Chapter 26 Re-examination of the glucocorticoid hypothesis of stress and aging

Abstract

The glucocorticoid cascade hypothesis of stress and aging is an attempt to formulate a causal relationship between the activity of the hypothalamicpituitary-adrenal axis (HPA axis) and the deleterious consequences of the actions of glucocorticoids upon the viability of cells in the brain as well as their structure and function. This chapter discusses the hypothesis in the light of old and new evidence on the aging of the HPA axis and the role of glucocorticoids in the generation of neural damage. The hypothesis is based on two lines of evidence: (1) that glucocorticoids cause hippocampal damage and (2) that hippocampal damage results in pituitary–adrenal hypersecretion. The chapter also presents some features of the results, such as a rat ages; there is a general decline in the plasticity of the brain to respond to environmental challenges, and with increasing age, there is increased vulnerability to stress-induced loss of hippocampal neurons. The glucocorticoid cascade hypothesis of stress and aging has served well as a stimulus and guide for research on endocrine factors in the aging of the brain; however, much more needs to be learned to uncover basic cellular mechanisms and to account for the sometimes disturbing variability among studies and among individual animals in their susceptibility to negative effects of stress and in degenerative changes in the brain.