Book Review

Stress, the Aging Brain, and the Mechanisms of Neuron Death

N Engl J Med 1993; 329:1049September 30, 1993

Article

Stress, the Aging Brain, and the Mechanisms of Neuron Death
By Robert M. Sapolsky. 429 pp., illustrated. Cambridge, Mass., MIT Press, 1992. $55. ISBN: 0-262-19320-5

In this book Dr. Sapolsky, an associate professor of biology at Stanford University and of neuroscience at Stanford University School of Medicine, details his thesis, based on work in rats, that glucocorticoids such as hydrocortisone (cortisol) and dexamethasone damage hippocampal neurons by increasing their sensitivity to ischemic insult or to excitatory neurotoxins, such as kainic acid, that act by stimulating excessive calcium uptake by the neurons. Since the hippocampus normally serves as a target for glucocorticoids and determines the “set-point” of feedback control of the hypothalamic-pituitary-adrenal axis, the deleterious effects of glucocorticoids on the hippocampus could account for accelerating damage to the brain.

To present this hypothesis in its proper context, Sapolsky describes the anatomical and physiologic basis of hypothalamic-pituitary function, the mechanism of glucocorticoid action at the cellular level, the nature and regulation of glucocorticoid receptors, the mechanisms of excitotoxin action, the effect of aging, and the effects of acute and chronic stress on adrenal function. This wide-ranging discussion is bolstered by an exceptionally complete and comprehensive bibliography. To a degree, Sapolsky is a modern-day counterpart of Hans Selye, whose general adaptation syndrome provided a persuasive model of the diseases of stress for two decades.

Most of the work cited was carried out in rodents and nonhuman primates; many crucial studies were performed with the author's collaborators, including Bruce McEwen, with whom he carried out the initial work. Of course, to most readers, the important question is whether this phenomenon applies to humans as well as rats. Here, Sapolsky gives a qualified yes. Yes, stress, depression, extremely advanced age, and advanced Alzheimer's disease raise the threshold for cortisol feedback inhibition of the secretion of corticotropin. Yes, people who have survived torture and terror show evidence of brain damage. But proof that this phenomenon occurs through changes in hippocampal steroid receptors or sensitization by glucocorticoids is not available, and Sapolsky tells us why it will be difficult to obtain.

This book is not written like most modern biomedical monographs. To a degree, it is didactic and polemic. Sapolsky outlines his theories, justifies them in detail, and considers, uses, and criticizes the work of others in the field, sometimes exhaustively. Each chapter is summarized and its essence repeated before the next topic is presented. At times the author is conversational, breezy, idiomatic, personal, and ingenuous, addressing his words to a (presumed) intelligent but uninformed audience. At other times, he addresses the neuroendocrine aficionado. Consequently, it is not easy to identify the readers who will get the most from the book. Scholarly students of psychobiology, stress, and models of stress will find new information or new viewpoints about well-recognized phenomena. They will also find criteria by which to judge the human consequences of disordered pituitary-adrenal function.

Seymour Reichlin, M.D., Ph.D.
Tufts University School of Medicine, Boston, MA 02111

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