Dehydroepiandrosterone, Cortisol, and Aging

ABSTRACT

Excess glucocorticoid exposure, which very likely causes the precipitous post-reproductive mortality of semelparous dasyurid marsupials through immunosuppression and infection, may also, in a more gradual way, contribute to aging in mammals. Excess glucocorticoid exposure, in addition to causing immunosuppression, has been linked to various age-related pathophysiologies, such as the metabolic syndrome and hippocampal atrophy, whereas dehydroepiandrosterone (DHEA), which acts as an anti-glucocorticoid, produces beneficial effects in models of the metabolic syndrome and hippocampal atrophy.

In addition to its anti-glucocorticoid action, DHEA is a potent inhibitor of mammalian glucose 6-phosphate dehydrogenase (G6PDH) and as a consequence inhibits NADPH-dependent reactive oxygen formation and oxidative stress, which is also believed to play an important role in the development of many age-related pathologic changes. Epidemiologic studies in G6PDH-deficient Sardinian males are consistent with the hypothesis that inhibition of G6PDH may beneficially affect aging.

Although DHEA is therapeutically effective in animal models of obesity, diabetes, atherosclerosis, and cancer prevention, early clinical trials in humans have produced disappointing results. Dosages used in clinical trials, which have failed to demonstrate efficacy, are more than a magnitude lower than equivalent dosages which produce efficacy in animals. These high oral dosages produce substantial androgenicity and are contraindicated in clinical studies. Less androgenic analogs of DHEA should provide an alternative to the native hormone for determination of safety and efficacy in humans.

Keywords:

Dehydroepiandrosterone, cortisol, glucose 6-phosphate dehydrogenase, NADPH oxidase, oxidative stress, inflammation, centenarians.