Immunosenescence, Inflammaging, and Lung Senescence in Asthma in the Elderly

Abstract

Prevalence of asthma in older adults is growing along with increasing global life expectancy. Due to poor clinical consequences such as high mortality, advancement in understanding the pathophysiology of asthma in older patients has been sought to provide prompt treatment for them. Age-related alterations of functions in the immune system and lung parenchyma occur throughout life. Alterations with advancing age are promoted by various stimuli, including pathobionts, fungi, viruses, pollutants, and damage-associated molecular patterns derived from impaired cells, abandoned cell debris, and senescent cells. Age-related changes in the innate and adaptive immune response, termed immunosenescence, includes impairment of phagocytosis and antigen presentation, enhancement of proinflammatory mediator generation, and production of senescence-associated secretory phenotype. Immnunosenescence could promote inflammaging (chronic low-grade inflammation) and contribute to late-onset adult asthma and asthma in the elderly, along with age-related pulmonary disease, such as chronic obstructive pulmonary disease and pulmonary fibrosis, due to lung parenchyma senescence. Aged patients with asthma exhibit local and systemic type 2 and non-type 2 inflammation, associated with clinical manifestations. Here, we discuss immunosenescence's contribution to the immune response and the combination of type 2 inflammation and inflammaging in asthma in the elderly and present an overview of age-related features in the immune system and lung structure.

Keywords: asthma; elderly; eosinophil; immunosenescence; inflammaging; neutrophil; senescence.

Figure 1

Concept of integrated inflammaging type-2 inflammation in asthma in the elderly. Diverse extrinsic and intrinsic stresses can upregulate various pathways and subsequently activate immune cells and airway epithelial cells or damage these cells. Induction of immune cells senescence, mitochondrial dysregulation, oxidative stress, and damage-associated molecular patterns (DAMPs) in response to these stresses contribute to immunosenescence, accompanied with lung parenchyma senescence. Cell senescence is also initiated by the immune response and produces the senescence-associated secretory phenotypes (SASPs), which lead to immunosenescence progression. Age-related alterations in the immune system promote inflammaging, which is influenced by lung parenchyma aging. Inflammaging may modify type-2 inflammation and promote mixed inflammation with type-1 and -2 immune response in elderly patients with asthma, leading to specific clinical manifestations.

Figure 2

Conspectus of inflammaging in asthma in the elderly. Aged bronchial epithelial cells increase and deteriorate mucociliary function and mucoid production, resulting in increased susceptibility to infection and noxious pathogens. Immunosenescence leads to inflammaging progression accompanied with enhanced type-2 inflammation. Senescent phagocytes play a role by affecting pathogens and influencing the production of proinflammatory cytokines, chemokines, and SASP with the decline of TLRs. Senescent and exhausted T cells generate those mediators and SASP. Type-2 cytokines produced by Th2 cells and ILC2s increase in recognition of IL-33, IL-25, and TSLP, though the effect of aged Th2 cells remains to be elucidated. Th17 cells increase in elderly patients with asthma due to increase in IL-6 and TGF-β. Increase in IL-17 contributes to immune response in circulating neutrophils due to rTEM on distant vascular endothelium, the form of which is modified by dysbiosis, accompanied with mast cells in aged humans. Senescent neutrophils easily promote NETs. Neutrophils activated by IL-8 and LPS through the release of LTB4 and PAF can enhance the accumulation of eosinophils through TMM, which is enhanced in severe asthma. Accumulated eosinophils and neutrophils corporate to promote airway inflammation and remodeling, leading to a stronger decline in pulmonary function. Type-2 inflammation with inflammaging could lead to the progression of unstable asthma conditions.