitochondrial number, and improved motor function. Gene set analysis revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways (Figure 3). 16, 27
However, although resveratrol (and to a lesser extent, quercetin) may increase the defence status of an organism, it is not established as yet whether sirtuin activation in higher animals or humans can accomplish all effects of caloric restriction on ageing when a sedentary lifestyle is maintained. 15
Figure 3: Resveratrol mimics many of the same genes expressed by caloric restriction. 27
Curcumin in Healthy Ageing
Curcumin has been found to upregulate protective mechanisms in mammalian cells against a variety of stresses, offering protection against diseases and malignancy. Research has demonstrated curcumin activates Nrf2, a transcription factor normally suppressed in the cytosol. Upon activation Nrf2 enters the nucleus and potentiates the cells own defence mechanism – the antioxidant response element (ARE).
ARE activation induces the expression of phase II detoxification enzymes: γ-glutamylcysteine synthetase, glutathione S-transferases and NADP(H):quinone oxidoreductase. In addition, curcumin also via the Nrf2 pathway induces expression of the enzyme haem oxygenase-1(HO-1). HO-1 degrades haem to CO, iron and biliverdin. Biliverdin acts as antioxidant and CO as signalling molecule to help counter cellular dysfunction that results from biological stressors. Collectively, the action of curcumin on ARE lead to enhanced detoxification and cellular protection potentially against a variety of diseases commonly experienced during ageing, including malignancy (Figure 4). 28,29
Neuronal function is of particular interest in healthy ageing, and Alzheimer’s disease (AD) is a major threat to quality of life in the ageing population. Oxidative stress (OS) causing DNA damage is thought to play a key role in the early stages of AD pathology and some evidence suggest that curcumin may provide protection from oxidative stress induced Alzheimer’s disease.
A study using a mouse model of AD found the addition of curcumin in the diet reduced the DNA damage in these animals. 30
Curcumin is also a potent anti-inflammatory agent, which is thought to be a key mechanism in turmeric’s chemopreventive effect. Preclinical cancer research on curcumin has shown it inhibits carcinogenesis in a number of cancer types, including colorectal, pancreatic, gastric, prostate, hepatic, breast, and oral cancers, and leukaemia, and at various stages of carcinogenesis. 31 The preclinical data also suggests curcumin can suppress tumour initiation, promotion and metastasis. 32
The anticarcinogenic action is believed to be mediated by the following anti-inflammatory effects: (1) inhibition of NF-κB and COX-2 (2) inhibition of arachidonic acid metabolism via lipoxygenase and scavenging of free radicals generated in this pathway (3) decreased expression of inflammatory cytokines IL-1b, IL-6, and TNF-α, resulting in growth inhibition of cancer cell lines; (4) down-regulation of enzymes, such as protein kinase C, that mediate inflammation and tumour-cell proliferation. 21
Figure 4: Curcumin activates Nrf2 induction of detoxification and cellular protection. 33
DNA Protection
The ingredients in Resveratrol Age Well provide a comprehensive protection against key areas associated with DNA dysfunction, such as micronuclei frequency, rapid telomere shortening and DNA double strand breaks. These errors and stresses on DNA are widely recognised as factors that can accelerate the ageing process. Agents that can inhibit and reverse DNA damage should significantly delay ageing and promote longevity.
Studies with resveratrol have found it has a dual benefit on DNA - it reduces DNA damage and promotes DNA repair. Resveratrol was found to completely inhibit rat kidney oxidative stress induced DNA damage (oxo8dG levels) with results superior to any other anti-oxidant tested. 34 Other research suggests that resveratrol can itself bind to DNA and upregulate DNA double strand repair. Resveratrol may also activate SIRT1 mediated DNA repair and there is some suggestion resveratrol may prevent telomere shortening. 35
Curcumin demonstrated a 10-fold reduction in micronuclei frequency in a mouse model of oxidative stress induced AD, suggesting it contributes to genomic stability. Also in this experiment, curcumin was found to increase the telomere length in the buccal mucosa of AD. 30 Research on human AD subjects were found to have shorter telomeres compared to matched controls. 36 These studies support the theory that curcumin provides protection against DNA damage-related diseases of ageing.
