Lifespan
Project Launched
by Richard Weindruch and Stephen R. Spindler
Page 2 of 4
Two Major
Questions
Two major question now face investigators of caloric
restriction. First, how does caloric restriction retard aging
in rodents? This is a very challenging question because the
most important mechanisms driving biological aging remain
unidentified. The second question concerns the relevance of
the rodent data to humans. This question is being addressed by
studies in monkeys and humans.
There are at least two reasons why the results of caloric
restriction studies are of major importance to The Lifespan
Project: First, the need to strictly control the caloric
intake of the mice used in the study; and secondly, the use of
caloric restricted mice as "positive controls." Since we know
that restricted mice age at a slower rate than normally-fed
mice, they can be used to compare the effectiveness of other
dietary changes.
Loss of body weight or slow growth can occur with
antioxidant feeding (for review, see Schneider & Reed,
1985) and after adding other potential anti-aging substances
to the diet - L-dopa, for example (Cotzias et al., 1977;
Papavasaliou et al., 1981); centrophenoxine (Hochschild,
1973); dehydroepiandrosterone (DHEA) (Nyce et al., 1984;
Weindruch et al., 1984). Thus, any positive findings in
animals that weigh less than controls cannot be attributed
with certainty to a particular agent because inadvertent
caloric restriction may have occurred. For The Lifespan
Project, where rodents are fed substances having the potential
to retard aging, it is crucial to make sure that all mice
consume the same number of calories. We will achieve this goal
by individually housing the mice and feeding them about
15-percent fewer calories than the average unrestricted
intake. This will provide the added advantage of minimizing
obesity in the mice.
The Lifespan Project includes a group of caloric-restricted
mice to be raised at Madison. These mice will allow us to
compare the agents tested (see the following story) to an
intervention known to slow the rate of aging.
Seeking Out Magic Bullets in The Fight Against Aging A
wide-ranging number of nutritional agents currently are being
taken by life extensionists in the hopes of retarding the
aging process. The Lifespan Project will examine a number to
determine their exact effects.
The agents to be tested in The Lifespan Project were chosen
because there is good scientific reason to think they will
block the formation or actions of free radicals and glycation
end products, or reverse age-related changes in hormone action
and energy production.
Free radicals are produced in our bodies as a necessary
by-product of life processes. A main site of free-radical
production is in cell structures known as mitochondria, which
serve as the cells' power plants by taking the energy derived
from the breakdown of the food we eat and converting it into
energy that the cell can use to do its work . . . make new
proteins, pump ions, repair damage and so forth.
The production of excessive free radicals causes the
slow-but-steady accrual of damage to proteins, membranes and
genetic material (Weindruch, 1996; Sohal & Weindruch,
1996). The accumulation of damaged proteins contributes to
cataracts, muscle deterioration and memory loss. Our bodies
can repair much of this damage. We have powerful enzymatic
mechanisms to detoxify them. We also have small molecules
called antioxidants which "trap" free radicals by combining
with them to form non-toxic by- products, which can then be
eliminated safely from our bodies. Many antioxidants come from
the diet.
Unfortunately our ability to repair free-radical damage
decreases with age, and we make more free radicals as we age.
Thus, the damage accumulates. For this reason, the consumption
of antioxidants in the diet becomes increasingly important as
we grow older.
Lycopene
There has been a great deal in the press lately about the
possible anti-cancer effects of beta-carotene. But you may not
have heard much about lycopene. An excellent review of the
biochemistry and physiology of lycopene and its consumption by
humans has been published recently (Stahl & Sies, 1996).
Both lycopene and beta-carotene are members of a family of
plant pigments called carotenoids. There are more than 600
different carotenoids, but lycopene and the carotenes are the
most prominent.
Carotenoids are an important part of the photosynthetic
complex of plants. The bright colors in leaves are covered by
green chlorophyll. In the fall, during "Indian summer," the
chlorophyll is degraded and the carotenoids can be seen for a
time in the reds and oranges of fall leaves. They also are the
pigments that give some fruits and vegetables, like tomatoes,
their bright colors. In fact, tomato and tomato products are a
major source of lycopene in our diet. We also get some
lycopene from watermelon, guava, rose hips and pink
grapefruit. Boiling tomato juice with a little corn oil
greatly increases absorption of lycopene into our bodies
(Stahl & Sies, 1992).
Lycopene levels are higher than beta-carotene levels in
people in the United States. And lycopene is a better
antioxidant than beta-carotene. Of all the plant carotenoids,
lycopene is one of the most efficient quenchers of a
particularly dangerous activated oxygen molecule called
singlet oxygen. Equally important, lycopene is regenerated
after quenching singlet oxygen, and can then detoxify toxic
molecules without being destroyed itself. Unfortunately,
lycopene levels in our bodies decline with age, even if we
continue to eat fruits and vegetables.
The first demonstration of the biological properties of
lycopene was in the late 1950s when it was shown to increase
the survival of irradiated mice and to increase the resistance
of mice to bacterial infections. It also decreases the
incidence of spontaneous and chemically induced cancers in
mice.
