The immune system in the elderly: activation-induced and damage-induced apoptosis

Apoptosis is a complex cell-death process that allows cells to die in a controlled fashion. Our overall health relies to a great extent on the proper balance between the normal removal of damaged or unneeded cells via apoptosis and proliferation of the cells that comprise our body. Increasing evidence suggests that apoptosis is involved in many physiological processes and pathological conditions. It plays an important role during development, in maintaining tissue homeostasis, in responding to cellular damage, and in preventing neoplastic diseases. Apoptosis is a key regulator of clonotypic diversity generation during lymphocyte ontogenesis and is essential for the proper function of the immune system, controlling lymphocyte activation and clonal expansion following antigenic stimulation. There are various types of apoptosis, induced by different kinds of stimuli and in cells and tissues of different natures. On the basis of the nature of the apoptosis-inducing stimuli, two main apoptotic pathways can be identified: an activation-induced apoptosis, initiated by a variety of signals, such as the binding of ligands to their death-promoting receptors on the cell surface, and a damage-induced apoptosis, triggered by a damage to the nucleous or other cellular components. Apoptosis is markedly involved in many changes characteristic of immunosenescence, such as thymic involution, alteration of T-cell repertoire, accumulation of memory/effector cells, and autoimmunity. The intense investigation of the age-related changes occurring in cell-death phenomena and on their precise impact on aging has resulted in controversial data. During senescence, the activation-induced and damage-induced apoptotic pathways could be differentially modulated, with variable impacts on the aging process. Changes in either of these two main apoptotic networks that may occur during aging could lead to disease. A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degenerative and inflammatory pathologies and neoplastic diseases whose incidence increases with age. Careful study of literature together with personal experience in the field of senescence causes us to propose a new reading register that better explains and integrates many of the apparently discordant results.