Figure 5: Balanced levels of ROS are necessary for healthy ageing. 38
Resveratrol is a powerful antioxidant at quenching excessive free radicals. Ex vivo investigations have shown that resveratrol appears to act as a scavenger for superoxide anions (O •–) and to protect against lipid peroxidation generated by free oxygen radicals. Resveratrol in itself has shown antioxidant properties as described above but also can increase the activity of the cell’s own anti-oxidant enzymes, particularly the gluatathione enzymes: glutathione peroxidase, glutathione S-transferase and glutathione reductase. 40
Interestingly however, research also suggests that resveratrol has a pro-oxidant effect depending on the concentration of resveratrol and cell type. As any anti-oxidant (reductant) has a biological reciprocal oxidation reaction (reduction–oxidation), it seems logical that this would be the case with resveratrol and other phytochemicals. The pro-oxidant effect of resveratrol is suggested to be one of its anti-cancer mechanisms by oxidant induced apoptosis and DNA damage of tumour cells. 40
Turmeric has anti-oxidant properties and as mentioned curcumin induces activation of the cells own anti- oxidant defence (antioxidant response element). The induction of the cell’s own protection mechanism may be a more balanced physiological response than the addition of an exogenous anti-oxidant substance. And, similar to resveratrol and quercetin, curcumin itself can be pro or anti-oxidant depending on other cellular factors.42 The stimulation of ROS by turmeric has been found in a number of in vitro human cancer cells lines to induce apoptosis, one potential mechanism of turmeric’s anticancer effect. 43,44 Collectively the components in Resveratrol Age Well are anti-oxidant for oxidative stress, induce homeostatic cellular anti- oxidant defence and may have appropriate pro-oxidant functions to pathological cells.Quercetin has been shown to be an excellent in vitro antioxidant. Within the flavonoid family, quercetin is the most potent scavenger of ROS, including O •–, and reactive nitrogen species like nitric oxide (NO •) and peroxynitrite (ONOO −). 41 On the contrary to its anti-oxidant action, there is evidence that quercetin exerts a pro-oxidant effect in mitochondria of cancer cells to a state of depolarization and general dysfunction, resulting in apoptosis and tumour reduction. 39
Resveratrol is a powerful antioxidant at quenching excessive free radicals. Ex vivo investigations have shown that resveratrol appears to act as a scavenger for superoxide anions (O 2 •–) and to protect against lipid peroxidation generated by free oxygen radicals. Resveratrol in itself has shown antioxidant properties as described above but also can increase the activity of the cell’s own anti-oxidant enzymes, particularly the gluatathione enzymes: glutathione peroxidase, glutathione S-transferase and glutathione reductase. 40
Interestingly however, research also suggests that resveratrol has a pro-oxidant effect depending on the concentration of resveratrol and cell type. As any anti-oxidant (reductant) has a biological reciprocal oxidation reaction (reduction–oxidation), it seems logical that this would be the case with resveratrol and other phytochemicals. The pro-oxidant effect of resveratrol is suggested to be one of its anti-cancer mechanisms by oxidant induced apoptosis and DNA damage of tumour cells. 40
Quercetin has been shown to be an excellent in vitro antioxidant. Within the flavonoid family, quercetin is the most potent scavenger of ROS, including O 2 •–, and reactive nitrogen species like nitric oxide (NO •) and peroxynitrite (ONOO −). 41 On the contrary to its anti-oxidant action, there is evidence that quercetin exerts a pro-oxidant effect in mitochondria of cancer cells to a state of depolarization and general dysfunction, resulting in apoptosis and tumour reduction. 39
Turmeric has anti-oxidant properties and as mentioned curcumin induces activation of the cells own anti- oxidant defence (antioxidant response element). The induction of the cell’s own protection mechanism may be a more balanced physiological response than the addition of an exogenous anti-oxidant substance. And, similar to resveratrol and quercetin, curcumin itself can be pro or anti-oxidant depending on other cellular factors.42 The stimulation of ROS by turmeric has been found in a number of in vitro human cancer cells lines to induce apoptosis, one potential mechanism of turmeric’s anticancer effect. 43,44 Collectively the components in Resveratrol Age Well are anti-oxidant for oxidative stress, induce homeostatic cellular anti- oxidant defence and may have appropriate pro-oxidant functions to pathological cells.
