Effects of dehydroepiandrosterone supplementation in aged humans and C57BL/6 mice

Abstract

DHEA (dehydroepiandrosterone) is a major adrenal hormone, with known accepted function. In both animals and humans low DHEA and DHEA-sulfate levels are associated with a number of problems in the aging: immunosenescence, increased mortality, increased incidence of several cancers, loss of sleep, decreased feelings of well-being, osteoporosis, atherosclerosis and premature death. DHEA hormone replacement in aged mice significantly normalized immunosenescence suggesting that this hormone plays a key role in aging and stimulating immune regulation in mice. Similarly osteoclasts and lymphoid cells, were stimulated by DHEA replacement which should delay osteoporosis. Recent studies do not support the original suggestion that low serum DHEA levels were associated with Alzheimer's and other losses of mental function in aged people. As DHEA modulates energy metabolism low levels should affect lipogenesis and gluconeogenesis, increasing the risk of diabetes and heart disease. Most of the actions of DHEA restoration are hypothesized from epidemiological or animal model studies and need to be tested in human trials. Those conducted in humans show essentially no toxicity of DHEA treatment at levels restoring serum DHEAS levels without evidence of altering some aging physiological systems. Thus DHEA is a steroid whose deficiency could facilitate development of some diseases common to the aged. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) are steroids, synthesized from cholesterol (Fig. 1.1). While DHEA is secreted primarily by the adrenal gland in larger quantities than any other adrenal steroid including cortisol, the precise functions of DHEA and DHEAS in humans are not known (1-5). The decline of DHEAS levels during aging is parallel to development of immunosensecence, an inability to conserve protein, a physical frailty, decreased muscle mass, an increased fat mass, decreased ability to cope, disrupted sleep patterns and increased incidence of disease. Thus DHEAS serves as a marker of aging in humans. While the precise biological functions of DHEA and DHEAS are not known, both animal and human studies suggest some hypotheses while dispelling others. Therefore key physiological dysfunctions are investigated here to determine biological relationships which participate in the declining blood levels of DHEA with age.