The role of glucocorticoids in brain aging and Alzheimer's disease: An integrative physiological hypothesis

The glucocorticoid hypothesis of brain aging, which proposes that exposure of brain cells to glucocorticoids can increase brain cell loss during aging, is a physiological aging hypothesis that emphasizes interactions among systems. Thus, it fits well with the concepts advanced by Nathan Shock. The historical background of the hypothesis, the hypothesis and supporting data, and several modificatios are briefly reviewed here, as are recent mechanistic studies linking hippocampal glucocorticoid receptor activation to increased voltage-activated calcium influx. These new data suggest that some aspects of the impact of glucocorticoids on brain cells may increase rather than decrease with aging, and that some of the etiology of aging-related neurotoxicity may depend on gradually accumulating endocrine dysregulation of neuronal calcium homeostasis.