Dehydroepiandrosterone and ageing

Abstract

Dehydroepiandrosterone (DHEA) is the crucial precursor of human sex steroid synthesis and thus mediates the majority of its effects indirectly, following downstream conversion to sex steroids and other steroids of potentially distinct activity. No specific receptor for DHEA or its sulfate ester DHEAS has been identified yet. However, there is evidence of specific binding sites for DHEA on immune and vascular cells and for direct interaction with cell signaling cascades, which may facilitate direct effects of DHEA. DHEA is mainly secreted by the adrenal zona reticularis and, together with cortisol and aldosterone, represents one of three major steroids produced by the adrenal glands. However, in contrast to cortisol and aldosterone, circulating concentrations of DHEA and its sulfate ester DHEAS show a physiological decline with ageing. Seminal studies in patients with adrenal insufficiency, who suffer from pronounced DHEA deficiency, have illustrated the physiological significance of DHEA (1–4) (Chaper 5.9) and its role as an efficient vehicle for female androgen replacement. Importantly, studies in systemic lupus erythematosus have started to define a role for DHEA as an immune modulatory drug. By contrast, the few randomized controlled trials on DHEA supplementation in healthy elderly adults have yielded largely disappointing results. However, irrespective of the very scarce evidence, DHEA is perceived by the lay public as a ‘fountain of youth’ hormone, based merely on the observation of declining serum levels with ongoing ageing. This has led to widespread, uncontrolled use, further facilitated by its inappropriate classification as a ‘food supplement’ by the US Food and Drug Administration. Two issues are important to consider when assessing the scientific literature on the potential clinical effects of DHEA. Firstly, the capability of the adrenal gland to produce DHEA is only observed in some but not all mammals, and thus represents a recent evolutionary development. Most importantly, the adrenal glands of rodents do not express CYP17 and therefore cannot synthesize DHEA. Therefore, the potential for transferring results of rodent experiments to the human situation is limited. To date, many reports on DHEA effects, in particular with regard to protection against cancer, heart disease, diabetes, and obesity (5) are based on the administration of grossly supraphysiologic DHEA doses in rodent models. The second problem in the scientific DHEA literature is the multitude of studies based on associations rather than mechanistic insights, which often results in oversimplification of perceived causalities. This is exemplified by the multitude of studies demonstrating various effects of DHEA on longevity, which then is used by many to claim a general antiageing effect. In this chapter, a closer look at the available current evidence with regard to the role of DHEA in ageing humans is provided.