by Richard Weindruch and Stephen R. Spindler
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 will be tested with
pregnenolone. Pregnenolone has been called the "mother"
steroid hormone. It is produced from cholesterol in several
steps, and subsequently 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 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.
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