Animal studies

An approach to this problem might be to study the regulation of the HPA axis in the ageing laboratory rat. Such animals are probably less exposed to varying external stressors than humans are. Furthermore, the primitive mechanisms involved are probably common to most mammals because they are essential for survival, and the results from rats should therefore be reasonably applicable to humans. The results of such studies indicate that the ageing rat has an increased corticosterone secretion after a stress challenge (Sapolsky et al 1983). The down-winding of the corticosterone response seems to be delayed after a stress response. This varies among different rat strains (De Kloet 1992) and between genders (Brett et al 1986). The reason for the slow return to basal values seems to be a down-regulation of central GR density, particularly in certain fields of the hippocampus region (Sapolsky et al 1984a). This is apparently an effect of extended exposure to glucocorticoids (Sapolsky et al 1984b) and is amplified by toxins (Sapolsky 1985), including alcohol (Walker et al 1980). The mechanisms involved have been suggested to be effects of glucocorticoids on glucose uptake and utilization in the cells involved, in analogy with the well known sensitivity of brain cells to such insults. This is seen after prolonged administration of glucocorticoids at concentrations corresponding to those after stress, resulting in about 50% lower GR density of hippocampal receptors (Sapolsky et al 1985a). Interestingly, the neonatal rat, which has a low number of GRs in critical areas of the brain that develop slowly to adult density, is sensitive to impacts during this developmental period. Interference with this development results in persistent hypersecretion of cortisol (Sapolsky et al 1985b).

The end result of such down-regulation of GRs will then be an inefficient feedback control of corticosterone production which will amplify further damage to the regulatory system. When exposure to noxious agents occurs for a shorter time, the changes are reversible, while longer periods of exposure are followed by slower or no restitution (Sapolsky 1985). This corresponds to a loss of glucocorticoid binding cells in the critical areas of the hippocampus which are replaced by glial cells. When the insults are sufficiently large and extended, loss of brain substance occurs.

Interestingly, these are the same changes that are seen in the ageing rat, and are the basis for the 'glucocorticoid cascade hypothesis' (Sapolsky et al 1986). This hypothesis suggests that repeated stress insults, particularly when accompanied with exposure to toxins, down-regulate GR density in specific areas of the hippocampus region in the brain. This is reversible up to a certain point, beyond which permanent, irreversible loss of hippocampal neurons occurs with persistent oversecretion of glucocorticoids as a result.

This hypothesis suggests that with ageing and the experience of repeated stress periods during life, such changes may occur. The best evidence for this possibility seems to be the identical functional and anatomical changes seen with ageing with less or no such exposure.

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