High Doses Of Vitamin E Boost Survival Rate 40%; Brain Function And ‘High Wire’ Neuromuscular Performance Gains Also Significant

Two-years of tightrope and ‘T-maze’ testing

BETHESDA, Md. (Sept. 4, 2005) – Studying how much longer and “better” mice will live on high doses of vitamin E involves much time and work – two years of feeding, testing and studying. But based on earlier results, a joint team from the University of Cadiz, Spain, and the University of Buenos Aires, Argentina, figured the payoff would be worth the effort.

Their just-published paper shows that using vitamin E supplementation physiologically comparable to recent human experiments in Alzheimer’s Disease patients, resulted in these major findings:

• male mice showed a 40% increase in median lifespan (to 85 ± 4 weeks from 61 ± 4).

• 17% increase in maximal lifespan (to 136 weeks from 116 weeks).

• increases in the ability to perform tests measuring neuromuscular performance (high-wire tightrope) and cognitive exploratory activity (T-maze); the increases on both tests ranged 9%-24% at 52 weeks, and 28%-45% at 78 weeks of age.

• brain alpha-tocopherol content increased 2.5-fold in male mice taking vitamin E.

• vitamin E supplementation offset various measures of mitochondrial function loss in a range of 37%-66% at the 52- and 78-week test points.

• all results were significant to a greater than 99% confidence level.

The paper “Vitamin E at high doses improves survival, neurological performance and brain mitochondrial function in aging male mice” appears online in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, published by the American Physiological Society. Research was by Ana Navarro, Carmen Gomez, Maria-Jesus Sanchez-Pino, Hipolito Gonzalez and Manuel J. Bandez of the University of Cadiz, Spain, and Alejandro D. Boveris and Alberto Boveris of the University of Buenos Aires.

Results seen supporting ‘free radical’ theory of aging

Alberto Boveris, professor at the University of Buenos Aires, said the results of these extended experiments “are in line with the free radical theory of aging put forward by Gerschman and Harman in the 1950s. Our results show a significant negative correlation between the mitochondrial content of the oxidation products of free-radical mediated reactions and mitochondrial enzymatic activities.

“Moreover, brain mitochondrial enzymatic activities were linearly related to mice success in the tests of neuromuscular function and of exploratory and cognitive activity and to the maximal mice life span,” Boveris reported. He noted that the amount of vitamin E supplementation was metabolically and physiologically similar to the 1200-2000mg. daily dosage for two to three years used in two Alzheimer’s Disease experiments involving over 400 patients without adverse effects.

The paper observes that the “study shows the beneficial effects of high doses of vitamin E on the median and maximal lifespan of male mice, an effect that is parallel to a beneficial effect on the decline of neurological performance and mitochondrial function associated with aging.” It said the “marked increase” in median lifespan and the moderate rise of maximal lifespan “is properly described as a delay in the onset of the almost linear decay in mice survival.”

The mice used in the experiment, the CD-1/UCadiz, are a senescence accelerated strain with a median lifespan of 60-70 weeks and maximal lifespan of 100-120 weeks. Vitamin E supplementation of the test group began at age 28 weeks.

Role of vitamin E as antioxidant; support for ‘specificity’ concept

The researchers noted that the “mitochondrial content of lipid protein oxidation products, an indication of free-radical mediated reactions and oxidative damage, was increased in the brain and liver of aging mice, and the effect was partially [and significantly] prevented by vitamin E. The protein carbonyl content of brain mitochondria, taking 28-week-old mice as reference, increased 33%-69% at 52 and 76 weeks, and this increase was markedly prevented (76% and 65%) by vitamin E supplementation” measured at the two age points.

Vitamin E supplementation was “able to prevent the decrease in the activities of brain enzymes that are mitochondrial markers of aging: mtNOS (by 95%), Mn-SOD (by 60%), and NADH-cytochrome c reductase and cytochrome oxidase activity” by 35%, the paper said

“The activities of the inner membrane bound mtNOS and of the matrix enzyme MnSOD in brain and liver mitochondria also decreased upon aging, in agreement with earlier reports and with the concept of specificity rather than randomness in the inactivation of mitrondrial enzymes,” according to the paper. “The activity of mtNOS was decreased by 44%-66% and Mn-SOD by 28%-50% at 52-78 weeks of mice age, effects that were markedly prevented by vitamin E supplementation,” it added.

Clues to mitochondrial dysfunction -- and next steps

Finally, the authors noted two “interesting correlations”: The first is the inverse relationship between oxidative damage and enzymatic activities in the brain and liver, “which are due to oxidized and damaged proteins, and not to a direct inhibitory effect of lipid oxidation products (ie., malonaldehyde) due to the high dilution of the enzymes in the assays” where the reduced rates occurred. The second correlation shows “that decreased electron transfer rates and limited respiration and energy supply are the basis of the mitochondrial dysfunction in aging and that mitochondrial dysfunction is the pacemaker of the decline in neurological performances which has a determinant role in survival.”

• Further studies are needed to find the threshold for vitamin E “doses that provide beneficial effects in the neurological function in aging mammals,” the study noted.

• Boveris said the team has completed studies on the role of calorie reduction (CR), “which could yield interesting results especially in comparison with similar, but much longer, rhesus monkey studies being carried out by Richard Weindruch at the University of Wisconsin-Madison on CR and oxidative stress.”

Source and funding

The paper “Vitamin E at high doses improves survival, neurological performance and brain mitochondrial function in aging male mice” appears in the online edition of the American Journal of Physiology- Regulatory, Integrative and Comparative Physiology, published by the American Physiological Society. Research was by Ana Navarro, Carmen Gomez, Maria-Jesus Sanchez-Pino, Hipolito Gonzalez and Manuel J. Bandez of the Department of Biochemistry and Molecular Biology, School of Medicine, University of Cadiz, Spain; and Alejandro D. Boveris and Alberto Boveris of the Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.

Research was supported by grants from Ministerio de Sanidad y Consumo de España, and by Plan Andaluz de Investigación.

Editor’s note: The media may obtain a copy of Navarro et al. by contacting Donna Krupa, American Physiological Society, (301) 634-7209, cell (703) 967-2751 or dkrupa@the-aps.org.

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The American Physiological Society was founded in 1887 to foster basic and applied bioscience. The Bethesda, Maryland-based society has more than 10,000 members and publishes 14 peer-reviewed journals containing almost 4,000 articles annually.

APS  provides a wide range of research, educational and career support and programming to further the contributions of physiology to understanding the mechanisms of diseased and healthy states. In May 2004, APS received the Presidential Award for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).

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