Reducing fat in the liver can help stave off liver diseases such as cirrhosis and fibrosis, researchers note.

Previous studies have suggested that resveratrol — a substance found in grapes, peanuts, berries and red wine — may have anti-cancer and anti-inflammatory properties, as well as cardiovascular benefits. However, these findings have not been conclusive in humans.

The study, by researchers at the University of South Florida Health Sciences Center in Tampa, concluded that resveratrol cut down on the amount of fat produced in the livers of mice given alcohol and, simultaneously, increased the breakdown of fat in the liver.
The research was published in the American Journal of Physiology — Gastrointestinal and Liver Physiology.

The study adds to previous research that suggested alcohol shuts off two molecules — AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) — that are key to initiating the breakdown of fats in the liver. Resveratrol, however, appears to do the opposite, switching on the molecules and helping to clear out fat. This stops fat from accumulating in the mouse liver by both reducing the production of fat and burning off the fat that is there.

Surprisingly, alcohol with resveratrol appears to enhance the positive effects of resveratrol alone, according to study senior author Min You.
“Our study suggests that resveratrol may serve as a promising agent for preventing or treating human alcoholic fatty liver disease,” the authors concluded.

Treated mice tended to have better bone health, as measured by thickness, volume, mineral content and density, and bending stiffness compared to the non-treated control group.

At 30 months of age, resveratrol-treated mice were found to have reduced cataract formation, a condition found to increase with age in control-group mice.

Resveratrol enhanced balance and motor coordination in aged animals. Scientists found significant improvement in performance at 21 and 24 months versus 15 months in the resveratrol-treated mice but not in the untreated mice.

Resveratrol partially mimicked the effects of dietary restriction on the gene expression profiles of liver, skeletal muscle and adipose (fatty) tissue in mice.

Along with determining the effect of resveratrol on the health of mice, scientists also studied the effect of resveratrol on longevity.

“We found that while quality of life improved with resveratrol, the compound did not significantly affect overall survival or maximum lifespan for mice on a standard diet, compared to mice on the same diet without resveratrol,” said de Cabo.

Resveratrol did not have a significant effect on lifespan in animals fed standard chow, suggesting that the intervention did not affect all aspects of the basic aging process. Mice on a high-calorie diet without resveratrol lived the shortest length of time and mice on an every-other-day regimen lived the longest, regardless of resveratrol treatment. However, for mice on a high-calorie diet, mean and maximum lifespan increased for mice on resveratrol when compared with the control mice. Researchers found that resveratrol’s effects on longevity could be completely uncoupled from changes in body weight, meaning that mice on a high-calorie diet with resveratrol did not necessarily lose weight but did experience a longer (and healthier) life than mice on the same high-calorie diet not taking resveratrol. They speculate that improved cardiovascular health and reduced fatty changes in the liver may have contributed to the increased lifespan of resveratrol-treated mice.

Researchers still have much to learn before resveratrol can be recommended for human use. Basic questions of safety and biological effect in humans remain to be studied experimentally.

“We are learning a great deal about how resveratrol affects the health and survival of mammals,” said Sinclair. “Continued study of calorie restriction mimetics such as resveratrol may eventually point the way to new medicines to treat diseases of aging.”

In addition to scientists from the NIA and Harvard Medical School, researchers from the following institutions collaborated in this study: New York Medical College, Valhalla, N.Y.; University of Michigan, Ann Arbor; University of Sydney in Australia; Thomas Jefferson University, Philadelphia; University of California, San Diego, La Jolla; Hospital for Special Surgery, New York, N.Y.; University of Cincinnati, Ohio; University of Texas Health Science Center at San Antonio and Audie Murphy VA Hospital, San Antonio, Texas; Universidad Pablo de Olavide, Sevilla, Spain; Pennington Biomedical Research Center, Baton Rouge, La.; University of Washington, Seattle; and Sirtris Pharmaceuticals of Cambridge, Mass., a company founded by Harvard University co-lead author Sinclair.

De Cabo is a scientist in the NIA’s Intramural Research Program. In addition, the research was funded by grants from the NIA, the primary supporter of the work, as well as grants from the National Institute of General Medical Sciences; the National Heart, Lung, and Blood Institute; the National Institute of Child Health and Human Development; the National Eye Institute; and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH. The Ellison Medical Research Foundation, the American Heart Association, the Australian and Spanish governments and Paul F. Glenn and The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging also provided support to members of the research team.

