Abstract:
“Successful aging” - defined as long life in a good mental and physical health, requires appropriate immune function. However, dysregulated immunity in later life, known as “immunosenescence,” results in compromised immune functions and disturbed pro- and anti-inflammatory balance. The impact of these age-related immune alterations on physical and mental health, and hence successful aging, is currently not well understood. With few exceptions, the studies on aging have not attempted to integrate psycho-neurological, metabolic, and endocrine parameters with immune function in order to dissect out which influences which. Few have taken CMV-infection into account and even gender has not always been considered. The present dissertation contributes to this developing research field both conceptually and empirically. It is publication-oriented and consists of four publications.
Publication I presents data obtained from a subgroup of the Berliner Aging Study participants, which show significant age-associated differences of T-cell subset distribution. The modulatory impact of both sex and CMV-infection on T-cell naïve and memory phenotypes, but unaffected frequencies of T-stem cell-like memory cells, were found. For the first time, the frequency of the TSCM phenotype and of PD-1+ T-cells in peripheral circulation has been investigated, and the effects of age, CMV-serostatus, and sex on their frequency have been examined.
Publication II reviews the relevant literature on the dynamic neuroimmune interactions between the immune and the nervous systems. Bringing these two strands of research together, we propose that immunosenescence and peripheral low-grade inflammation at least partly contribute to neuroinflammation inducing neurodegeneration and age-related cognitive impairments. We review and discuss possible interventions that can prevent or at least postpone these age-related changes.
Publication III characterizes the baseline inflammatory status of aged individuals, recruited to undergo the cognitive, physical, and combined training interventions. By analyzing multiple circulating peripheral biomarkers and measures of objective cognitive function, we show that both CMV-serostatus and sex may modulate inflammatory immune factors, cognitive performance, and the relationship between the two domains, and should therefore be considered in comparative and interventional studies with elderly people.
In study IV, we propose a new strategy that allows the quantitative investigation of multiple interactions between different cytokines, receptor molecules, metabolic and neurotrophic factors, hormones, immune cells, and measures of cognitive performance. Using a graph-theoretical approach enables us not only to visualize biologically meaningful interconnections between different variables but also to compare the network topology dynamics between different groups of CMV-seronegative and -seropositive men and women in a statistically sound manner. In summary, results obtained from the studies III and IV suggest that highly integrated and segregated networks have optimal neuroimmune interactions.
Taken together, this dissertation contributes to the study of age-related functional alterations of immune and related physiological functions in two major ways. First, it expands the analysis methods that have been used to investigate markers of immunosenescence. Second, it has generated new findings on the modulatory effects of CMV-latency and sex on multiple peripheral biomarkers and cognitive function in older men and women.
Berliner Aging Study