Aging and the microbiome: implications for asthma in the elderly?

Abstract

In the elderly, asthma remains a clinical challenge. Recognition, diagnosis and treatment are all complex. Influenced by processes, such as aging, the identification of an ‘asthma microbiome’ presents a further challenge. This editorial discusses aging and the ‘asthma microbiome’ separately and then evaluates their potential relationship. Current evidence suggests that differences in the airway microbiome are associated with asthma, however, whether such associations are comparable or different for late-onset disease is yet to be established. Microbes are now linked to fundamental physiological processes, such as aging, based on data from invertebrate systems. This will likely confer implications for asthma in the elderly, and it is crucial that such emerging scientific data are considered in the context of aging, asthma and late-onset disease.

Keywords:

• asthma
• elderly
• immunosenescence
• inflammation
• late-onset
• microbiome

In the older population, asthma remains challenging. Its recognition, diagnosis and treatment are complex, and challenges exist in performing and interpreting pulmonary function testing. Combined with specific therapeutic issues, asthma in the elderly represents a disease entity further affected by the physiological aging process that we review elsewhere [1,2].

Our emerging understanding of the human airway ‘microbiome’ has presented new challenges particularly for chronic inflammatory diseases, such as asthma. Interestingly, the number of organisms outweighs number of host cells, and microbial genes encode antigens that can interact with the host immune system [3].

Although our fledgling understanding of these immunological interactions between host and microbiome grows, data continue to emerge in pulmonary disease, such as asthma. The microbiome is to date largely bacterial and, in vivo maintains immune homeostasis. In this context, renewed focus is necessary particularly in the way aberrant responses contribute to airway inflammation in disease, such as asthma.

Asthma may be diagnosed at any age, and various clinical or molecular phenotypes are described. Critically, aging influences the dynamic between immune function, environment and microbe to affect clinical outcome. Attention to date has focused on early life, and hence this editorial aims to draw attention to asthma in the elderly and the effect of emerging asthma microbiome data on the aging process, immunosenescence and our understanding of this disease subtype.

Immunosenescence & inflammaging

Immunosenescence reflects age-related declines in immune function at cellular and serological levels [2,4]. Specific responses to foreign and self-antigens ensue with an increased susceptibility of the elderly to infectious disease, poorer vaccine response and increased prevalence of cancer, autoimmune and other chronic disease. Innate and especially adaptive responses are both weakened [5]. Three theories are proposed to account for immunosenescence: autoimmunity, immunodeficiency and immune-dysregulation. It is most likely that a combination of these occurs.

A chronic state of low-grade inflammation also accompanies physiological aging [6]. This is characterized by increased levels of proinflammatory cytokines, including TNF-α, IL-1 and IL-6. This ‘inflamm-aging’ state is implicated in the pathogenesis of several inflammatory diseases, including atherosclerosis, diabetes and Alzheimer’s [7]. However, some individuals advance in age without health problems, so-called healthy aging in which this proinflammatory state is somewhat inhibited by cytokines, such as IL-10 [5]. Undoubtedly, genetic and environmental factors may also play key roles. The effects of immunosenescence and inflamm-aging on asthma in the elderly have been recognized but remain underexplored; however, association with a changing (and aging) microbiome is yet to be considered [2,8].

The airway microbiome & asthma

Microbes influence both health and disease making their interaction critical for therapeutics [9]. Advancing molecular-based techniques, including 16S rRNA sequencing, whole microbe genomic sequencing and meta-genomics, have revolutionized our practice of microbiology [10]. Microbial species richness, community evenness and diversity have been associated with variations in both normal and diseased states; however, direct causality is yet to be established.

Work on the gastrointestinal (GI) microbiome led the field and has progressed beyond broad associations [11]. Our understanding of the airway microbiome lagged behind because of preconceived notions of a ‘sterile airway’ but also challenges with sampling lower airways and avoiding oropharyngeal contamination. It has, however, become clear that abnormalities in bacterial load, composition and structure occur in airway diseases, such as cystic fibrosis (CF), chronic obstructive airways disease (COPD) and asthma [12].

Initial work on asthma microbiology focused on single causative agents such as M. or C. pneumonia; however, we know that a far more complex microbial community exists. Hilty et al. produced the seminal study identifying disordered bacterial airway communities in asthma and COPD illustrating members of the Proteobacteria phylum (in particular Haemophilus) at higher prevalence in patients with COPD and asthma. Members of the Bacteriodes phylum (such as Prevotella) were predominant in healthy subjects [13]. The study assessed upper and lower airway specimens separately and illustrated that airways were not sterile and that a particular microbiome was a characteristic of airway disease.

A larger study using bronchial brushings subsequently found consistent phyla but further correlated the severity of airway hyper-responsiveness with bacterial diversity in asthmatic airways. Certain taxa related to this clinical finding included Proteobacteria, Pseudomonadaceae, Enterobacteriaceae, Burkholderiaceae and Neisseriaceae [14]. Subsequent analysis of induced sputum from steroid naïve asthmatics compared with healthy subjects further confirmed greater bacterial diversity and higher proportions of Proteobacteria [15]. Several identified genera that demonstrate functional relevance to asthma include Sphingomonadaceae, which incite natural killer cell responses, Nitrosomonas possessing NO reductases, macrolide-susceptible Oxalobacter and Comamonadaceae capable of steroid metabolism [14]. This latter group has been further evaluated in corticosteroid-resistant asthma suggestive of a potential relationship among therapy, infection and disease within certain asthmatic phenotypes [16]. In severe asthma, asthma control and sputum neutrophilia are associated with Proteobacteria, whereas elevated BMI is linked to Bacteriodes [17].

