Sara van den Berg

1 13 General introduction evidence from longitudinal studies that CMV-specific antibody levels indeed increase over time within individuals. Whether CMV-specific antibody levels are a good marker for CMV- reactivation is still under debate. Figure 1. Rise of a theory: CMV-enhanced immunosenesence. Left panel: process of ageing of the immune system (immunosenescence). With age, changes in the T-cell pool arise, which are thought to be the basis for reduced function of the immune system and subsequently mortality. Right panel: the influence of CMV infection on immunosenescence. Paradoxically, the CMV-specific immune response does not decrease, but increases with age. This is thought to gradually exhaust the immune system based on the following lines of evidence: (1) CMV infection establishes similar changes to the T-cell pool as healthy ageing (Komatsu et al. 2003, Weinberger et al. 2007, Derhovanessian et al. 2011, Pera et al. 2016, van der Heiden et al. 2016, Hassouneh et al. 2017), (2) the first studies suggested a negative association between CMV and the immune response to influenza (Trzonkowski et al. 2003, Derhovanessian et al. 2014, Frasca et al. 2015, Merani et al. 2018), and (3) epidemiological evidence links CMV to increased mortality (Gkrania-Klotsas et al. 2012, Mathei et al. 2015).