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Public release date: 2-Sep-2005
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Contact: Mayer Resnick
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American Physiological Society
High doses of vitamin E boost rat survival rate 40%; brain function,
neuromuscular gains
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 Mayer
Resnick, American Physiological Society, 301.634.7209, cell 301.332.4402 or
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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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