Analysis of the mechanisms underlying the age-related impairment in long-term potentiation in the rat.

The process of ageing is common to all organisms but despite its universality, understanding of the cellular and molecular changes which accompany ageing is poor. With the increase in the ageing population, the need for systematic study of the process becomes a priority but the development of a systematic approach to the problem requires the development of a testable theory of ageing. While several theories of ageing have been proposed /336/, between which there is at least some overlap, no generally-accepted theory has been identified. In relation to the brain, four interrelated theories of ageing have received significant attention; these are (1) the membrane hypothesis, (2) the free radical hypothesis, (3) the calcium hypothesis and (4) the glucocorticoid theory. The overlap between these hypotheses is such that a causal relationship between them is very likely with age-related changes in membrane composition triggered by changes in free radical production, while changes in membrane composition are likely to account for changes in membrane function including age-related changes in calcium homeostasis. The glucocorticoid theory could equally well be termed the stress hypothesis of ageing, which in the hippocampus at least, might trigger age-related changes in free radical production. This review is not intended to be a balanced appraisal of each theory but emphasizes aspects of the membrane hypothesis of ageing and discusses some relevant aspects of the other hypotheses. Attention is focussed on analysis of the biochemical changes which might underlie age-related changes in hippocampal function, particularly maintenance of long-term potentiation (LTP), and these changes are discussed in the context of the four hypotheses of ageing.