Mitochondrial Function
The number and function of mitochondria are critical for energy production and aberrations in mitochondria function are associated with a number of diseases and with ageing itself. Resveratrol has demonstrated in a number of in vivo and in vitro studies to improve mitochondria function in skeletal, hepatic and endothelial cells. This includes resveratrol increasing mitochondrial mass and mitochondrial DNA content, upregulating protein expression of electron transport chain constituents, and inducing mitochondrial biogenesis factors (PGC-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A). 45
Curcumin may aid mitochondrial function via mechanisms that differ from resveratrol, making it a suitable companion in Resveratrol Age Well. A study on diabetic rats found curcumin increased cellular anti-oxidant defence resulting in protection of complex I and IV respiratory chain enzymes from oxidative damage. This protection lead to a significant increase in brain mitochondrial ATP levels, which is normally chronically reduced in rats with experimental-induced diabetes. 46
Quercetin has demonstrated experimental and clinical evidence of improved mitochondrial function. Seven day feeding of quercetin to mice found increased markers of biogenesis, with a significant increase in PGC- 1α, SIRT1 and cytocrome c concentrations. In addition, these mice had an increase in maximal endurance capacity and voluntary wheel-running activity, suggesting a benefit from the increased mitochondrial biogenesis. 47 Similar results in improved physical performance with short term quercetin ingestion have also been found in human research. In a randomised, double-blind, placebo-controlled trial 12 subjects took quercetin for seven days and found a modest increase in VO2max (3.9% vs. placebo; p < .05) along with a substantial (13.2%) increase in ride time to fatigue compared to controls. 48
Inflammation
ROS are not only involved in the occurrence of oxidative stress, but also in the promotion of inflammatory processes via activation of transcription factors such as NF-κB and activator protein (AP)-1, which induce the production of cytokines like tumour necrosis factor-α (TNF-α). Consequently, scavenging excess ROS would not only prevent the occurrence of oxidative stress but would also help mitigate inflammation.
Quercetin has demonstrated strong anti-inflammatory effects, by multiple mechanisms. In vitro, the administration of quercetin has been found to decrease the gene expression and production of TNF-α, interleukin-1 (IL-1 ), IL-6, and IL-8. Additionally, it was found to attenuate not just the activation of NF-κB, 41 but also that of p38 mitogen-activated protein kinase (MAPK), which is another key factor in the regulation of pro-inflammatory molecules. 49 The anti-inflammatory effects of attenuated NF-κB activity are achieved via inhibition of inhibitor of B kinase (IKK), which consequently prevents the activation of NF-κB. 50
Quercetin has also been found to suppress the production of the inflammatory cytokines, such as interferon-ƴ (IFN- ƴ) and IL-2 following stimulation of T cell receptors. It achieved this by independent mechanisms: IFN- ƴ suppression required a transcription factor called T-bet, while IL-2 inhibition occurred through diminished IL-2 receptor- expression. 51
Anti-inflammatory effects of resveratrol include the ability to inhibit the formation of 5-lipoxygenase and cyclo- oxygenase (COX) products and inhibit the degranulation of polymorphonuclear leucocytes. 4 Resveratrol appears to inhibit the activation of NF-κB and AP-1 and associated kinases, and these actions may contribute to the anti-inflammatory, anticarcinogenic, and growth-modulatory effects of resveratrol. [*] Resveratrol is a potent inhibitor of NF-κB and AP-1 activation, and has been found to do so in a dose and time-dependent manner. Resveratrol also has been demonstrated to inhibit the activation of other associated kinases. Both reactive oxygen intermediate generation and lipid peroxidation induced by TNF-α have been found to be suppressed by resveratrol.
