Life Extension Magazine March 2007
Growing Evidence Links Resveratrol to Extended Life Span
By Laurie Barclay, MD
The Life Extension Foundation has a 27-year history of introducing cutting-edge therapies for extending life and preventing disease. In 2003, we reported on findings that resveratrol (a substance found in red grapes and other plants) extended the life span of certain cells by as much as 70%.
Since our initial report, resveratrol has continued to demonstrate extraordinary potential in prolonging life. In numerous studies—including those at BioMarker Pharmaceuticals, a Life Extension-sponsored research institution—resveratrol has demonstrated effects that mimic those of caloric restriction, the best-documented anti-aging strategy to date. In all animals in which it has been tested, caloric restriction—the practice of restricting calorie intake while maintaining good nutritional status—improves multiple aspects of age-related decline. Caloric restriction does this, in part, by producing changes in gene expression that are associated with long life and a slowing of the aging process.
Resveratrol is also gaining growing recognition for its promise in fighting age-related diseases ranging from dementia to diabetes. For example, the National Institutes of Health is currently sponsoring a clinical trial investigating resveratrol’s ability to fight colon cancer.
In this article, we bring our readers up to date on the latest clinical research on resveratrol, and why leading researchers believe this remarkable nutrient may hold the key to living a longer, more vibrant, disease-free life.
Resveratrol and Caloric Restriction
To date, the most reliable, best-researched way to extend life span is through the practice of caloric restriction, which involves reducing calorie intake while simultaneously maintaining good nutritional status.
In numerous studies, restricting calorie intake in laboratory animals has been shown to prolong their life span by as much as 60%.1-3 While scientists have not yet determined whether caloric restriction extends life span in humans, the preliminary evidence is very promising. In humans, consuming a low-calorie diet is associated with several possible markers of greater longevity, such as lower insulin levels and reduced body temperatures, along with less of the chromosomal damage that typically accompanies aging.4 Furthermore, people who consume a low-calorie diet may be less prone to diseases associated with being overweight or obese, such as metabolic syndrome, diabetes, cancer, and atherosclerosis.
Although caloric restriction may be effective in promoting longevity, the problem is that most adults find this stringent lifestyle strategy to be impractical. As a result, scientists have sought to uncover the precise mechanisms by which caloric restriction promotes longevity, in order to help people capture its life-extending benefits through more practical means.
Resveratrol Offsets Perils of a High-Calorie Diet
Remarkable new research suggests that it may be possible to achieve the life-extending benefits of caloric restriction using the readily available, plant-derived compound known as resveratrol. Resveratrol and caloric restriction appear to work via similar mechanisms to promote health and longevity in numerous animal species.
In an interview, a leading resveratrol researcher, Dr. Xi Zhao-Wilson of BioMarker Pharmaceuticals, told Life Extension, “There has been a great deal of attention focused on resveratrol in the past few years, following a study showing that resveratrol activates molecular pathways involved in life-span extension, now demonstrated in yeast, worms, flies, fish, and mice, and which possibly bear a relationship to mechanisms under-lying caloric restriction.”
