The extent of published research on the phytochemical resveratrol is impressive and growing all the time, with now more than 6,000 studies reported. This pharmacologically promiscuous compound demonstrates an amazing array of favourable health outcomes, such as cardioprotective, antidiabetic, anticancer, antiviral, neuroprotective, antiplatelet, anti-inflammatory and modulation of fat metabolism. More importantly, the development of major chronic diseases might also be reduced by resveratrol, based on laboratory studies, including cardiovascular disease, dementia, type 2 diabetes and osteoarthritis. This is in addition to its touted effect on holding back the ageing process via SIRT1 (see below), implying that this one simple molecule has the potential to help prevent most of the chronic diseases associated with old age.
However, it is important to inject a note of caution here – most of the beneficial properties of resveratrol have only been shown in short-term test tube experiments using isolated cells or enzyme systems. Hence, we don’t yet know how most of these lab findings will translate to corresponding long-term benefits in people. On the other hand, results from human clinical trials are growing in number, with several positive studies suggesting that resveratrol can deliver marked clinical effects at relatively modest doses.
Over this and the next month’s articles, I will review many of the recent clinical trials on resveratrol not already covered in previous editions of Nutrition and Healing. In addition, the intriguing research related to resveratrol’s mechanisms of action (in particular with regard to SIRT1) and its bioavailability, are also updated. In a few places I will delve deeply into molecular biology, but please bear with me as the journey towards understanding how this important phytochemical acts in the body is well worth the effort.
Recent clinical trials: Keeping tabs on cardiovascular effects
There are few long-term clinical studies on resveratrol. Hence, the 2012 publication of a one-year trial by Spanish scientists has significance beyond its actual clinical focus. The trial used a triple-blind, randomized, placebo-controlled design to examine resveratrol’s impact on cardiovascular risk factors in statin-treated patients. Seventy-five patients consumed one capsule/day of either a resveratrol-enriched (8mg) grape extract, the same grape extract with no resveratrol, or a placebo for six months, and then double the dose for the next six months.1
Results from even these low doses of resveratrol were striking. Compared to the placebo and the conventional grape supplement, there was a significant 26% reduction (p=0.03) in high-sensitivity C-reactive protein (hs-CRP) by the end of one year. Other markers of inflammation were also significantly and beneficially changed: tumour necrosis factor-alpha (-19.8%, p=0.01) and the interleukin-6 (IL-6) to interleukin-10 (IL-10) ratio (-24%, p<0.001). Interestingly, the IL-6/IL-10 ratio deteriorated in the placebo group. The pro-clotting factor plasminogen activator inhibitor type 1 (PAI-1), an inhibitor of fibrinolytic activity, was also reduced (-16.8%, p=0.03). For PAI-1, the higher dose was needed to reach this significant decrease. No adverse effects were observed in any patient. The authors concluded that their results show for the first time that resveratrol therapy can complement statins in the primary prevention of cardiovascular disease, since heart disease and strokes are closely linked now to inflammation.
Given these findings, it could be relevant that a Spanish epidemiological (population-based) study conducted by different researchers found higher urinary levels of resveratrol metabolites (reflecting a higher intake of the phytochemical via grapes and wine) were associated with a reduction of cardiovascular risk in high-risk patients.2 The scientists studied 1,000 people and found a correlation between urinary resveratrol metabolites and higher plasma high-density lipoprotein (HDL) levels (p=0.02), lower triglyceride levels (p=0.012), and reduced heart rate (p<0.001). After adjusting for alcohol intake, there was also a correlation with decreased fasting blood glucose (p=0.037). In support of this, a randomized, double-blind clinical trial in 50 healthy smokers found 500mg/day resveratrol significantly reduced CRP and triglyceride levels.3 Oxidative stress was also reduced by resveratrol.
