Ageing, stress and the brain.

Ageing of the brain is an important factor in overall ageing and mortality, and new insights have clarified the relationship between neuroregulation and ageing. First, neuronal loss in normal ageing is now known to be a minor change. Loss of synapses through dystrophic neuronal change is the hallmark of normal ageing. Second, similar dystrophic changes occur in the brain with chronic stress. In both instances, forebrain sites experience loss of synaptic input from brainstem regulatory nuclei. Third, functional ageing is attributed in part to lifetime stress, under the concept of 'allostatic load'. Being inseparable from the functions of appraising and responding to stress, the brain is an ultimate mediator of stress-related mortality, through hormonal changes that lead to proximate pathologies like hypertension, glucose intolerance, cardiovascular disease and immunological impairment. In chronic stress the brain shows clear allostatic compensations that lead to pathology. Two subtle and chronic mechanisms that may mediate brain pathology and accelerated ageing in chronic stress are proposed. These are abnormal glucocorticoid receptor (GR) occupancy over the 24 h cycle, and elevated body temperature. These factors lead to GR-mediated tissue changes and to acceleration of general cellular ageing mechanisms. Human depression is discussed as an exemplary demonstration of these principles.