The Impact of Aging on the Lung Alveolar Environment, Predetermining Susceptibility to Respiratory Infections

Abstract

Respiratory infections are one of the top causes of death in the elderly population, displaying susceptibility factors with increasing age that are potentially amenable to interventions. We posit that with increasing age there are predictable tissue-specific changes that prevent the immune system from working effectively in the lung. This mini-review highlights recent evidence for altered local tissue environment factors as we age focusing on increased tissue oxidative stress with associated immune cell changes, likely driven by the byproducts of age-associated inflammatory disease. Potential intervention points are presented.

Tuberculosis in an Aging World

“…Aging by itself is a very significant risk factor for developing TB. The continuous accumulation of basal inflammation and an oxidative state as we age (inflammaging) exacerbates the homeostatic balance of stress responses, impairing the intrinsic mechanisms that aid cell regeneration, repair, and immunosurveillance [ 11 , 21 , 27 ]. These outcomes consequently increase susceptibility to acute and chronic diseases and result in increased morbidity and mortality in the elderly [ 11 ].…”

“…Importantly, lung tissue from elderly individuals has significantly decreased tissue-repair capacity compared to young individuals [ 26 ]. Therefore, age-associated changes in the alveolar space, such as decreased alveolar septae and elasticity and changes in the extracellular matrix, impair the ability of the lung environment to respond to chemical, mechanical, and biological stressors appropriately [ 11 , 27 ]. Moreover, aging leads to detrimental alterations in cellular function and cell-to-cell interactions of pulmonary resident cells and peripheral immune cells, leading to an imbalance and decline of appropriate innate and adaptive immune responses, associated with immuno-senescence [ 21 , 28 , 29 ].…”

“…Cell-mediated immunity is the primary mechanism of immune protection against M.tb infection. However, changes in the lung environment as we age can modify the cellular function of both pulmonary innate and adaptive cells [ 21 , 27 ]. For example, changes occur in macrophages (decreased phagocytosis and increased superoxide production), neutrophils (decreased phagocytosis and dysregulated chemotaxis), dendritic cells (decreasing antigen presentation), and T lymphocytes (reduced naïve T cell number, impaired T cell helper responses and cytotoxic responses), amongst others [ 21 , 27 , 28 ] ( Figure 1 ).…”

“…However, changes in the lung environment as we age can modify the cellular function of both pulmonary innate and adaptive cells [ 21 , 27 ]. For example, changes occur in macrophages (decreased phagocytosis and increased superoxide production), neutrophils (decreased phagocytosis and dysregulated chemotaxis), dendritic cells (decreasing antigen presentation), and T lymphocytes (reduced naïve T cell number, impaired T cell helper responses and cytotoxic responses), amongst others [ 21 , 27 , 28 ] ( Figure 1 ). It is necessary to better understand how increasing age influences the pulmonary environment at both molecular and cellular levels to appreciate how this can impact susceptibility to develop TB disease or mortality.…”

“…Inflammaging was originally characterized as a persistent low-grade pro-inflammatory state in the circulation that progressively increases with age [ 31 ], interfering with regulation of anti-inflammatory responses, driving immuno-senescence, and increasing the risk of chronic diseases as an individual ages [ 30 , 32 ]. The molecular composition of the alveolar lining fluid (ALF) components (e.g., innate soluble protein/cytokines and lipids) in the lung are also significantly altered in aged mice and elderly humans, resulting in a relatively oxidized environment [ 27 , 33 , 34 ]. Such studies confirmed that inflammation is not limited to the periphery, but can also be found within the lung and, likely, within other tissues too.…”