Cellular senescence is increased in airway smooth muscle cells of elderly persons with asthma

Abstract

Senescent cells can drive age-related tissue dysfunction partially via a senescence-associated secretory phenotype (SASP) involving pro-inflammatory and pro-fibrotic factors. Cellular senescence has been associated with a structural and functional decline during normal lung aging and age-related diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Asthma in the elderly (AIE) represents a major healthcare burden. AIE is associated with bronchial airway hyperresponsiveness and remodeling, which involves increased cell proliferation and higher rates of fibrosis, and resistant to standard therapy. Airway smooth muscle (ASM) cells play a major role in asthma such as remodeling via modulation of inflammation and the extracellular matrix (ECM) environment. Whether senescent ASM accumulate in AIE and contribute to airway structural or functional changes is unknown. Lung tissues from elderly asthmatics showed greater airway fibrosis compared to age-matched non-asthmatics and young age controls. Isolated ASM from elderly asthmatics showed increased expression of multiple senescent markers including phospho-p53, p21, telomere-associated foci (TAF), as well as multiple SASP components. Senescence and SASP components were also increased with aging per se. These data highlight the presence of cellular senescence in AIE that may contribute to airway remodeling.

Aging-Related Mechanisms Contribute to Corticosteroid Insensitivity in Elderly Asthma

“…While asthma commonly affects conducting airways, airway dysfunction in elderly asthmatics is more likely to also involve peripheral airways [ 58 ]. Using impulse oscillometry (IOS), a forced oscillation technique that more accurately distinguishes the origin of lung resistance between large airways and small airways, a recent study showed that elderly asthmatics had significantly higher resistance in both large and small airways than younger asthmatics [ 59 ]. Similar findings are observed in middle-aged 9-month-old mice, who had greater airway inflammation and AHR in response to acute house dust mite challenge than younger 3-month-old mice [ 60 ].…”

“…Similar findings are observed in middle-aged 9-month-old mice, who had greater airway inflammation and AHR in response to acute house dust mite challenge than younger 3-month-old mice [ 60 ]. In regard to airway thickening and remodeling, airway wall thickness is found to be decreased with age [ 61 , 62 ]; however, elderly asthmatics were observed to have thicker airway walls compared to nonelderly asthmatics [ 59 ]. Additionally, elderly asthmatics have higher sputum levels of pentosidine, a collagen cross-linker, than younger asthmatics [ 63 ].…”

“…Increased senescence is also observed in asthmatic bronchial fibroblasts, which exhibit lower DNA synthesis with cell passage and in vitro lifespan than healthy controls [ 58 ]. Asthmatic ASM isolated from aged individuals has increased expression levels of multiple senescence markers and pathways including phospho-p53, p21, telomere-associated foci (TAF), as well as multiple SASP factors (PAI-1, TNFα, MMP1, CCL2) [ 59 ]. In a similar study, human ASM from aged individuals had greater intracellular Ca 2+ response, fibronectin, and collagen III deposition than younger human ASM [ 60 ].…”

Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology

“…Asthma in elderly is generally characterized by an increase in sputum neutrophils, lower airway caliber variability, and air trapping 156 . Lung tissues from elderly asthmatics have an increased expression of multiple senescent markers such as phospho‐p53 and p21, and they show greater airway fibrosis compared with age‐matched elderly persons without asthma and young age controls 157 . In patients with stable and oral corticosteroid (OCS)‐independent asthma, urinary metabotype is characterized by reduced carnitine expression and in those with severe asthma by the carnitine transporter SLC22A5 158 .…”

Editorial: Airway remodeling in asthma—what is new?

“…Upon aging, pulmonary function reduction and residual volume increase are observed, with a more evident decline in pulmonary function in patients suffering from asthma ( 6 ). Aghahi et al reported greater airway fibrosis in older individuals with asthma compared with control groups consisting of young and older individuals ( 7 ). However, thickening of the smooth muscles of airways is not related to the duration of asthma ( 8 , 9 ).…”