Study Demonstrates Improved Health, Survival
In Aged Overweight Male Mice on Resveratrol
Overweight aged male mice whose high calorie (fat) diet was supplemented
by resveratrol, a natural compound found in common foods like grapes,
wines and nuts, had better health and survival than aged overweight
mice who did not receive it, according to a study published online
in the Nov. 1 issue of Nature. The study was conducted
and supported in part by the National Institute on Aging (NIA)
of the National Institutes of Health (NIH).
The findings are the first to demonstrate that resveratrol, an
activator of a family of enzymes called sirtuins, could affect
the health and survival of mammals. The findings build upon previous
research on resveratrol, a small molecule produced by certain plants
in response to stress. Studies over the last few years have found
that resveratrol can extend lifespan in yeast, worms, flies and
fish.
The study was a collaborative effort between the laboratories
of Rafael de Cabo, Ph.D., at the NIA, David A. Sinclair, Ph.D.,
at Harvard Medical School and an international group of researchers. “There
is currently intense interest in identifying interventions that
can be applied to improve health and survival, especially as our
society ages. Today’s basic science findings are a notable step
in this effort,” notes Richard J. Hodes, M.D., director of the
NIA. “At the same time, it should be cautioned that this is a study
of male mice, and we still have much to learn about resveratrol’s
safety and effectiveness in humans.”
The report describes the result of studies of year-old (middle-aged)
mice placed on three different diets for six months: a standard
mouse diet, a high calorie (fat) diet and a high calorie (fat)
diet supplemented with resveratrol. After six months, the scientists
observed a clear trend toward increased survival and insulin sensitivity
(important for the body’s efficient processing of glucose into
energy) in the high calorie diet supplemented with resveratrol
relative to that seen on the high fat diet without resveratrol
supplementation. In the study, resveratrol shifted the physiology
of middle-aged mice on a high calorie diet towards that of mice
on a standard diet and increased their survival.
The scientists reported that:
- At 60 weeks of age, the survival curves of the high calorie
and the high calorie/resveratrol groups began to diverge, when
the resveratrol group began to show a 3-4 month advantage in
survival. As the mice aged, the trend continued.
- At 114 weeks, when the mice reached old age, more than half
of the high calorie mice died compared to less than a third of
the high calorie mice receiving resveratrol. The overweight resveratrol-treated
aged mice were healthier than the overweight mice that were not
given resveratrol on a number of measures. For example, the untreated
high calorie mice had increased plasma levels of insulin, glucose
and insulin-like growth factor (IGF) 1 — markers that in
humans predict the onset of diabetes — when compared with
their overweight counterparts who did receive resveratrol.
- Some of the health-related findings were most evident in the
liver of the high calorie mice. At 18 months of age (six months
into the study), the livers of the high calorie, untreated mice
were twice the size and weight of those of the high calorie/resveratrol
animals, whose livers were comparable to the mice on standard
diets. The livers of the high calorie, resveratrol-treated mice
were more normal on a cellular level as well. They had considerably
more mitochondria (cell structures that metabolize glucose and
other sugars) than those of the untreated high calorie group
and resembled the levels of mice on the standard diet.
- Gene expression analysis in livers of these aged and overweight
mice indicated that resveratrol modified some of the known metabolic
pathways that are also affected by caloric restriction. Pathways
are a series of chemical reactions that take place in living
tissue
- A test of motor function determined the effect of resveratrol
on physical performance with age. Tests on a rotating device
to measure balance and motor coordination showed that the resveratrol-fed
overweight mice maintained their performance on one laboratory
measure of motor skills.
“After six months, resveratrol essentially prevented most of the
negative effects of the high calorie diet,” de Cabo concludes. “There
is a lot of work ahead that will help us better understand resveratrol’s
roles and the best applications for it.”
De Cabo and Sinclair did not observe toxic effects of resveratrol
on the mice at the doses studied. However, de Cabo emphasized,
the safety and effectiveness of the substance for humans to address
aging and age- or obesity-related conditions is far from demonstrated.
Some contraindications are already known, including evidence from
earlier animal studies that have shown high doses of resveratrol
to affect blood platelets, which could increase the risk of bleeding
when taken with anticoagulant, anti-platelet or nonsteroidal anti-inflammatory
drugs.
In addition to scientists from the NIA and Harvard Medical School,
researchers from the following institutions collaborated in this
study: Pennington Biomedical Research Center in Baton Rouge, La.,
Harvard Medical School in Boston, Mass., the University of Sydney
in Australia, Johns Hopkins University in Baltimore, Md., Universidad
Pablo de Olavide in Sevilla, Spain, the Salk Institute in La Jolla,
Calif., and Sirtris Pharmaceuticals of Cambridge, Mass., which
is developing therapeutics to modulate sirtuins. Sirtris Pharmaceuticals
was founded by Harvard University co-lead author David A. Sinclair.
De Cabo is a scientist in the NIA’s Intramural Research Program.
In addition, the work 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 and the National Institute of Diabetes
and Digestive and Kidney Diseases at the NIH. The Ellison Medical
Research Foundation, the American Heart Foundation, the Australian
and Spanish governments, the American Diabetes Association 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 NIA leads the federal effort supporting and conducting
research on aging and the medical, social and behavioral issues
of older people. For more information on research and aging,
go to www.nia.nih.gov. Publications
on research and on a variety of topics of interest on health
and aging can be viewed and ordered by visiting the NIA Web site,
or can be ordered by calling toll-free 1-800-222-2225.
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