Blood Glucose Implicated
The Diabetes Control and Complication Trial, a large prospective cohort study, has shown that higher mean blood glucose levels in non-diabetic humans correlate with a higher prevalence of diabetic retinopathy (damage to the retina), nephropathy (kidney damage) and neuropathy (damage to brain cells).
Caloric restriction in humans and experimental animals like mice, rats and monkeys ameliorates or eliminates all these aging and diabetic pathologies, perhaps just by lowering blood glucose levels. But, living with hunger probably will not be a widely practiced lifestyle. For these reasons, we will test two agents: aminoguanidine and alpha lipoic acid, which should reduce glycation damage during aging.
There are many data from animal studies showing that aminoguanidine inhibits the renal and vascular pathology found in diabetic animals. In aged rats, aminoguanidine protected against the accumulation of AGE and the decline in function of the cardiovascular system and kidney (Li, et al., 1996).
We will study the effects of aminoguanidine administered alone and in combination with alpha lipoic acid. Alpha lipoic acid also may reduce glycation damage as well as act as an antioxidant. This effect may arise from its ability to make muscle and fat tissues more sensitive to insulin, so blood glucose levels are lowered. (Stahl & Sies, 1996).
Why in combination? There are relatively few scientific studies of dietary supplementation with combinations of antioxidants, energy-enhancing agents, glycation inhibitors or hormones. Among the few such reports, there is evidence that multiple agents are able to work together to produce greater benefits than the separate agents alone. A good example is the studies discussed earlier showing that vitamins C and E are regenerated by a-lipoic acid, making them more potent. There are also recent studies showing that Vitamin-C supplementation is necessary to restore the health benefits of beta-carotene in smokers, and that mixed forms of vitamin E are more effective than alpha-tocopherol alone.
The hormonal theory of aging concerns pregnenolone. Pregnenolone has been called the "mother" steroid hormone. It is produced from cholesterol in several steps, and subsequently it then serves as a precursor for the steroid hormone DHEA (dehydroepiandrosterone), and its more abundant sulfate ester, DHEA-S. These, then, serve as a precursor for other steroid hormones, including the estrogens and testosterone.
Both men and women also suffer a precipitous drop in the levels of other steroid hormones, including DHEA and DHEA-S.
Perhaps not surprisingly, as men age they suffer a decrease in testosterone. Further, the secretion of growth hormone and the anabolic hormone insulin-like growth factor 1 (IGF-1) also decreases with age. During this same time, there is a progressive decline in protein synthesis, lean body mass, bone mass, and an increase in fat mass.
Because pregnenolone serves indirectly as the precursor to other steroids, we have chosen to study mice supplemented with pregnenolone. In doing so, we hope to maintain steroid hormones at higher levels in older animals. Since DHEA and DHEA-S increase levels of IGF-1 in both men and women, pregnenolone also may increase IGF-1.
There is increasingly good evidence that moderate supplementation of DHEA in elderly humans improves lean body mass, reduces heart disease, diabetes, memory loss, immune senescence, and other parameters negatively affected by aging. No large clinical trials have yet been completed. However, a recent DHEA study in mice did not result in lifespan extension. Perhaps pregnenalone will.
Vegetables, Fruit and Health
Two pieces of advice many of us remember receiving from our mothers are "eat all the food on your plate," and "eat your fruits and vegetables."
We know Mom was wrong about eating everything, but she was right about eating fruits and vegetables. During the past decade many scientists have begun to investigate the linkage between health and the consumption of vegetables, fruits, and of the chemical agents they contain.
By 1996, there were at least 20 prospective cohort studies showing that eating fruits and vegetables is linked to good health. In such studies, the eating habits of a large groups of healthy people (often 10,000 or more) are determined, usually by questionnaire. They are then followed for years to see which diseases they become afflicted with. Out of 20 such studies, 19 show that eating fruits and vegetables protects against cancers of various types, including colorectal, stomach, pancreatic, bladder, breast and especially lung cancer.
Many studies of another kind also show the positive effects of fruits and vegetables. In these "case-control studies," people with and without diseases are questioned about their dietary habits. The diets of the sick (case) and the well (control) are then compared.
The flaw in case-control studies is that sick people are influenced by the effect of their illnesses on their eating habits when they answer questions about their past dietary habits. Also, they may blame certain foods for their illnesses. This biases their information. Almost 200 such studies have been reported. While any one of them is not especially reliable, looking at them all can provide a reliable picture of the relationship between diet and cancer.
The vast majority of these 200 studies show that fruits and vegetables reduce the incidence of most kinds of cancer by about 50 percent. For example, there is particularly strong evidence that citrus fruit and raw green vegetables prevent stomach cancer. This is the most common cancer worldwide. One-hundred percent of the studies show that vegetables in general, but especially fruit, green vegetables and tomatoes, reduce death from lung cancer.
The effects of smoking and excessive alcohol consumption were taken into account in most of these studies. Green vegetables and citrus fruit consistently show a protective effect against cancers of the esophagus, oral cavity and pharynx. Tomatoes appear to be effective against esophageal cancer and carrots against cancer of the oral cavity and pharynx. Cruciferous vegetables (cabbage, broccoli and brussels sprouts) most consistently lower the incidence of rectal cancer. Fruit, green vegetables and carrots seem most effective against breast cancer. A reduction in bladder cancer also is associated with the consumption of green vegetables and carrots.
What is it in fruits and vegetables that causes these beneficial effects? And can we enhance beneficial effects on longevity by taking larger doses than we can get from fruits and vegetables themselves? Not surprisingly, many of the agents that appear to have beneficial health effects are antioxidants, such as are being studied in the Lifespan Project.
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