Page last updated: Tuesday, November 18, 2008
'Of Fat Mice and Men' by Harvey E. Finkel, MD
The life-span extending effects of red wine’s resveratrol are being followed up the evolutionary scale by David A. Sinclair’s research group at Harvard Medical School, which, in late 2006, reported positive results in a mammal, the mouse.

Recall that prolongation of life had been demonstrated previously in resveratrol-treated yeast, roundworm, fruitfly, and fish. The latest study describes three groups of middle-aged mice. They neither smoked nor consumed alcohol. One group was fed a standard diet, and led a lifestyle normal for male laboratory C57BL/6NIA mice. Two groups of the same sort of mice were fed a high-calorie, high-fat diet, and both became obese. One of the groups of fat mice was also plied with large doses of resveratrol, the behaviour and performance, life span, numerous biochemical measurements, and organ pathology of the three groups of mice were compared.

Another study of the effects of resveratrol on mice, published in Cell, December, 2006, by a group led by Johan Auwerx, serves to affirm and amplify the Sinclair study. The Auwerx program used young male C57BL/6J and KKAy mice, with free access to food and water. Half received resveratrol in addition.

Results of the studies seem clear. Resveratrol is salutary, at least for mice. The obese mice treated with resveratrol remain as healthy as the lean mice. They live much longer and look younger than untreated fat mice, and are as active and agile as their lean cousins fed a standard

diet. Resveratrol increases energy-producing mitochondria, preserves insulin sensitivity, and reduces the damaging effects of obesity and the unhealthy diet on the tissues of the heart, blood vessels, and pancreas.

In the Auwerx study, resveratrol protects mice from obesity, diabetes, and aging. It stimulates energy efficiency, induces mitochondrial activity and tolerance to cold, and raises resistance to muscle fatigue.

Resveratrol is thought to work to extend life in the same way as severe calorie restriction--a reduction of 30 to 40 percent fewer than normal: not an easy sell. The physiological stress induced by calorie restriction, and, it is believed, compounds like resveratrol without such restriction, activate the sirtuin enzyme group, stimulating a complex of metabolic benefits. Resveratrol, whose richest source is grape skins (thus, red wine) is just the most potent in extending life span of a number of antioxidant polyphenols. White wine, dark beer, and cask-aged spirits contain some too, but in lesser quantity.

Resveratrol-induced sirtuin activation also causes a loss of body fat, which itself tends to extend life span.

A study performed at the Massachusetts Institute of Technology demonstrates that the increased life span in diet-restricted roundworms depends on signaling from central nerve cells to body tissues, likely by means of a hormone messenger.

There may be important implications here for human fitness, health, and longevity, and for understanding of the French paradox. Athletes may be interested, though such use will engender controversy. Further research is being considered on rhesus monkeys, which are more similar to humans than are mice. Obesity increases the risks of cardiovascular disease and diabetes, which has its own ravages, and probably other age-related disorders, such as cancer and inflammation. It is hoped that, by stimulating energy-producing mitochondria in cells, the prevalence of neurodegenerative diseases, e.g., Alzheimer’s and Huntington’s diseases, might be reduced by resveratrol.

It is not time, however, to take all this to the bank. The first caveat, obviously, is the lack, so far, of evidence that these effects associated with resveratrol administration would also occur safely in humans. The evidence regarding lower doses seems conflicted. The dose of resveratrol given the mice is equivalent in humans to hundreds of glasses of wine daily. Both the Sinclair and Auwerx studies cited owe support to Sirtis Pharmaceutical, cofounded by Sinclair, a prospective commercial producer of a high-dose resveratrol pill, but wine is so much nicer than a pill.

And don’t forget alcohol, the component of wine that is believed to provide more than half of its health benefits.

Harvey Finkel is a valued member of the AIM Social, Scientific and Medical Council.

Of Fat mice and Men - References

Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444: 337-342.

Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay aging in metazoans. Nature 2004; 430: 686-689.

Bauer JH, Goupil S, Garber GB, et al. An accelerated assay for the identification of lifespan-extending interventions in Drosophilia melanogaster. Proc Natl Acad Sci 2004; 101: 12980-12985.

Howitz KT, Bitterman KJ, Cohen HT et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425: 191-196.

Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1a Cell 2006; 127: 1-14.

Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-g. Nature 2004; 429: 771-776.

Bishop NA, Guarente L. Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 2007; 447: 545-549.

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