Figure 4. The brain as a potential regulator of organismal ageing.

The ageing of the brain may be coordinated with the ageing of organ systems through hormonal feedback circuits. The left-hand side of the diagram shows how glucocorticoid hormonal signalling may contribute to brain ageing. Stressors induce hypothalamic production of corticotropin-releasing hormone (CRH), leading to glucocorticoid release from the adrenal glands. The hippocampus, in turn, senses glucocorticoid concentrations through the glucocorticoid receptor (GR), resulting in feedback inhibition of glucocorticoid release through the hypothalamus. Chronically elevated glucocorticoid concentrations during ageing may be detrimental to hippocampal function, blunting the ability of the hippocampus to repress glucocorticoid release and potentially setting up a self-reinforcing process of hormonally mediated hippocampal decline. The right-hand side of the diagram shows how hormonal feedback circuits, similar to the pathways shown on the left-hand side, may be a general mechanism contributing to the decline of other functional systems in the brain. Dashed arrows indicate effects that may be indirect and/or are poorly understood mechanistically.