This heightened interest in resveratrol has produced several recent breakthroughs. In a landmark study, Harvard University scientists showed that resveratrol could prolong survival by regulating a gene associated with aging that is present in all life forms.5 They demonstrated that while middle-aged mice fed a high-calorie diet suffered the ravages of obesity—including metabolic changes resembling diabetes, liver and heart damage, and premature death—mice that were fed resveratrol in addition to the high-calorie diet actually exhibited beneficial changes in their physiology, resembling those of mice fed a standard diet.5
Among the life-prolonging benefits of resveratrol supplementation demonstrated in the study were:
While mice on the non-supplemented high-calorie diet developed enlarged, fatty livers, resveratrol supplementation prevented these changes. Similarly, heart disease and evidence of atherosclerosis were seen in mice fed the high-calorie diet, but not in those that were also given resveratrol. Resveratrol significantly increased survival, reducing the risk of death from the high-calorie diet by 31%. Together, these findings offer powerful evidence that resveratrol protected the animals from the harmful effects of a high-calorie diet.5
Resveratrol’s positive impacts on insulin sensitivity and survival were apparent after only six months of treatment.5 Resveratrol also improved the animals’ quality of life, as reflected in their physical abilities. On a test of balance and coordination, the resveratrol-fed mice on the high-calorie diet steadily improved as they aged.5 The obese resveratrol-supplemented animals experienced all of these benefits without a significant reduction in body weight.5
“These data demonstrate that resveratrol can alleviate the negative impact of a high-calorie diet on overall health and life span,” the Harvard scientists concluded. “The ability of resveratrol to prevent the deleterious effects of excess caloric intake and modulate known longevity pathways suggests that resveratrol and molecules with similar properties might be valuable tools in the search for key regulators of energy balance, health, and longevity.”5
Mechanisms by Which Resveratrol May Extend Life
Today, scientists around the world are studying resveratrol to determine how it helps fight aging and prolong life span. Current evidence suggests that resveratrol exerts antioxidant effects, boosts energy production, and favorably alters patterns of gene expression.
Oxidative stress is implicated in numerous disease processes and in aging itself. Resveratrol demonstrates powerful antioxidant capabilities, with profound implications for human health. Scientists report that resveratrol inhibits the oxidation of dangerous low-density lipoprotein (LDL) and scavenges harmful hydroxyl radicals. Resveratrol also helps preserve levels of glutathione, one of the body’s most essential antioxidants.6 According to prominent resveratrol investigator Dr. Milos Sovak, “There is no question that resveratrol is one of the best free-radical scavengers and that it has many effects whose ramifications might affect not only longevity but also general health.”
Resveratrol stimulates energy production in the cellular powerhouses known as the mitochondria. Diminished mitochondrial energy production is associated with reduced longevity. By enhancing the production of life-sustaining energy, resveratrol may help protect against metabolic disease and obesity, thereby improving health and prolonging survival in animals.7
Growing evidence indicates that resveratrol influences many genetic pathways, which may underlie its ability to lengthen life. In the recent Harvard study, investigators noted that a high-calorie diet produced numerous changes in gene expression. However, supplemental resveratrol opposed the effects of this high-calorie diet in 144 of 153 significantly altered genetic pathways. Moreover, resveratrol’s effects were dose dependent, with larger amounts yielding greater effects, leading the investigators to suggest that resvera-trol may offer “new approaches for treating obesity-related disorders and diseases of aging.”7
Some of the genetic pathways influenced by resveratrol are similarly affected by caloric restriction. For example, caloric restriction is associated with long-term activation of AMP-activated kinase (AMPK), a metabolic enzyme promoting insulin sensitivity and fatty-acid oxidation. Resveratrol likewise increases AMPK activity, which is associated with life-span extension.5
Scientists believe that caloric restriction increases life span in part through its effects on the sirtuin genes.5 Present in all life forms, sirtuin genes are associated with aging and longevity. Resveratrol may confer benefits similar to those of caloric restriction by influencing the sirtuin gene known as SIRT2.5,8-10 In the Harvard study, resveratrol helped counteract changes in SIRT2 expression induced by a high-calorie diet.5
“The genes and pathways [affected by resveratrol or by caloric restriction] are related to activation of sirtuins, a class of histone deacetylase enzymes (HDACs) involved in cell death and life-span regulation,” Dr. Zhao-Wilson told Life Extension. “Based on the large body of evidence, the resveratrol/sirtuin activators have become the focus of pharmaceutical drug discovery efforts now [targeting] HDACs.”
Researchers believe that compounds like resveratrol that either activate or inhibit sirtuin activity may have therapeutic potential for a broad array of human diseases, including cancer, diabetes, heart failure, and neurodegenerative conditions such as Alzheimer’s and Huntington’s disease.11