Current Medicinal Chemistry, 2007, 14, 1389-1397 1389 Apoptosis Remodeling in Immunosenescence: Implications for Strategies to Delay Ageing Massimo De Martinis 1 , Claudio Franceschi 2 , Daniela Monti 3 and Lia Ginaldi *,1 1 Department of Internal Medicine, University of L’Aquila, Italy 2 Department of Experimental Pathology, University of Bologna, Italy 3 Department of Experimental Pathology and Oncology, University of Florence, Italy Abstract: Immunosenescence is characterized by a peculiar remodeling of the immune system, mainly induced by lifelong antigenic burden and oxidative stress. Apoptosis or programmed cell death plays a central role in the ageing process. Both recurrent antigenic stimulations and oxidative metabolism by-products, impinging upon the immune system, modify the apoptotic capability of lymphocytes, driving immunosenescence. The apoptosis remodeling, in addition to inflamm-ageing, i.e. the upregulation of anti-stress responses and inflammatory cytokines, represents one of the major determinants of ageing rate and longevity, as well as of the most common age-related diseases. The cells of the immune system undergo two different kinds of apoptotic processes: activation-induced cell death (AICD), geared towards the elimination of unnecessary lymphocytes following clonal expansion, and damage-induced cell death (DICD), particularly important for preventing the onset of neoplastic proliferations. During senescence these apoptotic pathways are differentially modulated, with variable impacts on the ageing process. A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degenerative, inflammatory and neoplastic diseases whose incidence increases with age. This review focuses on the role of AICD and DICD dysfunction in the ageing process and highlights emerging anti-ageing therapeutical strategies offered by apoptosis re-modulation. The challenge for the future is to identify factors and signals that regulate apoptotic processes and determine if selective apoptosis manipulation in specific lymphocyte subsets could preserve immune function in the elderly, contributing to successful ageing. Keywords: Immunosenescence, apoptosis, therapeutic intervention. INTRODUCTION controlled fashion. It plays an important role during embryonic development, in maintaining tissue homeostasis in adults and in responding to cellular damage, tissue injury and disease. All cells have the intracellular machinery necessary for programmed cell death. Whether or not they use that machinery depends on the cell type, its tissue context, the presence or absence of physiological death-promoting signals, and the extent to which a cell is damaged or dysfunctional [4]. The process of ageing consists in a postmaturational deterioration of cells and organs with the passage of time, an increased vulnerability to challenges and a decreased ability to survive. People are very interested in learning what they can do to live longer as well as to remain healthy during their later years. In view of the growing percentages of elderly people in the population, along with an increasing incidence of age- related diseases, such as inflammatory, degenerative and neoplastic disorders, novel therapeutic alternatives for their treatment are of particular interest [1,2]. On the basis of the nature of apoptosis inducing stimuli, two main apoptotic pathways can be identified: an activation- induced apoptosis (AICD), initiated by a variety of physiological signals, such as the binding of ligands to their death-promoting receptors on the cell surface, and a damage- induced apoptosis (DICD), triggered by damage to the nucleus, mitochondria, or other cellular components [5]. These two main apoptotic patterns have, in reality, many links and share common steps (mitochondria, various caspases, etc.). Major pathways and steps in apoptotic cell death are illustrated in (Fig. 1). During senescence, these kinds of apoptosis could be differentially modulated, with variable impacts on the ageing process. Changes in either of these highly complex apoptotic- signaling networks that may occur during ageing could lead to disease. The immune system exhibits profound age-related changes, collectively termed immunosenescence. The most visible of these is the decline in protective immunity, which results from a complex interaction of primary immune defects and compensatory homeostatic mechanisms. The sum of these changes is a dysregulation of many processes that normally ensure optimal immune function. Immunosenescence is the consequence of the continuous attrition caused by lifelong antigenic burden and oxidative stress. The most important characteristics of immunosenescence (accumulation of memory and effector T cells, reduction of naive T cells, shrinkage of T cell repertoire, reduction of the immunological space, up-regulation of anti-stress responses and inflammatory cytokines) are compatible with this assumption [3]. APOPTOTIC PATHWAYS IN THE IMMUNE SYSTEM The immune system (IS) has a unique peculiarity in respect to other systems and organs: its physiological function is based on multiple and successive waves of clonal expansion of T and B lymphocytes in response to diverse and repeated antigenic solicitations. This mechanism would rapidly lead to saturation of the system and exhaustion of the immunological space if each immune reaction were not down regulated with a process of apoptosis or programmed cell death which quickly brings the number of lymphocytes, expanded following activation and clonal proliferation, to a level only moderately superior to the initial one. This physiological mechanism of activation-induced cell death is initiated, in the great majority In this complex scenario apoptosis processes play a central role. APOPTOSIS Apoptosis or programmed cell death (PCD) is a highly orchestrated cell death process that allows cells to die in a *Address correspondence to these authors at the Department of Internal Medicine and Public Health, University of L’Aquila, Coppito – L’Aquila, Italy; Fax and Tel: 0039 0861 211395; E-mail: liaginaldi@alice.it 0929-8673/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.