Curcumin has been found to reduce inflammation by modulating a number of inflammatory mediators. Laboratory studies have identified curcumin inhibits many inflammatory signals including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12). 52
Of particular interest curcumin has also been found to attenuate the action of NF-κB via inhibition of IKK. In vitro research on human colon cells found that curcumin prevented NF-κB binding to DNA and subsequent COX expression. This inhibition was due to curcumin also inhibiting IKK, preventing NF-κB activation. 53 The anti-inflammatory properties of curcumin also extend also into clinical research. Curcumin has shown clinical improvements in a variety of inflammatory diseases, including ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, inflammatory eye diseases and psoriasis. 54,55,56,57,58
Cardiovascular Protection
Polygonum, resveratrol, and quercetin all have potential protective effects against cardiovascular disease. Polygonum cuspidatum has been demonstrated to dilate capillaries, improve blood microcirculation and inhibit thrombosis. 2 Resveratrol’s cardioprotective effects may occur through its abilities to block platelet aggregation, inhibit oxidation of low density lipoprotein, induce nitric oxide production and through its structural similarity with oestrogen. Resveratrol’s abilities to inhibit ribonucleotide reductase and DNA polymerase and to suppress cell growth have also been suggested to play a role in cardioprotection.
With regard to platelets, investigations have shown that resveratrol has a protective effect against ROS production in resting and activated blood platelets, and it reduced not only platelet aggregation, but other aspects of platelet activation, such as platelet adhesion to collagen and fibrinogen, secretion and eicosanoid synthesis. In comparison to vitamin C, resveratrol has been shown to have superior potency as an antioxidant in platelets, including outcomes such as free radical scavenging, lipid peroxidation and superoxide formation, at concentrations 1/500 th to 1/3000 th that of vitamin C. 59
A number of other mechanisms have been described for resveratrol’s cardioprotective role. Ramprasath and Jones have reviewed the research on resveratrol in atherosclerosis and suggest it may act by preventing lipid oxidation and platelet aggregation, aid arterial vasodilation and modulate the levels of lipids and lipoproteins. In addition resveratrol may regenerate vitamin E, promoting vitamin E’s cardioprotective effects (Figure 6). 60
Figure 6: The multiple pathways of resveratrol in reducing atherosclerosis. 60
In addition to resveratrol, quercetin has been demonstrated to inhibit platelet aggregation. In an ex vivo study, platelet-rich plasma was taken from healthy volunteers who had not taken aspirin or NSAIDs for at least two weeks. In these samples, both trans-resveratrol and quercetin dose-dependently inhibited both thrombin-induced and ADP-induced platelet aggregation. Resveratrol also significantly inhibited the production of thromboxane B2 from platelets, while quercetin inhibited production of 12-HETE (12- hydroxyeicosatetraenoic acid), which has been postulated to be proatherogenic via impairment of endothelial function and prostacyclin production. These results are consistent with the notion that trans-resveratrol may contribute to the presumed protective role of red wine against atherosclerosis and coronary heart disease. 61
In vitro studies have demonstrated that quercetin inhibits the oxidative modification of low density lipoprotein (LDL) cholesterol by macrophages, probably by inhibiting the generation of hydroperoxides and by protecting against the oxidation -tocopherol present in lipoproteins. Quercetin, in vitro, also inhibited the cytotoxicity of oxidised LDL. As oxidised LDL is atherogenic and thought to be important in the formation of atherosclerotic plaques, it is possible that quercetin and other flavonoids may reduce the formation of atherosclerotic plaques. Flavonols, such as quercetin, also inhibit cyclo-oxygenase, leading to lower platelet aggregation and reduced thrombotic tendencies. A high intake of dietary flavonoids (predominantly quercetin, at 63%) in elderly men has been associated with a lower mortality from coronary heart disease and lower incidence of myocardial infarction. 62
Spanish researchers have conducted a number of open clinical trials using a standardised curcumin extract. Curcumin at doses of 10-20 mg/day for 15-60 days were associated with an increased HDL cholesterol, decreased LDL cholesterol, increased APO A, decreased APO B, decrease APO a/b ratio, reduced blood lipid peroxide, reduced lipoprotein peroxide and a reduction in high fibrinogen in subjects with atherosclerosis. 63,64,65
Improve Glycaemic Control
Treating obesity and metabolic syndrome is currently a major focus of resveratrol research. From the earlier study finding that mice on a high calorie diet were resistant to obesity and metabolic dysfunction, researchers have explored resveratrol’s mechanisms in protection against metabolic disease. Initial interest in resveratrol focussed on SIRT1 activation, however recent research has found other pathways are also responsible for resversatrol’s metabolic effects.
