INTRODUCTION
Supplements that mimic the health-protection effects of a chemical compound in red wine could form the basis of the next generation of treatment for diabetes and aging-related diseases.
An extract of red wine, resveratrol, is known to temper the damage done by fatty diets, helping to extend healthy life and battle fat-related disease. But tests in mice have suggested that gallons of wine would be necessary for humans to stand a chance of getting the same benefits.
Now scientists have discovered several chemicals that mimic resveratrol but have positive effects at more modest doses. The drugs have already been shown to do as well as another type 2 diabetes treatment in rodent tests of the disease, and will soon be tested in people.
Sirtuins like SIRT-1, SIRT-2 and SIRT-3 may be able to control age-related disorders in various organisms and in humans. These disorders include the aging process, obesity, metabolic syndrome, type II diabetes mellitus and Parkinson’s disease. It is known that resveratrol, found in red wine, can stimulate the production of these sirtuins for slowing down the aging process. However, the amount of resveratrol found naturally in red wine is too low to activate sirtuin, so potential therapeutic use would mandate purification and development of a specific supplement .
Biochemistry
Resveratrol is a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi. Resveratrol has also been produced by chemical synthesis[, and is sold as a nutritional supplement derived primarily from Japanese knotweed. A number of beneficial health effects, such as anti-cancer, antiviral, neuroprotective, anti-aging, and anti-inflammatory effects, have been reported, but all of these studies are “in-vitro” (test tube) or in yeast, worms, fruit flies, fish, mice, and rats. Resveratrol is found in the skin of red grapes and is a constituent of red wine but, based on extrapolation from animal trials, apparently not in sufficient amounts to explain the “French paradox” that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats.
Resveratrol was detected in grape, cranberry, and wine samples. Concentrations ranged from 1.56 to 1042 nmol/g in Concord grape products, and from 8.63 to 24.84 micromol/L in Italian red wine. The concentrations of resveratrol were similar in cranberry and grape juice at 1.07 and 1.56 nmol/g, respectively.
Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than ten percent of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half.
Life Extension
In 2006, Italian scientists obtained the first positive result of resveratrol supplementation in a vertebrate. Using a short-lived fish, Nothobranchius furzeri, with a median life span of nine weeks, they found that a maximal dose of resveratrol increased the median lifespan by 56%. Compared with the control fish at nine weeks, that is by the end of the latter’s life, the fish supplemented with resveratrol showed significantly higher general swimming activity and better learning to avoid an unpleasant stimulus. The authors noted a slight increase of mortality in young fish caused by resveratrol and hypothesized that it is its weak toxic action that stimulated the defense mechanisms and resulted in the life span extension.
Later the same year, Sinclair reported that resveratrol counteracted the detrimental effects of a high-fat diet in mice. The high fat diet was compounded by adding hydrogenated coconut oil to the standard diet; it provided 60% of energy from fat, and the mice on it consumed about 30% more calories then the mice on standard diet. Both the mice fed the standard diet and the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet. Gene expression analysis indicated the addition of resveratrol opposed the alteration of 144 out of 155 gene pathways changed by the high-fat diet. Insulin and glucose levels in mice on the high-fat+resveratrol diet were closer to the mice on standard diet than to the mice on the high-fat diet. However, addition of resveratrol to the high-fat diet did not change the levels of free fatty acids and cholesterol, which were much higher than in the mice on standard diet.
Athletic Performance
Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal CELL in November 2006. Mice fed resveratrol for 15 weeks had better treadmill endurance than controls. The study supported Sinclair’s hypothesis that the effects of resveratrol are indeed due to the activation of SIRT-1.
Nicholas Wade’s interview-article with Dr. Auwerx states that the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (176 lb) person, the 400 mg/kg of body weight amount used in Dr. Auwerx’s mouse study would come to 32,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4571 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There is limited human safety data (see above). It is premature to take resveratrol and expect any particular results. Long-term safety has not been evaluated in humans.
In a study of 123 Finnish adults, those born with certain increased variations of the SIRT-1 gene had faster metabolisms, helping them to burn energy more efficiently?indicating that the same pathway shown in the lab mice works in humans.
Mechanisms of Action
The mechanisms of resveratrol’s apparent effects on life extension are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction. A new report indicates that resveratrol activates SIRT-1 and PGC-1α and improve functioning of the mitochondria. Other research calls into question the theory connecting resveratrol, SIRT-1, and calorie restriction.
Resveratrol interferes with all three stages of carcinogenesis – initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor NF-kB, inhibition of the cytochrome P450 isoenzyme.
Resveratrol was reported effective against neuronal cell dysfunction and cell death, and in theory could help against diseases such as Huntington’s disease and Alzheimer’s disease. Again, this has not yet been tested in humans for any disease.
Research at the Northeastern Ohio Universities College of Medicine and Ohio State University indicates that resveratrol has direct inhibitory action on cardiac fibroblasts and may inhibit the progression of cardiac fibrosis.
In mice, resveratrol reverses the toll of gluttony, keeping their livers healthy and insulin down. Scientists think this effect is thanks to the compound’s ability to activate a protein that affects metabolism – called SIRT-1.
Scientists are also eyeing other conditions that resveratrol might be useful for. The effects of boosting SIRT-1 aren’t limited to diet, says Leonard Guarente, a biologist at the Massachusetts Institute of Technology in Cambridge. Activating the Sirt-1 protein could help stave off the cellular damage that causes other diseases that come with age, such as cancer, Alzheimer’s and heart disease.