The role of calcium regulation in brain aging: reexamination of a hypothesis

Studies of the central nervous system have a long history; however, it is only recently that we have begun to understand brain function in health and disease states. And, the topic of the aging brain has become a subject of intense study for a short period. At present, the process of normal aging is relatively poorly understood. Although there are a number of theories of aging, no single theory appears to account for most age-dependent brain changes. This review provides a re-evaluation of the “Calcium Hypothesis of Brain Aging” in light of new evidence which supports the proposition that cellular mechanisms, which maintain the homeostasis of cytosol Ca²⁺ concentration, play a key role in brain aging; and that sustained changes in [Ca²⁺]_i homeostasis provide the final common pathway for age-associated brain changes. This revision of the calcium hypothesis suggests that there is a complex interaction between the amount of [Ca²⁺]_i perturbation and the duration of such deregulation of Ca²⁺ homeostasis and it proposes that a small disturbance in Ca²⁺ homeostasis with a sustained increase in [Ca⁺]_i over a long period has similar cell injuring consequences as that produced by a large increase in [Ca²⁺]_i over a shorter period. Although there are several alternative mechanisms through which the regulation of cytosol [Ca²⁺]_i can be disrupted (such as changes in ion channels, extrusion pumps, and sequestration), this review focuses on disruptions in energy metabolism and changes in the structure and function of membranes as the most likely antecedent events which lead to disruption of Ca²⁺ homeostasis. The principle purpose of this review is to identify scientific opportunities and stimulate further research into cellular mechanisms of brain aging.