Another stress adaption pathway found to be activated by resveratrol is AMPK signalling. AMPK is a cellular energy sensor which can be activated by fasting and exercise, and AMPK signalling triggers energetic events in the cell. Resveratrol has been shown to activate AMPK leading to increased mitochondrial oxidation, increased fatty acid oxidation, mitochondrial biogenesis, decreased pathogenic lipid intermediates (diacyglycerol and ceramides) and ultimately improved insulin-stimulated glucose disposal via GLUT-4 (Figure 7). 66
Figure 7: Resveratrol improves glucose and lipid metabolism. 67
Many in vitro and in vivo animal studies have explored resveratrol’s effect on glycaemic control and have found it: improved mice survival on a high calorie diet, reduced body fat including visceral fat, reduced body weight, decrease plasma triglycerides, reduced cardiac and skeletal muscle ageing, reduce fatty acid synthesis, enhanced epinephrine-induced lipolysis, and inhibited adipogenesis. 48
A number of mouse studies demonstrate tumeric to have many potential benefits for improving glycaemic control and metabolic syndrome. Collectively, these experiments have found turmeric to decrease blood glucose, improve insulin resistance, reduce leptin levels and decrease HBA1c levels, all common parameters involved in metabolic syndrome. 68,69,70 In addition, the carbonyl groups in curcumin were found to bind to proteins on toll like receptor 4 (TLR-4), inhibiting dimerisation of TLR4. Attenuation of TLR4 activity by curcumin inhibits downstream signalling such as NF-κB induced inflammation. This action is considered to be another mechanism of curcumin in mitigating insulin resistance. 71,72
Other positive effects on metabolic syndrome of turmeric appear to target adipocytes. Adipocyte dysfunction plays a key role in the development of metabolic syndrome such as adipocyte hypertrophy and the release of inflammatory adipokines. Activation of peroxisome proliferator activated receptor γ (PPAR–γ) by a ligand in adipose tissue may help attenuate metabolic syndrome. PPAR-γ is a nuclear transcriptional factor that regulates lipid metabolism, glucose homoestasis and inflammation. A number of studies have found curcumin to act as a ligand for PPAR- γ, increase adipocyte differentiation, reduce macrophage accumulation and increase adiponectin secretion. 73 ,74
Safety Information
Disclaimer: In the interest of supporting health Practitioners, all safety information provided at the time of publishing (XXX 2025) has been checked against authoritative sources. Please note that not all interactions have been listed.
For further information on specific interactions with health conditions and medications, refer to clinical support on 1800 777 648(AU), 0508 227 744(NZ) or via email, anz_clinicalsupport@metagenics.com, or via Live Chat www.metagenics.com.au, www.metagenics.co.nz
Pregnancy
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Prescribing Tips and Notes
Contraindications
Cautions
Footnotes
[*] The carcinogenic, inflammatory, and growth-modulatory effects of many chemicals are mediated by NF-κB. AP-1 is another transcription factor that mediates tumorigenesis and invasiveness, and is often activated alongside NF-κB.
References
[1] Hempen CH, Fischer T. A Materia Medica for Chinese Medicine. Edinburgh; Churchill Livingstone, 2009: pp566-7.
