Aging-Related Mechanisms Contribute to Corticosteroid Insensitivity in Elderly Asthma

Abstract

Asthma in elderly populations is an increasing health problem that is accompanied by diminished lung function and frequent exacerbations. As potent anti-inflammatory drugs, corticosteroids are commonly used to reduce lung inflammation, improve lung function, and manage disease symptoms in asthma. Although effective for most individuals, older patients are more insensitive to corticosteroids, making it difficult to manage asthma in this population. With the number of individuals older than 65 continuing to increase, it is important to understand the distinct mechanisms that promote corticosteroid insensitivity in the aging lung. In this review, we discuss corticosteroid insensitivity in asthma with an emphasis on mechanisms that contribute to persistent inflammation and diminished lung function in older individuals.

Keywords: aging; airway inflammation; asthma; corticosteroid insensitivity; senescence.

Figure 1

Notable Inflammatory Mechanisms in the Aged Asthmatic Lung. The aged asthmatic airway has persistent airway inflammation that includes increased senescent epithelial and airway smooth muscle (ASM) cells, which secrete pro-inflammatory and pro-fibrotic factors that contribute to airway inflammation. The senescence-associated secretory phenotype (SASP) can include IL-1β, IL-6, IL-8, TNFα, matrix metalloproteinases, and extracellular matrix proteins such as fibronectin and collagen. Among these inflammatory mediators are cytokines that are known to promote T helper (Th) 1 and Th17 cell differentiation and effector functions which can promote neutrophil infiltration and activation. Figure was created using BioRender.com accessed on 7 March 2023.

Figure 2

CD38 NAD⁺ metabolism increases cADPR levels and limits SIRT1 activity. CD38 consumes nicotinamide adenine dinucleotide (NAD⁺) to convert it to cyclic adenosine diphosphate ribose (cADPR) which is used intracellularly to induce calcium (Ca²⁺) release from the sarcoplasmic reticulum, which allows the contraction of airway smooth muscle (ASM). Sirtuin 1 (SIRT1) inhibits NFκB activation; however, this consumption of NAD⁺, the SIRT1 cofactor, limits SIRT1 deacetylase activity, which allows the production of pro-inflammatory mediators via NFκB activation. Figure was created using BioRender.com accessed on 20 March 2023.