Lifespan Project Launched
by Richard Weindruch and Stephen R. Spindler
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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.
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 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.
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