[2] Li WL, Zheng HC, Bukuru J, De Kimpe N. Natural medicines used in the traditional Chinese medical system for therapy of diabetes mellitus. J Ethnopharmacol. 2004 May;92(1):1-21.
[3] Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 2000;164(12):6509-19.
[4] Kimura Y, Okuda H. Resveratrol isolated from Polygonum cuspidatum root prevents tumour growth and metastasis to lung and tumor- induced neovascularization in Lewis lung carcinoma-bearing mice. J Nutr 2001;131(6):1844-9.
[5] Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS. Molecular mechanisms underlying chemopreventative activities of anti-inflammatory phytochemicals; downregulation of COX-2 and iNOS through suppression of NF-kB. Mutat Res 2001; 480-481: 243- 268
[6] Ignatowicz E, Baer-Dubowska W. Resveratrol, a natural chemopreventive agent against degenerative diseases. Pol J Pharmacol 2001;53:557-69.
[7] Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies. Anticancer Res 2004;24(5A): 2783-840.
[8] Signorelli P, Ghidoni R. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 2005;16(8):449-466
[9] Shaik YB, Castellani ML, Perrella A, Conti F, Salini V, Tete S, Madhappan B, Vecchiet J, De Lutiis MA, Caraffa A, Cerulli G. Role of quercetin (a natural herbal compound) in allergy and inflammation. J Biol Regul Homeost Agents. 2006 Jul-Dec;20(3-4):47-52.
[10] Hendler SS, Rorvik D, Eds. PDR for Nutritional Supplements. 1st ed. Montvale, NJ; Thomson. 2001: pp390-3.
[11] De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum. Xenobiotica. 2000 Jun;30(6):609-17.
[12] De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. Sulphation of resveratrol, a natural compound present in wine, and its inhibition by natural flavonoids. Xenobiotica. 2000 Sep;30(9):857-66.
[13] De Santi C, Pietrabissa A, Mosca F, Pacifici GM. Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver. Xenobiotica. 2000 Nov;30(11):1047-54.
[14] Benny M, Antony B. Bioavailability of BiocurcumaxTM (BCM-95TM). Spice India 2006; 19(9): 11-15.
[15] Wenzel U. Nutrition, sirtuins and aging. Genes Nutr. 2006 Jun;1(2):85-93.
[16] Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42.
[17] Westphal CH, Dipp MA, Guarente L. A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci. 2007 Dec;32(12):555- 60.
[18] Chung S, et al. Regulation of SIRT1 in cellular functions: Role of polyphenols. Arch Biochem Biophys. 2010 May 5. [Epub ahead of print]
[19] Wang RH, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008 Oct 7;14(4):312-23.
[20] de Kreutzenberg SV, et al. Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes. 2010 Apr;59(4):1006-15.
[21] Julien C. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol. 2009 Jan;68(1):48-58.
[22] Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008 Apr 15;177(8):861-70.
[23] Finkel T, ET AL. Recent progress in the biology and physiology of sirtuins. Nature. 2009 Jul 30;460(7255):587-91.
[24] Arunachalam G, et al. SIRT1 regulates oxidant- and cigarette smoke-induced eNOS acetylation in endothelial cells: Role of resveratrol. Biochem Biophys Res Commun. 2010 Feb 26;393(1):66-72.
[25] Fischer-Posovszky P, et al. Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. Am J Clin Nutr. 2010 Jul;92(1):5-15.
[26] Pervaiz S, Holme AL. Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal. 2009 Nov;11(11):2851-97.
[27] Barger JL, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One. 2008 Jun 4;3(6):e2264.
[28] Mattson MP. Dietary factors, hormesis and health. Ageing Research Reviews 7 (2008) 43–48.
[29] Balogun E, Hoque M, Gong P, Killeen E, Green, CJ, Foresti R, Alam J, Motterlini, R. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem. J. 2003, 371, 887–895.
[30] Thomas P, Wang YJ, Zhong JH, Kosaraju S, O'Callaghan NJ, Zhou XF, Fenech M. Grape seed polyphenols and curcumin reduce genomic instability events in a transgenic mouse model for Alzheimer's disease. Mutat Res. 2009 Feb 10;661(1-2):25-34.