In an Italian case-control study, high consumption of
tomatoes was associated with protection from digestive-tract
cancers. A prospective study of micronutrient serum levels and
bladder cancer suggested that lycopene may protect against
this cancer. A case-control study of pancreatic cancer found a
protective effect for both lycopene and selenium. Lycopene
intake is associated with reduced risk of cervical and
prostate cancer. Age-related macular degeneration also is
associated with low serum levels of lycopene.
Vitamin E
Vitamin E protects our membranes from oxidation damage. In
fact, vitamin E is the major membrane antioxidant. It
addition, it can break the self-perpetuating chain of
oxidative reactions initiated by damage to unsaturated fatty
acids in our membranes. Vitamin E also keeps selenium reduced
chemically, which is important for selenium's antioxidant
activity. It may also decrease cancer-causing nitrosamine
formation in the stomach.
High blood levels of vitamin E in the diet, or from
supplementation are associated with health and longevity
(Diplock, 1994; Diplock, 1996). The populations of entire
European countries with higher-than-average blood levels of
vitamin E have lower mortality from coronary heart disease
than populations with low vitamin E levels. This correlation
is even stronger when corrected for the effects of blood
cholesterol and smoking.
A prospective investigation of 39,910 male health
professionals found that men with intakes of vitamin E of at
least 100 to 400 IU per day were protected from coronary heart
disease. No greater protection was found at higher dosages
(Rimm et al., 1993). The Nurses' Health Study, which began in
1976, examined the dietary habits of more than 87,000 women
(Stampfer et al., 1993). Women with a high dietary intake of
Vitamin E (above 100 IU per day) showed a significant
reduction in the risk of heart disease.
A study in Linxian County, China, suggests that vitamin E
also may help prevent cancer. The people in and around Linxian
have low intake of micronutrients, and one of the highest
rates of esophageal and stomach cancer in the world.
Supplementation with vitamins and minerals (one to two times
the recommended daily allowance, or RDA) in 30,000 adults from
1985 to 1991 showed a significantly lower death rate,
especially from cancer, in subjects receiving beta carotene,
vitamin E and selenium. (Blot et al., 1993). Other
case-control studies show some evidence that low serum
concentrations of vitamin E and beta-carotene are risk factors
for senile cataracts.
Finally, the results of placebo-controlled clinical trials
conducted in elderly men and women indicate that vitamin E
raises levels of vitamin E in the blood and increases immune
system responsiveness. These data suggest that a part of the
decline in immune function with age may be related to
oxidative damage, which can be prevented by vitamin E
supplementation.
Alpha Lipoic
Acid
Both humans and animals synthesize alpha lipoic acid, but
we do so in only very small amounts. Most of our alpha lipoic
acid is bound to an enzyme complex which functions in energy
production inside our cells.
When the diet is supplemented with alpha lipoic acid, the
serum and membrane levels of the antioxidant rise slowly, with
relatively low toxicity. Alpha lipoic acid acts both in
membranes and in the water-containing parts of the cell. It is
fat-soluble like vitamin E, but is converted into a
water-soluble form called dihydrolipoic acid. Both the
membrane and water-soluble forms of the antioxidant accumulate
in the body to work together as a very potent antioxidant
(Stahl & Sies, 1996).
Alpha lipoic acid is especially effective in recycling
other antioxidants, such as vitamin E, back to their original
form after they detoxify free radicals. In the late 1950s
alpha lipoic acid was found to prevent scurvy in vitamin
C-deficient guinea pigs, and to prevent the symptoms of
vitamin E deficiency in rats. This showed that small amounts
of vitamin C and E had been preserved and regenerated in the
deficient animals. There is normally only about one molecule
of vitamin E per 1,000 to 2,000 phospholipid molecules in our
membranes. But this small amount goes a long way because it is
constantly regenerated by other antioxidants.
After vitamin E detoxifies a free radical, it becomes a
free radical itself, but is quickly returned to its
antioxidant form by interaction with other antioxidants like
alpha lipoic acid. Alpha lipoic acid also increases the
intracellular concentration of glutathione to maintain the
proper level of oxidation-reduction potential for proteins
inside cells.
Alpha lipoic acid detoxifies and chelates, or combines
chemically with, transition-state metal ions like cadmium,
copper, zinc, and possibly iron. Each of these metal ions can
generate toxic oxygen radicals if they are freely present in
cells or blood.
Alpha lipoic acid may be beneficial for diabetes (Stahl
& Sies, 1996), which many gerontologists regard as a form
of accelerated aging. Much of the damage in diabetes results
from free-radical generation during a process known as
glycation, which involves the binding of glucose with protein
molecules. Alpha lipoic acid reduces glycation damage caused
by blood glucose. It seems to make muscle and fat tissues more
sensitive to insulin, which enables them to take more glucose
from the blood, thus lowering blood glucose levels. Once
inside cells, glucose is converted into compounds that produce
little glycation damage. Because glycation leads to
atherosclerosis, kidney disease and loss of vision, alpha
lipoic acid may ameliorate these conditions.
Alpha lipoic acid seems to reduce the kind of damage that
occurs during heart attack and stroke, although these results
have been found only in animal models thus far. There also are
a few reports that alpha lipoic acid may improve memory in
experimental animals.
Continued on Page 3 of 4
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