Edinburgh Napier University

  Human ageing is associated with a progressive decline in the function of the immune system, commonly referred as immunosenescence. This is characterized by the shrinkage of the naïve T-cell repertoire and a concomitant accumulation of highly differentiated effector-memory cells and dysfunctional senescent T-cells. These systemic immune alterations have clinical implications and have been associated with increased morbidity and mortality in the elderly. However chronological ageing may not be the only factor influencing immunosenescence and certain lifestyle factors may moderate or potentiate the rate at which immune alterations occur. The studies comprised within this thesis investigated the effects of lifestyle factors such as physical activity or obesity, along with latent viral infections on the proportions of highly differentiated and senescent T-cells.

Data were gathered from individuals of various age, physical activity, body composition and latent viral infection status to assess the effects of a wide range of lifestyle factors on T-cell proportions. The different levels of T-cell differentiation were assessed by four-colour flow cytometry using monoclonal antibodies specific to cell surface markers associated with T-cell phenotypes. The role played by leptin on T-cell activation was assessed by in vitro stimulation assays followed by cell surface phenotype and gene expression analysis. The effects of acute bouts of exercise on T-cells subsets were characterized using a submaximal cycling protocol.

Aerobic fitness was associated with lower proportions of senescent and higher proportions of naïve T-cells, particularly within the CD8+ T-cell compartment in healthy adult men. The beneficial impact of aerobic fitness, and consequently of regular physical activity, on the ageing immune system was independent of age, latent viral infection status and body composition. Furthermore, the moderating effect of higher estimated VO2max on the proportions of senescent T-cells suggested that a transition from low physical activity, characterized as having an estimated VO2max below average, to regular physical activity, characterized as having a VO2max above average, could prevent the age-associated accumulation of senescent T-cells during decades. Obesity and excess serum leptin in adolescents were shown to be associated with changes in T-cell subsets associated with immunosenescence, such as reduced proportions of naïve and early T-cell and increased proportions of effector-memory and senescent T-cells. In addition, high physiological concentrations of leptin enhanced the mitogen-induced T-cell activation in vitro suggesting a potential role in the accumulation of senescent T-cells observed in obese individuals. Latent CMV infection was also associated with similar reductions in naïve T-cell proportions and increased proportions of highly differentiated and senescent T-cells in young adults. Although CMV infection appeared to be associated with an amplified exercise-induced preferential mobilization of highly differentiated and senescent T-cells in blood, those cells may not have been specific for CMV.

It is concluded from this work, therefore, that chronological ageing is not the only factor associated with the accumulation of senescent T-cells in the elderly. By preventing obesity, and by potentially inducing senescent T-cells frequent mobilization and subsequent deletion via apoptosis, regular physical activity may prevent the accumulation of highly differentiated and senescent T-cells in the elderly, and consequently reduce morbidity and mortality in later life.