Daan Pieren

19 General introduction and scope of this thesis Figure 2. Processes that contribute to immunosenescence. Schematic representation of the three processes that contribute to ‘immunosenescence’. Both T-cell senescence and T-cell exhaustion are characterized by the loss of T-cell function, such as reduced proliferative capacity. However, T-cell senescence is thought to develop as a consequence of exposure to different antigens over a lifetime, leading to irreparable cell damage and expression of tumor suppressor proteins which in turn limit T-cell function. T-cell exhaustion is thought to develop as a consequence of chronic viral infection and/or presence of a high antigen load, but has also been shown to develop during aging in the absence of these causes. Inflammaging is characterized by the low-grade constant presence of pro-inflammatory proteins, such as IL-6 and TNF- α . The source of these pro-inflammatory mediators that lead to inflammaging lies at lifestyle (e.g. obesity) and environmental factors (e.g. antigen exposure), but also as a consequence of senescent cells secreting the senescence-associated secretory phenotype (SASP). Together, immunosenescence contributes to susceptibility to disease, reduced response to vaccination, prolonged and more severe disease, and aging-related diseases, such as cardiovascular disease and diabetes. 1