The findings, published July 3, 2008, in Cell Metabolism, may increase interest in resveratrol as a possible intervention for age-related declines, said NIA scientists. The authors emphasized, however, that their findings are based on research in mice, not in humans, and have no immediate and direct application to people, whose health is influenced by a variety of factors beyond those which may be represented in the animal models.

The study is a collaborative effort between the laboratories of Rafael de Cabo, Ph.D., of the Laboratory of Experimental Gerontology at the NIA; David A. Sinclair, Ph.D., of the Glenn Laboratories for Molecular Biology of Aging at Harvard Medical School; and an international group of researchers. The investigators compared mice fed a standard diet, a high-calorie diet, or an every-other-day feeding regimen with or without high- or low-dose resveratrol to study the impact of resveratrol on aging and health. In previous studies, different forms of dietary restriction, including every-other-day feeding, have been shown to improve markers of health.

“Research is attempting to understand the process of aging and to determine how interventions can influence this process. Dietary restriction has well-documented health benefits in mammals, and the study of possible mimetics of it, such as resveratrol, are of great interest,” said NIA Director Richard J. Hodes, M.D. “Resveratrol has produced significant effects in animal models, now including mice, where it mimics some, but not all, consequences of caloric restriction. Its effects in humans remain to be studied.”

A major finding of the study reported today is that resveratrol prevented age-related and obesity-related cardiovascular functional decline in the mice as determined by several parameters. Total cholesterol was significantly reduced in 22-month-old non-obese mice after 10 months of resveratrol treatment, although triglyceride levels had only a slight, non-significant trend toward a decrease. Further, the aortas of 18-month-old obese and non-obese mice treated with resveratrol functioned significantly better than untreated mice. Resveratrol also moderated inflammation in the heart.

Resveratrol has been shown to reduce tumor incidence in animals by affecting one or more stages of cancer development. It has been shown to inhibit growth of many types of cancer cells in culture.

Recent evidence from animal studies suggests this anti-inflammatory compound may be an effective chemopreventive agent in three stages of the cancer process: initiation, promotion and progression.

Red wine is a rich source of biologically active phytochemicals, chemicals found in plants. Particular compounds called polyphenols found in red wine-such as catechins and resveratrol-are thought to have anti oxidant or anti cancer properties.

1. What are polyphenols and how do they prevent cancer?

Polyphenols are antioxidant compounds found in the skin and seeds of grapes. When wine is made from these grapes, the alcohol produced by the fermentation process dissolves the polyphenols contained in the skin and seeds. Red wine contains more polyphenols than white wine because the making of white wine requires the removal of the skins after the grapes are crushed. The phenols in red wine include catechin, gallic acid and epicatechin.

Polyphenols have been found to have antioxidant properties. Antioxidants are substances that protect cells from oxidative damage caused by molecules called free radicals. These chemicals can damage important parts of cells, including proteins, membranes and DNA. Cellular damage caused by free radicals has been implicated in the development of cancer. Research on the antioxidants found in red wine has shown that they may help inhibit the development of certain cancers.
2. What is resveratrol and how does it prevent cancer?

Resveratrol is a type of polyphenol called a phytoalexin, a class of compounds produced as part of a plant’s defense system against disease. It is produced in the plant in response to an invading fungus, stress, injury, infection or ultraviolet irradiation. Red wine contains high levels of resveratrol, as do grapes, raspberries, peanuts and other plants.

Resveratrol has been shown to reduce tumor incidence in animals by affecting one or more stages of cancer development. It has been shown to inhibit growth of many types of cancer cells in culture. Evidence also exists that it can reduce inflammation. It also reduces activation of NF kappa B, a protein produced by the body’s immune system when it is under attack. This protein affects cancer cell growth and metastasis. Resveratrol is also an antioxidant.

3. What have red wine studies found?

The cell and animal studies of red wine have examined effects in several cancers including leukemia, skin, breast and prostate cancers. Scientists are studying resveratrol to learn more about its cancer preventive activities. Recent evidence from animal studies suggests this anti-inflammatory compound may be an effective chemopreventive agent in three stages of the cancer process: initiation, promotion and progression.

Research studies published in the International Journal of Cancer show that drinking a glass of red wine a day may cut a man’s risk of prostate cancer in half and that the protective effect appears to be strongest against the most aggressive forms of the disease. It was also seen that men who consumed four or more 4-ounce glasses of red wine per week have a 60 percent lower incidence of the more aggressive types of prostate cancer.

However, studies of the association between red wine consumption and cancer in humans are in their initial stages. Although consumption of large amounts of alcoholic beverages may increase the risk of some cancers, there is growing evidence that the health benefits of red wine are related to its nonalcoholic components.