The ER and ageing II: Calcium homeostasis

Increase in intracellular Ca2+ concentration occurs by Ca2+ influx through the plasma membrane and by Ca2+ release from intracellular stores. The ER is the most important Ca2+ store. Its stress, characterized by the impairment of Ca2+ homeostasis and by the accumulation of misfolded proteins, can be induced by different factors. In turn, it induces defense mechanisms such as unfolded protein response, and when it is severe and prolonged, activation of the apoptotic pathway. Damage to the ER, impairment of its function, and a decreased level of its Ca2+-handling proteins might all play a role in physiological ageing by handicapping the ER stress response. Thus, healthy ageing is accompanied by subtle alterations of Ca2+ homeostasis and signaling, including alterations in the ER Ca2+ load and release. The expression and/or function of ryanodine receptors, IP3 receptors, and SERCA Ca2+ pumps located in the ER membrane, and Ca2+-binding proteins within ER lumen all seem to be affected in aged cells. Data are presented on age-dependent, tissue-specific changes in ER-related Ca2+ homeostasis in skeletal, cardiac and smooth muscles, as well as in the nervous and immune systems. Disturbances of Ca2+ homeostasis and of signaling are potential targets for intervention in aged humans.