Anti-aging effects of the adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone sulfate: mechanisms of action and beneficial effects in older people.

We review the recent remarkable progress of the molecular mechanisms of action of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) regarding their beneficial effects on older people and adrenal regenerative therapy by looking back on our research extending over 50 years since 1971. DHEAS is the most abundant circulating steroid hormone in humans and apes. DHEAS is essential for brain development in adrenarche and for anti-aging in adrenopause as shown by the evolutionary process in primates. The molecular mechanisms of action of DHEA and DHEAS have been clarified by the discovery of many membrane receptors and by the concept of intracrinological action, which is especially important in menopausal women. The genes associated with serum DHEAS concentrations were identified by genome-wide association study meta-analysis of cohort studies. Recent advances in aging research have shown that DHEA and DHEAS have anti-aging action via antioxidants, anti-inflammation, telomere protection, p38MAPK inhibition, anti-cortisol effects, and chaperone induction. DHEA has beneficial effects on the prevention of atherosclerosis based on visceral obesity-induced metabolic syndrome in middle-aged people. DHEA also prevents infection, frailty via reverse metabolism, sarcopenia, and osteoporosis in older people, with a marked decrease in serum DHEAS concentrations. This review discusses adrenal regenerative therapy using steroid-producing cell replacement by overexpressing Ad4BP/steroidogenic factor 1 in mouse or human bone marrow mesenchymal stem cells. This therapy replaces cortisol and DHEAS treatment for the prevention of sudden death by adrenal crisis and severe infection in primary adrenal insufficiency (Addison's disease).