Do glucocorticoids contribute to brain aging?

The hippocampus, an area with abundant glucocorticoid receptors, continues to be the focus of research on effects of glucocorticoids on the aging brain. Based on recent studies, the primary structural change found during aging is synaptic loss, rather than neuronal loss. High levels of glucocorticoids are associated with synaptic loss in the hippocampus, hippocampal atrophy, and cognitive decline during aging in some individuals. However, increasing levels of glucocorticoid are not always found since early experiences can alter sensitivity to negative feedback and the level of activation of the hypothalamic-pituitary-adrenal axis in aged individuals. New ways in which glucocorticoids may contribute to brain aging are discussed, including decreased responses to glucocorticoids possibly as a result of decreased glucocorticoid receptors and also altered regulation of neuronal turnover in the dentate gyrus. Decreased responsiveness of glial fibrillary acidic protein to glucocorticoids during aging could facilitate reactive gliosis and loss of synapses by altering neuron-astrocyte interactions. Neuronal turnover is regulated by glucocorticoids in the dentate gyrus where ongoing neurogenesis may be important for hippocampal-based memory formation in adulthood. Although the age-related decline in neurogenesis can be reversed by removal of adrenal steroids, the death of dentate granule neurons is also greatly increased by this treatment. Recent studies show age-related resistance to induced apoptosis and neurogenesis in the dentate gyrus following adrenalectomy, which is associated with increased expression of transforming growth factor-beta1. Therefore, the contribution of glucocorticoids to brain aging depends on the physiological and cellular context and some of these effects are reversible.