The effect of ageing on immune function

1.6.1 Respiratory illness in older adults

There are many immunological changes that occur with ageing including an increase in the incidence of respiratory illness [10, 119]. In adults over the age of 65 years, influenza is the fourth leading cause of death, after heart disease, cancer and stroke [120, 121]. The immune remodelling that occurs with ageing can also result in a reduced immune response in some individuals such as antibody response to vaccination. In a population of 210 older adults hospitalised with influenza, 129 had been vaccinated. This may have been due to a suboptimal response to the vaccine [121], or the strain of influenza may have been different to the vaccination. Changes to immune function may be further exacerbated in the frail elderly due to the effects of malnutrition including protein, calorie, vitamin and mineral deficiencies [120].

There has been increased interest in the use of nutrient formulae to enhance immune function in older adults and some studies have shown that supplementation with various nutrients can enhance antibody responses to influenza vaccination in this age group [121]. Reduced incidence of URTI and a higher antibody titre to vaccination were observed in older adults who took a trace element supplement to correct selenium deficiency [121]. In another group of 16 healthy older adults who consumed a nutrition supplement (which included antioxidants, vitamins, minerals [zinc, selenium], and fermentable oligosaccharides) for 183 days, there was less reportage of URS, a better antibody response to influenza (Beijing strain [H1N1]) and greater lymphocyte proliferative response to influenza vaccine than in the placebo group [121].

1.6.2 Immune remodelling during senescence

The immune system is not fully developed at birth and undergoes significant changes as it becomes exposed to microbes and other inhaled and consumed environmental antigens [122]. The gastrointestinal tract is colonised throughout life, and maintenance of mucosal integrity and a balanced flora are essential to

prevent infection [122]. Differentiation of the immune system continues through adolescence, adult life and during senescence when complex remodelling occurs. The function of some immune parameters does not change, for example populations of B-cells [37] and antibody production in secondary responses are not diminished [123]. It is possible that B-cell function may play a key role in successful ageing, as was shown in a study of 513 Swedish octogenarians where survival was associated with higher percentages of cells expressing CD19 (B-cell activation marker) after controlling for age and gender [124]. While immune remodelling during senescence is characterised by thymic involution, the extent of this is varied. This suggests other factors such as nutritional status impact on immune function, and changes in metabolism may also contribute to remodelling of the immune system [122].

The effect of ageing on the innate immune system

In the healthy older adult the main change in innate immune function appears to be a variance in the antigen presenting cells (APC) ability to communicate with T-cells [119]. With ageing the expression of co-stimulatory molecules changes resulting in altered cytokine production by APCs and therefore affecting downstream T-cell function [119]. In addition the number of immunocompetent T-cells is affected by age-related involution of the thymus [119].

The effect of ageing on T-cell function

Impairment of T-cell function is thought to affect the helper CD4 T-cells more than the cytotoxic CD8 T-cells [125]. Evidence for this is the loss of ability of CD4 T-cells to up-regulate telomerase activity (essential for lymphocyte proliferation) [125]. There is a slow decline in proliferation of naïve CD4 T-cells [119] post-thymic involution, suggesting clonal expansion of CD4 T-cells is still occurring in the peripheral circulation [126]. There will be a smaller pool of naïve T-cells that can respond to novel antigens. Deterioration of CD4 T-cell function will impact on protection at mucosal surfaces because of their involvement in the regulation of antibody production and could contribute to autoimmunity in the aged [126]. T-cell subset distribution also changes with ageing. Increased numbers of CD4cells have been found in nasal associated lymphoid tissue in aged mice compared to young mice, in response to

vaccination [127]. In humans accumulation of CD4+ T-cells has been observed in the air spaces of the lower respiratory tract in healthy older adults [128] which suggests CD4 lymphocyte activation could be protective for normal lung function [129]. This may be an example of immune system remodelling in older adults.

The effect of ageing on B-cells

With ageing the absolute number of B-cells is reduced, but a larger proportion of these remaining cells are memory cells with a noticeable reduction in the naïve B-cell pool (CD27-) [123]. B-cells from older populations have impaired activation and proliferation that may be related to changes in co-stimulatory molecule expression [119]. Primary and secondary responses to vaccination can be impaired especially when T-cell involvement is required, and the specificity and efficacy of antibody production in older individuals is lower than that produced in younger individuals [119]. Changes to B-cell sub-populations observed in older adults include a decrease in B-cells expressing CD5 (considered to be responsible for T-cell independent antibody production), no changes in CD40/CD19 (T-cell dependent), and increases in CD27 (which is a marker of primed or memory cells) and natural killer cells [123]. It is thought that there is increased co-operation between B-cells and natural killer cells, which might be important in regulation of antibody formation in the absence of T-cell control, and might be advantageous to the host in early protection [123]. This immune remodelling also partly explains why antibody production appears to be largely unaffected with ageing, alternatively the early B-cell response may contribute to increased autoimmunity in older adults [123].

