Immunosenescence: emerging challenges for an ageing population

Abstract

It is now becoming apparent that the immune system undergoes age-associated alterations, which accumulate to produce a progressive deterioration in the ability to respond to infections and to develop immunity after vaccination, both of which are associated with a higher mortality rate in the elderly. Immunosenescence, defined as the changes in the immune system associated with age, has been gathering interest in the scientific and health-care sectors alike. The rise in its recognition is both pertinent and timely given the increasing average age and the corresponding failure to increase healthy life expectancy. This review attempts to highlight the age-dependent defects in the innate and adaptive immune systems. While discussing the mechanisms that contribute to immunosenescence, with emphasis on the extrinsic factors, particular attention will be focused on thymic involution. Finally, we illuminate potential therapies that could be employed to help us live a longer, fuller and healthier life.

Figure 1

The effect of age on the different components of the innate and adaptive immune systems. Stem cells from the bone marrow give rise to the haematopoietic progenitors under signals from the different microenvironments. Age-associated defects are highlighted in the different haematopoietic stages of development. In addition, potential therapies are described. CLP, common lymphoid precursor; CMP, common lymphoid progenitor; DHEAS, dehydroepiandrosterone sulphate; DN, double-negative; ETP, early thymic precursors; HSC, haematopoietic stem cell; Ig, immunoglobulin; IFN-γ, interferon-γ; NK, natural killer cell; RAG, recombination activating gene; ROS, reactive oxygen species; SP, single-positive; TCR, T-cell receptor.

Figure 2

Crumbling architecture with faulty foundations – a proposed model of thymic involution. T-cell development initiates when HSC enter into the thymus. It is still unknown whether the number of HSC entering the thymus is reduced with age and there are still debates over the development potential of these cells. HSC are instructed by the TEC through the developmental pathway of successful T-cell differentiation by a combination of cell–cell contact and soluble factors. In the left diagram, the young thymus is distinctly orientated into the cortex and medulla directing the early and late stages of thymopoiesis, respectively, generating functional T cells. The presence of immunocompetent T cells is imperative to the maintenance of the thymic architecture. However, with increasing age the thymus shrinks, becomes disorganized and the TEC lose defining molecules such as keratin (right diagram) contributing to aberrant T-cell development. As the nature of the relationship between TEC and T cells is symbiotic, these defective T cells have a negative influence on the already age-altered TEC. This leads to a decrease in the number of RTE exiting the thymus and entering the peripheral pool, which in turn results in a constriction of the TCR repertoire in the older individuals by expansion of specific memory clones and decreased naive T-cell numbers. HSC, haematopoietic stem cells; RTE, recent thymic emigrants; TCR, T-cell receptor; TEC, thymic epithelial cells.