Growing Evidence Links Resveratrol to
Extended Life Span
By Laurie Barclay, MD
The Life Extension Foundation has a 27-year history of introducing cuttingedge
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%. 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. 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. 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.
Among the life-prolonging benefits of resveratrol supplementation demonstrated in the study
were: increased insulin sensitivity n lower blood sugar n enhanced mitochondrial energy
production n improved motor function. 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.
Resveratrol’s positive impacts on insulin sensitivity and survival were apparent after only six
months of treatment. 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. The obese resveratrol-supplemented animals
experienced all of these benefits without a significant reduction in body weight. “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.”
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. 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. 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 13 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.” 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. Scientists believe that caloric restriction
increases life span in part through its effects on the sirtuin genes. 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.
In the Harvard
study, resveratrol helped counteract changes in SIRT2 expression induced by a high-calorie
diet. “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.
RESVERATROL AND EXTENDED LIFE SPAN: WHAT YOU NEED TO KNOW
Resveratrol,
a health-promoting compound found in grapes, has been shown to increase life span in several
animal species. In a recent Harvard study, mice that consumed a high-calorie diet known to
shorten life lived longer when they also consumed resveratrol. These mice also had better
coordination, less heart and liver damage, and better insulin sensitivity than overweight mice that
were not fed resveratrol. Scientists have proposed that resveratrol in red wine may help explain
the “French paradox”—the fact that cardiovascular disease rates in France are relatively low,
despite a diet traditionally high in fat. Because widespread use of pesticides has diminished the
amount of resveratrol contained in grapes and red wine, supplemental resveratrol may the best
way to ensure optimal intake. Laboratory and animal studies suggest that resveratrol may have
therapeutic potential for cardiovascular disease, cancer, inflammatory arthritis, Alzheimer’s
disease, and other neurodegenerative conditions. Clinical trials studying resveratrol’s effects on
cancer and diabetes are also under way. Resveratrol may enhance health and support longevity
via several mechanisms. These include its potent antioxidant effects, ability to enhance cellular
energy production, and ability to influence patterns of gene expression in a manner similar to
caloric restriction (the best-documented method of extending life span in animals). n Because
resveratrol exerts protective effects through a variety of mechanisms, it may be a useful
supplement for healthy adults wishing to reduce their risk of chronic disease and live a long and
healthy life. Studies to date suggest that resveratrol is safe and nontoxic.
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