The effect of ageing on changing lymphocyte subsets

Ageing increases the CD4/CD8 T-cell ratios in human peripheral blood (and to a lesser extent in the lower respiratory tract) and it is thought that this is genetically controlled [129]. An increase in numbers of CD4 lymphocytes is thought to be due to an accumulation of memory cells and primed T-cells in response to cumulative antigenic stimulation at mucosal surfaces [129]. This may be a protective effect to an ageing immune system as older populations with low levels of CD4 T-cells have an increased mortality risk [129].

The distribution of lymphocyte subsets also changes with age and may be site- specific [130]. In the ageing mouse an increase in the numbers of lymphocytes in the liver, small intestine, colon and appendix was observed along with thymic involution [130]. These are extrathymic sites and as the lymphocyte subsets carried auto-reactivity it was thought the aged mouse may require auto-reactive cells that can act against altered self-cells developing with ageing [130]. The change in distribution of lymphocyte subsets observed in aged mice could therefore be considered to be beneficial to their immune health and could be another example of how the immune system remodels.

1.6.3 Age-related changes to mucosal immunity

Ageing is associated with more infections at mucosal sites such as the respiratory tract, in part because the development of a mucosal response to new antigens is diminished [127]. However the exact nature of the decline in mucosal immunocompetence is still unknown [131]. Changes in salivary gland function occur with ageing and these differences may be important to salivary S-IgA levels. Saliva secretion rates and levels of salivary S-IgA were investigated in 142 older adults (46 men, 96 women) aged 18–82 years [132]. The results indicated there was no impairment of the secretion rate from the minor salivary glands however flow rate of whole unstimulated saliva was reduced with ageing [132]. Concentrations of S-IgA in saliva were also positively correlated with reduced saliva flow rates [132]. This suggests that older adults with lower saliva secretion rates would also experience reduced levels of salivary S-IgA.

In aged mice reduced size of PPs have been observed which may affect oral tolerance and induction of mucosal immunity such as S-IgA production [133]. This may be an example of immune dysregulation that contributes to the decline of mucosal immunity in older adults. Additionally investigations indicate that the homing ability of IgA immunoblasts to the effector site is also compromised with age [134]. This is evidenced by a decreased expression of α4β7 homing receptor on mononuclear cells in aged adult rats compared to young adult rats [135].

In humans age-related changes appear to affect lymphocytes in the LP, but not the ability of intraepithelial lymphocyte to produce IL-2 [122]. Age-related decline in cellular regeneration of those cells with a high turnover rate such as intestinal and colonic mucosal epithelium [136] occurs which in turn has an effect on the ability to repair lesions to the mucosal layer [61]. The gut microenvironment may be further affected by changes to intestinal pH and enzyme functions which favour bacterial overgrowth in the proximal small intestine [136] and also impact on gut motility. Regulated gastrointestinal motility is important in the maintenance of the mucosal barrier [61].

Maintenance of the gut microenvironment requires energy, especially when the host experiences a new infection [122]. When rapid growth or a disease state exists there is an additional nutrient requirement for nucleotides which are essential for rapidly dividing tissue such as the gastrointestinal tract [122]. The immune response may be impaired if these additional nutrient requirements are not met. It is possible that maintenance of the mucosal immune response during ageing is related to a continual need to maintain a response to microbial flora in the gastrointestinal tract. Therefore managing the changes in the gut microenvironment that occur with ageing could have an important role in immune function [122].

The effect of exercise on mucosal immunity in older adults

Moderate levels of exercise may be of benefit to mucosal immunity in older adults. Salivary S-IgA levels and secretion rate were enhanced in 45 older adults (18 men, 27 women) aged 64.9 years +8.4 years after a twelve month exercise programme [137]. In another study of 274 older adults (114 men, 170 women), aged 71.3+3.1 years (mean+SEM), salivary S-IgA levels were significantly enhanced in those who performed more than 7000 steps per day (measured by a pedometer) for 14 days [138]. There were no changes in saliva secretion rate over this period [138]. The effect of exercise training on a health outcome such as the incidence of URTI was not investigated in either study. However the results from these two studies may indicate there is a beneficial effect of moderate exercise (such as performed by exercising free-living individuals) to mucosal immune health.