[31] Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev. 2009 Jun;14(2):141-53.
[32] Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003 Jan- Feb;23(1A):363-98. Review
[33] Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ, Mattson MP. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal. 2010 Dec 1;13(11):1763- 811.
[34] Cadenas S, Barja G. Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. Free Radic Biol Med. 1999 Jun;26(11-12):1531-7.
[35] Gatz SA, Wiesmüller L. Take a break--resveratrol in action on DNA. Carcinogenesis. 2008 Feb;29(2):321-32.
[36] Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, Cummings JL, Effros RB. Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol Aging. 2003 Jan-Feb;24(1):77-84.
[37] Duračková Z. Some current insights into oxidative stress. Physiol Res. 2009 Nov 20. [Epub ahead of print]
38 Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000 Nov 9;408(6809):239-47.
[39] Tapia PC. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality. Med Hypotheses. 2006;66(4):832-43
[40] de la Lastra CA, Villegas I. Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans. 2007 Nov;35(Pt 5):1156-60.
[41] Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008 May 13;585(2- 3):325-37.
[42] Ahsan H, Parveen N, Khan NU, Hadi SM. Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem Biol Interact. 1999 Jul 1;121(2):161-75.
[43] Sanchez Y, Simon GP, Calvino E, de Blas E, Aller P. Curcumin Stimulates Reactive Oxygen Species Production and Potentiates Apoptosis Induction by the Antitumour Drugs Arsenic Trioxide and Lonidamine in Human Myeloid Leukaemia Cell Lines. J Pharmacol Exp Ther. 2010 Jul 6. [Epub ahead of print].
[44] Suphim B, Prawan A, Kukongviriyapan U, Kongpetch S, Buranrat B, Kukongviriyapan V. Redox modulation and human bile duct cancer inhibition by curcumin. Food Chem Toxicol. 2010 May 25.
[45] Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang H, Losonczy G, Pearson K, de Cabo R, Pacher P, Zhang C, Ungvari Z. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H13-20.
[46] Rastogi M, Ojha RP, Rajamanickam GV, Agrawal A, Aggarwal A, Dubey GP. Curcuminoids modulates oxidative damage and mitochondrial dysfunction in diabetic rat brain. Free Radic Res. 2008 Nov;42(11-12):999-1005.
[47] Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R1071-7.
[48] Davis JM, Carlstedt CJ, Chen S, Carmichael MD, Murphy EA. The dietary flavonoid quercetin increases VO(2max) and endurance capacity. Int J Sport Nutr Exerc Metab. 2010 Feb;20(1):56-62.
[49] Min YD, Choi CH, Bark H, Son HY, Park HH, Lee S, Park JW, Park EK, Shin HI, Kim SH. Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappaB and p38 MAPK in HMC-1 human mast cell line. Inflamm Res. 2007 May;56(5):210-5.
[50] García-Mediavilla V, Crespo I, Collado PS, Esteller A, Sánchez-Campos S, Tuñón MJ, González-Gallego J. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol. 2007 Feb 28;557(2-3):221-9.
[51] Yu ES, Min HJ, An SY, Won HY, Hong JH, Hwang ES. Regulatory mechanisms of IL-2 and IFN-gamma suppression by quercetin in T helper cells. Biochem Pharmacol. 2008 Jul 1;76(1):70-8.
[52] Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med 2003;9(1):161-8.
[53] Plummer SM, Holloway KA, Manson MM, Munks RJ, Kaptein A, Farrow S, Howells L. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene. 1999;18(44):6013-20.
[54] Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 2005 Nov;50(11):2191-3.
[55] Hanai H, et al Curcumin maintenancetherapy for ulcerative colitis: randomized, multicenter, double-blind,placebo-controlled trial. Clin Gastroenterol Hepatol. 2006 Dec;4(12):1502-6.
[56] Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res 1980;71:632-4.
