Dehydroepiandrosterone sulfate and longevity: new clues for an old friend.

D (DHEA) was isolated in urine in 1934, and DHEA 3b-sulfate (DHEAS) was identified 10 years later (1, 2). It took another decade to identify DHEA and DHEAS in peripheral blood (3, 4). More recently, fatty acid esters of DHEA, testosterone, and estradiol (5) were isolated from a variety of tissues, particularly fat (6), and their presence in circulation (5). In 1981, Corpéchot et al. (7) reported the presence of DHEAy DHEAS in the mammalian brain, but isolation of the key enzyme P450c17 required for the biosynthesis of DHEA was unsuccessful. Recently, P450c17 expression and biosynthesis of DHEA were found to interact by way of a tripartite contribution of astrocytes, oligodendrocytes, and neurons (8, 9). These neurosteroids act as an antagonist of the g-aminobutyric acid type A receptor and as a modulator of the N-methyl-D-aspartate receptor (10) and may have sleep-inducing (rapid eye movement sleep) (11), memory-enhancing, and anxiolytic properties (see review in ref. 10). The adrenals of humans and a few higher primates synthesize and secrete large amounts of DHEA and DHEAS (via sulfatransferase) that are biotransformed into biologically active androgens and estrogens in peripheral tissues. It is estimated that more than 30% of total androgen in men and over 90% of estrogen in postmenopausal women are derived from peripheral conversion of DHEAyDHEAS (12). Thus, intracellular biotransformation of DHEA to active sex steroids may bind locally to their specific intracellular nuclear receptors with minimal loss of concentration or time, an economical system to exert maximal functional activities (12). During the past five decades, a myriad of animal experiments has suggested that DHEA is a multifunctional hormone with beneficial effects, including antiaging properties. Because a backdrop of these studies was conducted in rodents with little or no detectable circulating DHEA, it may be viewed as a pharmacological model with a naı̈ve environment that is devoid of endogenous DHEA. The secretion of DHEA by the human adrenal gland exhibits a pulsatile pattern with increasing frequency and amplitude at night. This pattern of DHEA synthesis and secretion by the zona reticularis is, in large measure, mediated by corticotropin (ACTH) but without the feedback regulatory function. With aging, the progressive blunting of ACTH mediates pulsatile activities, particularly the nocturnal amplification of DHEA (13), without affecting the pulsatile rhythm of cortisol (14). Although the decline of DHEAS levels persists into advanced age with a sexually dimorphic pattern, in contrast, cortisol levels in men and women show a parallel linear increase with aging (15). The age-related decline in DHEAS shows marked individual differences with a wide range of values and is under partial hereditary control. It has been suggested that DHEAS may be a measurable component of the individuality of the aging