The healthy ageing of the Ca2+ hypothesis

Normal brain ageing is associated with a varying degree of cognitive impairment. One of the early hypotheses proposed to explain such changes was the “Ca2+ hypothesis of ageing”. This review revisits this hypothesis and uses the Ca2+ dependency of neuronal excitability as an integrator to discuss the age-dependent changes in the activity of the various systems and mechanisms that control neuronal Ca2+ homeostasis. Amongst these systems, special attention is given to the mitochondrial involvement in the regulation of neuronal Ca2+, and to the fact that changes in mitochondrial functions induced during the ageing process might represent the fulcrum between normal, physiological ageing and the neurodegenerative processes. However, it is important to understand that the ageing process, with its various effects on neuronal function, is multifactorial, and results from a high degree of interactions between various systems, at the cellular but also at the tissular level. Thus, changes in Ca2+ homeostasis are just one element in the multifactorial fabric that underlies the process of normal, physiological ageing.