The aging lung: Physiology, disease, and immunity

Abstract

The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.

Keywords: COPD; COVID-19; aging; healthspan; immunity; inflammaging; lung; lung cancer; metabolism; oxidative stress; proteostasis; pulmonary fibrosis; senescence; stress response.

Figure 1

Cellular composition and functional changes in the aging lung Schematic of changes in young (left) and aged (right) lung showing major changes in cellular composition and structure by anatomic region.

Figure 2

Contribution of cell-autonomous and non-autonomous factors to pulmonary age-related functional decline Cellular function is a composite of intrinsic biological processes and extrinsic interactions with other cell types and bioactive molecules. Left: both qualitative and quantitative changes have been described in specific cellular compartments in the aged lung. Red arrows: decrease in cell number or in pathway activity. Green arrows: increase in cell number or pathway activity. Right: lung-resident cells interact with neighboring cells and acellular structures in a way that alters their function with advancing age. Age-related changes have been described for extracellular matrix (ECM) components, tissue and circulating cytokines, senescent-associated secretory phenotype (SASP), and environmental insults which contribute to alterations in tissue architecture. Qualitative deficits during aging lead to abnormal cell-cell communications mechanisms and are manifested by aberrant interactions with microbial pathogens and skewing of innate and adaptive immunity toward heightened inflammation, disrupted adaptive immune responses, and impaired immunosurveillance.

Figure 3

Stress response pathways in the aging lung and potential therapeutic strategies Top: exogenous and endogenous insults have the potential to accrue in lung tissues throughout the lifespan of an organism. Bottom: various mechanisms that are critical to maintaining cellular homeostasis have been shown to decline with age in the lung. Decreasing chaperone and proteolytic capacity results in compromised protein homeostasis leading to a proteome plagued by misfolded, aggregated, or covalently modified proteins. Oxidative stress responses are hampered in endothelial, inflammatory and epithelial compartments of the aged lung, resulting in compromised mucociliary clearance in upper airways and compensatory Nrf2-mediated stress response in alveolar epithelial cells. Metabolic imbalance with age stems from the convergence of abnormal signal transduction pathways and mitochondrial dysregulation. The increasing burden of senescent cells in the lung with age impacts ECM remodeling which ultimately disrupts airway architecture and contributes to fibrogenesis and altered interactions with microbrial pathogens. ROS, reactive oxygen species; NOX, NADPH oxidase; OXPHOS, oxidative phosphorylation; SASP, senescent-associated secretory phenotype; ECM, extracellular matrix.

Figure 4

Age-related changes in systemic and pulmonary immunity Advanced age leads to immunosenescence and inflammaging through effects on primary lymphoid, secondary lymphoid, and target tissues. Top: thymic involution and bone marrow fibrosis decreases circulating levels of naive T/B lymphocytes. Center: loss of lymph node architecture disrupts dendritic cell (DC) priming of T cells and B cell activation. Bottom: defects in T/B cell priming and activation results in loss of effector T cell protection, decreased antibody production. Defects in neutrophil migration from lung tissue results in increased immune pathology. Inflammaging results in the increased production of inflammatory cytokines from macrophages in the absence of infection.

Figure 5

Age-related modifiers of lung tumorigenesis Left: in youth, protective factors are in in place to thwart the development of a primary lung cancer. However, there are certain molecular subtypes of lung adenocarcinomas that are enriched in younger adults (i.e., ALK and ROS1 translocations) which challenge the notion that advanced age drives tumorigenesis in these patients. Middle: as humans age, there is a precipitous rise in the incidence of lung cancer diagnosis. There are certain molecular subtypes of lung adenocarcinomas that are enriched in elderly patients. The increase in lung-resident senescent cells and the decrease in immunosurveillance may potentiate other cell-intrinsic pro-mitogenic alterations that may ultimately result in lung tumorigenesis. Right: in centenarians, rates of lung cancer incidence and prevalence surprisingly decreases, but why this occurs is not fully understood.

Figure 6

Age-related molecular and immunological determinants that may contribute to worse outcomes in elderly patients infected with SARS-CoV-2 Putative molecular and immunologic alterations with age may provide a biological basis for why elderly patients with COVID-19 have increased mortality. Top: SARS-CoV-2 infects AT2 cells where the angiotensin-converting enzyme 2 (ACE2) serves as a receptor for cellular entry. ACE2 is an interferon-stimulated gene (ISG) in lung tissue. It is unknown how ACE2 levels change with age and whether altered interferon signaling cascades with age impact the expression dynamics of the SARS-CoV-2 receptor. Middle: multiple pulmonary immune effector cells undergo changes in the aging lung including neutrophil infiltration and alveolar macrophage (AM) activation. An over-exuberant proinflammatory response triggered by SARS-CoV-2 in the background of inflammaging and an already skewed population of aged lung-resident macrophages may be a lethal combination leading to increased mortality in infected older adults. Bottom: reduction in naive T/B lymphocytes in aged individuals leads to decreased antigen-specific T cell responses and reduced antibody titers. The increased frequency of terminally differentiated T cells and cytokine dysregulation from inflammaging leads to a T cell autoinflammatory loop with macrophages resulting in cytokine release syndrome and severe systemic inflammation with end organ dysfunction.