[57] Lal B, Kapoor AK, Agrawal PK, Asthana OP, Srimal RC. Role of curcumin in idiopathic inflammatory orbital pseudotumours. Phytother Res. 2000 Sep;14(6):443-7.
[58] Kurd SK, Smith N, VanVoorhees A, Troxel AB, Badmaev V, Seykora JT, Gelfand JM. Oral curcumin in the treatment of moderate to severe psoriasis vulgaris: A prospective clinical trial. J Am Acad Dermatol. 2008 Apr;58(4):625-31. Epub 2008 Feb 4. Erratum in: J Am Acad Dermatol. 2008 Jun;58(6):1050.
[59] Olas B, Wachowicz B. Resveratrol and vitamin C as antioxidants in blood platelets. Thromb Res 2002;106(2):143-8.
[60] Ramprasath VR, Jones PJ. Anti-atherogenic effects of resveratrol. Eur J Clin Nutr. 2010 Jul;64(7):660-8. Epub 2010 May 19.
[61] Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta. 1995 Mar 31;235(2):207-19.
[62] Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993 Oct 23;342(8878):1007-11.
[63] Ramírez-Boscá A, Soler A, Carrión MA, Díaz-Alperi J, Bernd A, Quintanilla C, Quintanilla Almagro E, Miquel J. An hydroalcoholic extract of curcuma longa lowers the apo B/apo A ratio. Implications for atherogenesis prevention. Mech Ageing Dev. 2000 Oct 20;119(1-2):41-7.
[64] Ramírez-Bosca´ A, Soler A, Carrio´n-Gutie´rrez MA, Laborda Alvarez A, Quintanilla Almagro E. Antioxidant curcuma extracts decrease the blood lipid peroxide levels of human subjects. Age.1995 (18):167–169.
[65] Ramírez-Boscá A, Soler A, Carrión-Gutiérrez MA, Pamies Mira D, Pardo Zapata J, Diaz-Alperi J, Bernd A, Quintanilla Almagro E, Miquel J. An hydroalcoholic extract of Curcuma longa lowers the abnormally high values of human-plasma fibrinogen. Mech Ageing Dev. 2000 Apr 14;114(3):207-10.
[66] Fullerton MD, Steinberg GR. SIRT1 takes a backseat to AMPK in the regulation of insulin sensitivity by resveratrol. Diabetes. 2010 Mar;59(3):551-3.
[67] Szkudelska K, Szkudelski T. Resveratrol, obesity and diabetes. Eur J Pharmacol. 2010 Jun 10;635(1-3):1-8.
[68] Kuroda M, Mimaki Y, Nishiyama T, Mae T, Kishida H, Tsukagawa M, Takahashi K, Kawada T, Nakagawa K, Kitahara M. Hypoglycemic effects of turmeric (Curcuma longa L. rhizomes) on genetically diabetic KK-Ay mice. Biol Pharm Bull. 2005 May;28(5):937-9
[69] Gonzales AM, Orlando RA. Curcumin and resveratrol inhibit nuclear factor-kappaB-mediated cytokine expression in adipocytes. Nutr Metab (Lond). 2008 Jun 12;5:17.
[70] Weisberg SP, Leibel R, Tortoriello DV. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology. 2008 Jul;149(7):3549-58.
[71] Lubbad A, Oriowo MA, Khan I. Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol Cell Biochem. 2009 Feb;322(1-2):127-35.
[72] Dasu MR, Devaraj S, Park S, Jialal I. Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care. 2010 Apr;33(4):861-8. Epub 2010 Jan 12.
[73] Siddiqui AM, Cui X, Wu R, Dong W, Zhou M, Hu M, Simms HH, Wang P. The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma. Crit Care Med. 2006 Jul;34(7):1874- 82
[74] Nishiyama T, Mae T, Kishida H, Tsukagawa M, Mimaki Y, Kuroda M, Sashida Y, Takahashi K, Kawada T, Nakagawa K, Kitahara M. Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice. J Agric Food Chem. 2005 Feb 23;53(4):959-63.
