Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity

Dehydroepiandrosterone (DHEA) is an abundantly produced adrenal steroid whose biological role has never been clarified. DHEA is a potent uncompetitive inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH) and as a consequence lowers NADPH levels and reduces NADPH-dependent oxygen-free radical production. Overproduction of oxygen-free radicals, or oxidative stress, upregulates inflammation and cellular proliferation and is believed to play a critical role in the development of cancer, atherosclerosis, and Alzheimer's disease, as well as the basic aging process. Both in vitro and in vivo experimental studies strongly indicate that DHEA and related steroids inhibit inflammation and associated epithelial hyperplasia, carcinogenesis, and atherosclerosis, at least in part, through the inhibition of G6PDH and oxygen-free radical formation. Recent epidemiological findings in Sardinian males bearing the Mediterranean variant of G6PDH deficiency are consistent with the hypothesis that reduced G6PDH activity has a beneficial effect on age-related disease development and longevity. Clinical trials with DHEA are encumbered by the high oral doses required as well as the conversion of DHEA into active androgens. The use of less androgenic congeners as well as non-oral formulations may facilitate testing of this class of compounds.