Scientists have found that the compound resveratrol
-- found in red wine and grape skin -- slows age-related
deterioration and functional decline of mice on a standard
diet, but does not increase longevity
when started at middle age.
This study, conducted and supported in part by the
National Institute on Aging (NIA), part of the National
Institutes of Health, is a follow-up to 2006 findings
that resveratrol improves health and longevity of overweight,
aged mice. The report confirms previous results suggesting
the compound, found naturally in foods like grapes and
nuts, may mimic, in mice, some of the effects of dietary
or calorie restriction, the most effective and reproducible
way found to date to alleviate age-associated disease
in mammals.
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.
In addition to cardiovascular function, the scientists
found resveratrol to have a variety of positive effects
on other age-related problems in mice:
- 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.