Flow mediated dilatation (FMD) is a measure of vessel wall function in arteries, and hence indicates early cardiovascular disease changes. It is correlated with obesity, poor memory and hypertension. Twenty-eight obese (BMI 33.31±0.6 kg/m2) but otherwise healthy adults aged around 61 years were randomized to take resveratrol (75mg/day) or a matching placebo in a six-week, double-blind and crossover clinical trial.4 Compared with the placebo there was a significant 23% decrease in FMD following chronic resveratrol supplementation (p=0.021). The extent of improvement was greater in participants with poorer initial vasodilator function.
Recent clinical trials: Spotlight on metabolic syndrome and type 2 diabetes
Blood vessel lining (endothelial) function (FMD) was also improved in patients with metabolic syndrome taking 100mg/day of resveratrol in a proprietary formulation.5 An open-label, crossover design was used with 34 patients, who took the resveratrol for three months.
Sixty-two patients with type 2 diabetes were enrolled in an open-label, randomized, controlled trial conducted in India.6 The control group received only oral hypoglycaemic drugs, whereas the active intervention group additionally took resveratrol (250mg/day) for three months. At the end of the trial there were significant (p<0.05) reductions in glycosylated haemoglobin, systolic blood pressure and total cholesterol.
Interestingly, oral resveratrol helped heal diabetic foot ulcers, suggesting either it helps diabetic complications and/or improves healing. The study was a randomized, placebo-controlled, examiner blind clinical trial in 24 type 2 diabetic patients with newly diagnosed diabetic ulcers.7 The active treatment was 100mg/day of a proprietary resveratrol product for 60 days. The change in ulcer size was more marked in the resveratrol group, with an average reduction of 3.1 cm versus 2.1 cm in the placebo group. Complete wound closure occurred in 36% of resveratrol-treated patients against only 10% of control patients. Visual assessment of ulcers revealed patients in the resveratrol group tended to have more circularly shaped ulcers with a well-pronounced demarcation zone and healthy pink granulation tissue. There was also a statistically significant decline in plasma fibrinogen, an independent cardiovascular risk factor associated with inflammation and clotting.
The link between calorie restriction, SIRT1 and resveratrol
All the scientists researching ageing, universally acknowledge that dietary or calorie restriction (CR) by 20 to 40% is proven to extend lifespan by up to 50%. No other known intervention has such a generally consistent and profound effect: experiments on single yeast cells up to primates have verified this. But the key story here is not just the extension of lifespan; it is the significant compression of morbidity (or extension of healthspan) that also takes place. At advanced ages CR animals are more youthful-looking, display inquisitive behaviour and are highly active, just like much younger animals. The exact way that CR works to extend youthfulness and lifespan is not fully understood, but several researchers have proposed that it is due to hormesis, with CR acting as a moderate healthy stressor.8, 9, 10
A strong advocate of the hormesis hypothesis for CR is Prof David Sinclair, an Australian scientist working at Harvard on ageing research. He argues the hormesis hypothesis links so many of the diverse observations about CR from experimental models. The pathways involved are a hardwired survival mechanism to enhance the chance of survival during stress and reduced food availability – a defensive response to a survival threat. He proposed that this very basic survival mechanism should be and is regulated by a few genes and their corresponding proteins. These genes have been identified and are called SIRT1 to SIRT7. However, SIRT1 is particularly important. Sirtuin proteins coded by these genes are increased in CR and regulate a multitude of beneficial metabolic effects. They are described as master metabolic regulators.
Since phytochemicals (plant chemicals) can cause hormetic responses and may act as environmental signals to shift into survival mode ahead of an environmental decline, Sinclair’s team investigated whether simple phytochemicals might increase SIRT1 protein activity. Resveratrol, found in grapes and several other foods and herbs, was identified to be the most active natural agent at activating SIRT1.11 Polygonum cuspidatum, the giant knotweed from Chinese traditional medicine, is a rich source of resveratrol.
To your better health,
Nutrition & Healing
Vol. 8, Issue 8 – August 2014
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