Human innate immunosenescence: causes and consequences for immunity in old age

Abstract

The past decade has seen an explosion in research focusing on innate immunity. Through a wide range of mechanisms including phagocytosis, intracellular killing and activation of proinflammatory or antiviral cytokine production, the cells of the innate immune system initiate and support adaptive immunity. The effects of aging on innate immune responses remain incompletely understood, particularly in humans. Here we review advances in the study of human immunosenescence in the diverse cells of the innate immune system, including neutrophils, monocytes, macrophages, natural killer and natural killer T (NKT) cells and dendritic cells-with a focus on consequences for the response to infection or vaccination in old age.

Figure 1. Proposed consequences of the age-related loss of human neutrophil function

1) Neutrophil adhesion to vascular endothelium and initial extravasation into tissue is unaffected by aging [89]. 2) Chemotaxis appears to be compromised by aging whilst chemokinesis remains intact [112], reducing the efficiency of migration to the infected site. 3) Migration through tissue involves secretion of proteases such as neutrophil elastase from azurophilic granules. Reduced chemotactic activity would increase exposure of tissue to such proteases, increasing collateral damage to healthy tissue. 4) At the site of infection itself neutrophil uptake of microbes and subsequent killing involving generation of superoxide are both reduced with age [76,77,112], due in part to reduced responsiveness to priming agents such as GM-CSF [81]. GM-CSF also extends neutrophil lifespan at sites of infection and thus reduced responsiveness to this cytokine increases apoptosis. Each of these factors will contribute to the reduced ability of aged adults to clear bacterial infections and to resolve inflammation promptly.