The role of limited cell replicative capacity in pathological age change. A review

Physiological functions are carried out by differentiated cells, with finite lifespans, which age and need to be replaced. In young individuals, tissue functions are sustained at optimal levels because cellular dysfunction and cell loss are balanced by the emergence of newly differentiated cells as stem cells and their partially differentiated descendants replicate. However, with the passage of time the mitotic rates of these cells diminish. Eventually, replications occur too infrequently to offset the loss. It is at this point that the tissue begins to show structural changes and declining function which, as they become pervasive, are identified as "ageing". In this paper the theory is set forth that: (1) Diminishing mitotic activity in older tissues results from limited stem cell replicative capacity. (2) All stem cells, regardless of tissue, exhibit similar replicative patterns over time, progressing from the actively proliferating to the nonproliferating state. However, stem cells in different kinds of tissue have different rates of replicative decline, with the result that some tissues show age earlier than others. (3) The combination of two cellular properties--differentiated cell ageing and limited stem cell replicative capacity--is sufficient to establish the framework in which other pathological changes characteristic of aged people and animals take place.