Introduction
Asthma is a chronic and complex pulmonary inflammation disease which is characterized by aberrant immune responses to allergen, reversible airflow obstruction, and airway hyper-responsiveness (AHR). Although bronchodilators and inhaled/systemic corticosteroids are highly effective in most asthma patients, approximately 5-10% asthma patients are still steroid-refractory which always have lower lung function and higher mortality [1, 2]. Classical ”allergic constitution” or ”airway inflammation” cannot fully explain the occurrence and development of asthma. Thus, accumulating studies are attempted to further elucidate the inner pathogenesis of asthma and identify novel therapeutic targets.
Intriguingly, asthma is common among older adults (age over 65 years) which is usually more severe, with little opportunities of remission [3]. Accumulative studies have demonstrated the involvement of aging in the parthenogenesis of chronic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary diseases (COPD). As is known that the pathological changes in asthma resemble COPD, such as airway remodeling, chronic inflammation and decreased lung function [4, 5]. It is feasible to speculate the possible involvement of aging in the development of asthma. Indeed, some valuable evidences have implicated that aging is a vital dangerous factor for the development of asthma [6]. Aging-related changes have also been found in structural cells and immune cells of asthma patients. Of particular note is that the hallmarks of aging such as telomere attrition, epigenetic alterations, loss of proteostasis, and altered intercellular communication have also been detected in asthma patients [7]. Besides, aging can affects the asthma severity along with its diagnosis and management which is significant for the treatment of asthma [6]. The aging of different targeted cells can also contribute to the pathobiology of asthma, including airway inflammation, airway remodeling and decreased lung function [8]. Furthermore, it has been confirmed that anti-aging strategies can improve pathological processes such as airway inflammation and airway remodeling in asthma patients [9].
Although more and more undeniable studies have evidenced the association between aging and asthma. It is still obscure about the role of aging and the mechanism
behind differential expression of aging-related genes remains unknown. A serious of recent researches have confirmed that epigenetic mechanisms are involved in the regulation of the expression of aging-related gene [10, 11]. Epigenetic mechanisms containing DNAm, microRNAs expression and histone modifications could regulate the transcription activities of target genes without alteration of nucleotide sequence. In particularly, DNAm is the most deeply studied epigenetic regulation, which have been proven to play a crucial role in the regulation of aging-related genes [12]. Specifically, it has been verified that cytosine methylation at the CpG site affected multiple regulatory mechanisms of aging-related genes during transcription [13, 14] and further participated in aging-related disease such as asthma and COPD [15-17]. However, there is still no definitive literature on the DNAm variations of aging-related genes in asthma patients.
Our previous study screened and evaluated the differentially mRNA expression and altered methylation levels of 9 aging-related genes (AREG, ATG3, E2F1, FOXO3, HDAC1, MMP2, NUF2, TGFB1and TP53) in COPD patients [18]. It is found that DNAm was involved in regulating the expression of 9 aging-related genes in peripheral venous blood of COPD patients. Besides, the methylation level of certain special CpG sites was associated with the incidence and severity of COPD [18]. In this study, we further aim to probe the potential involvement of these previous screened 9 aging-related genes in the parthenogenesis of asthma. Firstly, we inspected the changes in DNAm and mRNA expression of the 9 aging-related genes in peripheral venous blood of HCs and asthmatic patients. Then, we analyzed the correlation between DMSs and clinical indicators in asthmatic patients. Finally, we assessed the feasibility of the candidate CpG sites as biomarkers for asthma.