| Resveratrol
Mimics Caloric Restriction to Turn on “Longevity Genes”
by Jim English
Caloric restriction has been shown to be one of
the most effective means of slowing the pace of aging and extending
lifespan. Studies show that severely reducing the food intake of
laboratory mice can increase their lifespan to the human equivalent
of 162 years. Other experiments demonstrate similar gains in maximum
lifespan with fruit flies and worms. Yet despite the potential increase
in lifespan observed with caloric restriction, few humans would
willingly choose to live in a constant state of semi-starvation
for even a few days, let alone 162 years.
Researchers from Harvard Medical School just announced
that resveratrol, a polyphenolic compound found in red wine, duplicates
the life-extending benefits of caloric restriction in a yeast model.
In a paper published in the August 24 online edition of the journal,
Nature , they report that resveratrol was shown to extend the lifespan
of yeast by up to 80 percent.
Researchers have known for decades that reducing daily intake of
calories by up to 40 percent dramatically slows down the aging process
and extends lifespan of lab animals. Caloric restriction also has
been shown to protect mammals from cancer and other age-related
diseases. Recently scientists identified a class of regulatory “longevity
genes” that are shared by almost all living organisms. These
genes function as a feedback system to enhance survival during times
of stress, such as during drought or famine. The process begins
when external signals indicate a deterioration of environmental
conditions. Once triggered by environmental cues, the longevity
genes “switch on” and induce defensive changes at the
cellular level, such as slowing metabolism and enhancing cellular
respiration to help the body adapt to a more beneficial survival
program.
In their study, the Harvard researchers focused
on a family of enzymes, called sirtuins, produced by almost all
life forms—from single celled organisms, to plants and mammals—during
times of stress, such as famine (or caloric restriction). Sirtuins
(silent information regulator proteins) are known to act as guardian
enzymes that protect cells and enhance cellular survival. The human
sirtuin, SIRT-1, for example, has been shown to suppress the p53
enzyme system normally involved in suppressing tumor growth and
instigating cell death (apoptosis). By suppressing p53 activity
SIRT-1 prevents the cycle of premature aging and apoptosis normally
induced when cellular DNA is damaged or stressed, thus giving cells
enough time to repair any damage and prevent unnecessary cell death.
A second sirtuin found in yeast, SIR2, has also been shown to become
activated when placed under stress. SIR2 has been shown to increase
DNA stability and speed cellular repairs, while increasing total
cell lifespan.
“We think sirtuins buy cells time to repair
damage,” said molecular biologist David Sinclair, assistant
professor of pathology at Harvard Medical School and co-author of
the new study. “There is a growing realization from the aging
field that blocking cell death—as long as it doesn’t
lead to cancer—extends lifespan.”
Intrigued by the positive health benefits
of caloric restriction, the Harvard research team began to search
for other methods of modulating sirtuin activity without resorting
to starvation. After an initial screening process, the researchers
discovered that several plant metabolites acted as sirtuin-activating
compounds (STACs). Plants produce a variety of polyphenols, such as
resveratrol, flavones, stilbenes, isoflavones, catechins and tannins
in response to environmental stresses, such as drought, nutrient depleted
soils, ultraviolet radiation and pathogens. As they refined their
screening process the researchers discovered that the most potent
activator of sirtuins was resveratrol.
To test the ability of resveratrol to activate sirtuins in
living creatures the Harvard researchers selected yeast, a single-celled
organism that is closely related to animals, including humans. The
research team hypothesized that if resveratrol was effective in
modifying the newly identified target genes to trigger sirtuin production
it would closely reflect the protein’s role in animals to
formally link the protein to lifespan extension, at least for yeast.
Their study found that even small doses of resveratrol helped yeast
cells live as much as 60 to 80 percent longer, as measured by the
number of generations (Fig. 1). Yeast treated with resveratrol lived
for an average of 38 generations, as compared to only 19 generations
for untreated yeast.
Additional experiments with human cells found
that resveratrol activated a similar pathway requiring SIRT1 that
enabled 30 percent of the treated human cells to survive gamma radiation
compared to 10 percent of untreated cells. In the paper, the researchers
also report that preliminary experiments with flies and worms are
encouraging, and mouse studies are in the works.
The fact that human sirtuin SIRT1
turns off the tumor suppressor gene p53 has raised some concern
that activating the sirtuin pathway to switch on the cellular longevity
program might actually promote cancer. In addressing this issue,
Sinclair noted that calorie-restricted animals in experiments by
others have lower, not higher rates of cancer. Additional studies
also found that resveratrol is able to block all three mechanisms
of cancer formation by helping the body inhibit tumor initiation,
promotion and progression. Resveratrol has also been shown in numerous
clinical trials to benefit heart disease by reducing platelet aggregation
and increasing HDL-cholesterol. Resveratrol, in combination with
other bioflavonoids and vitamins C and E, may have a synergistic
effect by reducing pathological platelet aggregation, stimulating
healthy blood flow via the dilation of arteries, and minimizing
free radical damage to blood vessel linings.
Research indicates that plant polyphenols,
which increase in plants in response to stressful conditions, (similar
to conditions found in humans while dieting), help to cue organisms
to prepare for impending harsh conditions by switching to a more
beneficial survival program. The plant polyphenol, resveratrol,
has been shown to act in just such a manner to activate sirtuins
to mimic the benefits of caloric restriction to slow aging and extend
lifespan—in the case of yeast, up to 80 percent beyond untreated
samples. Furthermore, resveratrol has been shown to activate sirtuins,
which are also active in human cells, suggesting a potential for
lengthening life and preventing or treating aging-related diseases
in humans.
Resveratrol, found in the skins of young
unripe red grapes, occurs naturally in two related forms, or isomers,
referred to as trans -resveratrol and cis -transrevatrol. Of the two,
the trans form (3,5,4'-trihydroxy-trans-stilbene), is the one that
has been shown in numerous studies to be the most bioactive and clinically
beneficial form of resveratrol. Recommend doses range from 5 mg of
trans-resveratrol daily for preventive purposes up to 20 mg, twice
daily, for therapeutic purposes.
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