Ageing stress and the brain

Bernard J. Carroll

Pacific Behavioral Research Foundation, 26386 Carmel Rancho Lane, Suite 202, PO Box 223040, Carmel, CA 93922-3040, USA

Abstract. 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.

2002 Endocrine facets of ageing. Wiley, Chichester (Novartis Foundation Symposium 242) p 26-45

In 1988 Joseph Meites described a neuroregulatory theory of ageing, emphasizing the integrative role of the nervous system for neuroendocrine axes and circadian rhythms (Meites 1988). As the brain aged, Meites proposed, so would the hypothalamus age, leading to menopause, andropause, somatopause and dysregulated circadian rhythms. Meites tested pharmacological strategies to augment hypothalamic neurotransmitter function, which he found could reverse these 'biomarkers of ageing', a result that comports with the age-associated decline of hypothalamic monoamine neurotransmitter systems (Rodriguez-Gomez et al 1995). Though it can be modified by recent insights, the general perspective of Meites that we endocrinologists are also neuroscientists remains valid. Ageing of the brain is an important factor in overall ageing and mortality.

Since that time, four new insights have changed our understanding of neuroregulation and ageing. First, neuronal loss in normal ageing is minor; loss of synapses through dystrophic neuronal change is the hallmark of normal ageing. Second, similar dystrophic changes occur in the brain with chronic stress. 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. Fourth, neurogenesis does occur in the adult mammalian brain, which opens new possibilities for treatments. The topic of neurogenesis is beyond the scope of this chapter, though we may say with Pasko Rakic (1998) that, as a result of this discovery, 'the word impossible is not in the vocabulary of contemporary neuroscience'.

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