Role of CMV in immune senescence
Introduction
In the industrialised nations, death rates from infectious disease accelerate with age but unlike classical age-associated diseases (cardiovascular, cancer) this acceleration seems not to plateau in late life, but to continue to accelerate (Horiuchi and Wilmoth, 1997). Thus, the chance of dying of an infection in very old age continues to increase up to the maximum lifespan achievable. Because immunity evolved to protect against pathogens, it is likely that immunosenescence is one of the reasons for the increased sensitivity and susceptibility of the elderly to infectious disease. As long as 3–4 decades ago, researchers have sought age-associated alterations to immune parameters and tried to establish correlations between these changes and clinical outcome or mortality (Murasko et al., 1987, Roberts-Thomson et al., 1974, Wayne et al., 1990). These early studies had proposed that the level of in vitro responsiveness of T cells to mitogens predicted longevity; later, the level of natural killing at baseline was also implicated as correlated with susceptibility to infectious disease in later life (Ogata et al., 2001). Increased levels of inflammatory indicators such as the cytokine interleukin 6 (IL 6) and especially tumor necrosis factor-α (TNF) have also been associated with frailty and compromised survival (Bruunsgaard and Pedersen, 2003, Cohen et al., 2003). Many other age-associated changes to immune parameters have been reported, but correlations with health and longevity have mostly only been proposed, not tested, because the studies have been almost entirely based on cross-sectional approaches. However, such studies fail to compare like with like because young and old groups studied at the same time clearly differ in many important but undefined ways, for example, in pathogen exposure, developmental and nutritional factors, population genetics and many others. Longitudinal studies of the same individuals would overcome this problem, but are clearly challenging in humans. One approach along these lines has been to study populations already advanced in years, so that mortality at follow-up can be compared with measured parameters within a reasonable time frame (Wikby et al., 1994). The rationale is that provided informative factors can be identified in the very elderly, it can be tested whether they are also informative in younger people. In this contribution to the special issue, we will first review data from the Swedish longitudinal OCTO/NONA-immune studies and then consider how these may apply to other populations.
Section snippets
The immune risk profile (IRP) and CMV infection
The OCTO longitudinal studies carried out by the Institute of Gerontology in Jönköping, Sweden focussed on free-living people > 85 years of age selected for extremely good health according to slightly modified SENIEUR criteria (Ferguson et al., 1995). Several waves of recruitment yielded baseline data on many health parameters including, unusually at that time in such studies, some immune parameters (Wikby et al., 1998). In contrast to the exceptionally healthy OCTO subjects, the NONA
Impact of CMV on immune signatures
Studies have documented that the major difference between elderly OCTO/NONA subjects in the IRP group was in the accumulation of CD8+ late differentiated cells (defined by lack of both costimulatory receptors CD27 and CD28). The absolute number of these cells per microliter of blood was markedly increased, as well as their percentage within all CD8+ cells (Pawelec et al., 2005). In contrast, there was no difference between the IRP and non-IRP groups for other CD8 memory cells (as defined by
CMV as a risk factor for mortality
The above results would suggest that CMV drives immune ageing processes that are associated with mortality. Therefore, CMV infection by itself might be predicted to have some impact on survival. Surveys are beginning to suggest that CMV infection may indeed be associated with an increased risk of all-cause mortality. In longitudinal studies of CMV-seropositives, antibody levels have been reported to correlate inversely with survival in people with stable cardiovascular disease (Strandberg et
Would it be beneficial to eradicate CMV?
Given the above considerations, it would appear that the answer to whether CMV should be eradicated would be an unequivocal “yes”. However, it is also conceivable that infection with CMV might convey some advantage in early life, or might have done so in the evolutionary past when infectious disease was a major killer of the young. Infection with CMV is associated with higher background levels of inflammatory mediators which might be protective. There may be an analogy here with a murine model
Acknowledgements
The authors’ own work discussed in this contribution was most recently supported by DFG PA 361/14-1; part of the immunological analysis in the OCTO/NONA studies was supported by the European Commission (T-CIA, contract QLK6-2001-02283).
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