Besides bacteria, other members of the airway microbiome with potentially greater allergenic potential, such as fungi, are yet to be comprehensively examined. This is due to a lack of fungal reference sequence databases; however, increased fungal abundance is described in asthma, and mechanisms other than persistent allergen are touted including the expression of fungal lipooxygenases with homology to human 5-lipooxygenase [18–20].

It is likely that microbes influence asthma in particular phenotypes including neutrophil predominant and treatment-resistant asthma, both sharing characteristics of asthma in the elderly [14,17].

The association between aging & the microbiome

Evidence presented to date illustrates key roles for the microbiome in asthma; however, emerging data illustrate that microbes even influence central physiological processes, such as aging. This may have implications for asthma in the elderly. Key experiments originate in invertebrate systems, such as Drosophila melanogaster and Caenorhabditis elegans. Despite their limitations, such models determine causality from microbe exposure, which otherwise are expensive and technically challenging in mammalian settings [21]. Genes modulating the ‘healthy aging’ process have been uncovered and include the IGF-1 signaling pathway, target of rapamycin (TOR) and AMP-activated protein kinase (AMPK). Major mechanisms to explain how the microbiome influences these pathways and affects aging includes direct interspecies signaling, manipulation of microbial metabolites, deprived nutrient conditions and remodeling of host metabolic networks. These effects occur through influences on host transcriptional pathways and cross-species regulation of RNA and microRNAs [8]. Although it is premature to suggest how such invertebrate-derived results will influence our understanding of mammalian aging, it is fair to speculate the effect it will have on age-related disease phenomena, such as late-onset asthma. Coupled with effects of immunosenescence and inflamm-aging, the microbiome in late-onset disease is likely to influence the clinical phenotype observed in practice. Factors associated with aging, such as immune and inflammatory change, combined with the lifelong effects of antimicrobial, allergic and infective exposures places the microbiome found in the elderly asthmatic likely unique when compared with other asthma phenotypes.

‘Microbiomic’ implications for asthma in the elderly?

As we age, our microbial composition changes and effects on immunity vary. From infancy, decreased microbiome diversity increases allergic tendencies compared with an increased burden of Proteobacteria in adult asthma [22]. No information, however, is currently accessible addressing the microbiome of elderly asthmatics (>65 years). This is imperative because increases of knowledge in this field will influence future treatment approaches. Key mechanisms by which the asthmatic microbiome, particularly in the elderly, are likely affected, include lifelong antibiotic use, a relative state of immunodeficiency, airway neutrophilia and interactions with the gut microbiome. Manipulation of microbial composition and functional derivatives with antibiotics or vaccines may represent novel approaches to asthma care. Asthma remains a heterogeneous disease with many phenotypes all with likely influences from the microbiome that are potentially different.

Although the microbiome has been investigated in neutrophil-dominant and treatment-resistant asthma, it is similarly likely to be important in elderly asthma, which share some of the characteristics of the previous studied populations. The airway microbiome is likely further influenced by immunosenescence, inflamm-aging and medication in the older patient, which contributes to misdiagnosis and the lack of classical asthmatic features.

Animal models, in vitro data and epidemiological studies suggest relationships between the microbiome and development of allergic disease; however, transferring such findings to interventions are difficult. Despite this, attempts at interventions targeting initial childhood colonization are unproven, and consequently a lack of incentive exists for similar approaches in later life. Asthma in the elderly is likely less allergic, however, perhaps provides a better model to understand relationships between immune cross talk, the host and microbe.

Age-related changes to the GI microbiome influence childhood asthma. As one ages, however, eating habits and cultural differences add complexity [23]. The largest elderly microbiome study to date originates from Ireland [24]. The frailest older people harbor similar intestinal microbial communities driven by diets high in fat and lacking fiber. Declines in microbial make-up subsequently underlie ill health as one ages; however, this relationship may be applicable conversely: an individual’s health and immune state affects the microbiome. If this mutually interdependent relationship is true and the microbiome is driven by eating habits, what are the pulmonary consequences? Could this promote asthma in the elderly? What influence do medications have? What are the effects of living environments or infections in older individuals? Most importantly is the undetermined effect of immunosenescence on interindividual airway microbiome variability as one ages and its relationship with onset of airway hyper-reactivity. The effect of age-related changes in gut microbiota promotes imbalance that in turn affects immunosenescence and inflamm-aging, two concepts that have implications for asthma in the elderly.

What remains unclear is whether interindividual microbiome variation mediates inflammation and pathologic airway changes directly or indirectly through underlying systemic differences in immune function. The concept of a ‘common mucosal system’ has, therefore, been proposed because variations in gut microbiome development during early life may drive systemic immune differences. Could the airway and gut both be a part of the same continual mucosal spectrum? Additional considerations important for the older asthmatic include immunological and infective effects and the role of comorbidities/polypharmacy complicating the inflammatory milieu. What does remain clear, however, is that there is much to be learned about the asthma microbiome and its association with the physiological process of aging.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.