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

The innate immune pathway initiates the recognition of pathogens via PRR, such as toll-like receptors (TLRs). TLR activation leads to the generation of proinflammatory cytokines through the activation of NF-κB-dependent cascades, production of type-1 interferons (IFNs), and upregulation of INF-dependent genes, resulting in rapid defense against pathogens and subsequent formation of adaptive T and B cell immune responses [21,22,23,29,30,32,33]. The expression of certain TLRs is depressed in immune cells including monocytes, DCs, and leukocytes in aged humans and macrophages in aged mice. TLR1 expression was decreased in aged human monocytes, leading to the reduction of TLR1/TLR2-mediated production of TNF-α and IL-6 [23,38,39,40]. Neutrophils from older individuals also expressed lower TLR1, which may reduce TLR1-related proinflammatory cytokines [30,41]. Levels of TLR2 or TLR4 expression depend on innate immune cells, showing an increase or no change in neutrophils, a decrease in DCs, and no change in macrophages in older humans [23,30,31,32]. The heterogeneity of age-related changes in TLR2 or TLR4 expression on the immune cell surface is likely involved in the sustained magnitude of their mRNA expression in human whole blood leukocytes (PBMC) independent of aging, essentially involving a basic level of TNF-α in older humans [23,30,31,32].

The function of downstream signals declines with aging after ignition of TLRs, accompanied with a decrease in those receptors. After stimulation via TLR1, neutrophils from older individuals showed reduced activation marker expression, chemokine production, and signaling intermediate phosphorylation compared to neutrophils from younger individuals [30,39].

The function of older murine TLR2 or TLR4 was also impaired regarding TLR-induced cytokine production [23,30,31,32]. The production of TNF-α by TLR2 or TLR4 agonist-stimulated human PBMC was diminished, associated with aging [23,30,31,32]. In contrast to this, TLR agonist-stimulated monocyte-derived DCs, following activation by IL-4 plus GM-CSF, enhanced cytokine production in older humans [30,39]. Transcriptional profiling revealed that peripheral blood mononuclear cells (PBMCs) stimulated by TLR4, TLR7/8, and RIG-I agonists delayed the downstream signaling pathway, especially in IFN-related signaling in older humans [42]. This evidence suggests that aging in humans decreases the capacity of initial responses to environmental stimulation, leading to reduced elimination of pathogens, impaired and prolonged recovery of tissue injury, and inflammation. Consequently, low-grade inflammation persists in older humans.

Neutrophils serve as crucial effector cells that first respond to microbes or DAMPs to protect hosts. The proper initiation of their response can remit infections, suitably resolve inflammation, and prevent chronic inflammation following persistent nonspecific tissue damage, constituted by proper migration, phagocytosis, intracellular destruction through pH change, destruction by reactive oxygen species (ROS) and cytotoxic enzymes, release of cytotoxic ROS, and degranulation of proteinases [43,44,45]. Neutrophils can also burst network-like structures of chromatin filaments coated with histones and granular and cytosolic proteins, referred to as neutrophil extracellular traps (NETs), to grab and kill pathogens more efficiently [46,47].

Studies on neutrophils in aged donors demonstrated a decline of cell properties, particularly regarding innate immunological response [23,30,31,32,41]. Decreased expression of TLR1 in neutrophils in older humans diminished the upregulation of integrin activation markers, such as CD11b and CD18, production of IL-8, and recovery from apoptosis [41]. Neutrophils in healthy older individuals exhibit impairment of chemotaxis, phagocytosis, intracellular erasing, degranulation, generation production of cytokines, and NET [30,31,32,47,48]. Peripheral blood neutrophils were reported to exert less phagocytosis of gram-negative bacteria because of decreased CD16 expression in those cells, which is necessary for Fc-mediated phagocytosis, in healthy older individuals compared to younger individuals [49]. Neutrophils treated with GM-CSF, IL-2, or lipopolysaccharide (LPS) did not remarkably prevent their apoptosis in healthy older individuals compared to younger individuals [50]. This functional deficiency could lead to the insufficient elimination of pathogens in older adults, which could enhance infectious micro-organism colonization of the airways and microbiome population changes [51,52,53,54]. Collaborating with other phagocytes and lymphocytes, impaired neutrophils in older adults could lead to some degree of persistent inflammation, attributed to tissue damage by pathogens.

In contrast to the impaired function of neutrophils, a small study on older patients with mild to moderate asthma reported equal production of LTB4 by GM-CSF-stimulated peripheral blood neutrophils compared to younger individuals [55]. These facts suggest that some specific signaling pathways that initiate the production of proinflammatory mediators are preserved. Neutrophils also maintain an adequate ability to invade from the blood vessels into tissue, including their integrin expression, adhesion to endothelial cells, and migration to inflamed sites [49,56].

Interestingly, a study on the interaction between neutrophils and the inflamed vascular endothelium in aged mice demonstrated that once neutrophils adhered to the vascular endothelium of inflamed tissues, numerous numbers of those attached cells migrated in the reverse direction through the transendothelial layer back to the circulation [57]. Neutrophils that exerted reverse transendothelial migration (rTEM) at the distant inflammatory tissue were also reported to be retained in the lungs of aged mice and to be progressively activated after a while, showing increased expression of CD11b, ICAM-1, neutrophil elastase, CD66α, and CXCR4, and reduced expression of CD62L and CXCR2. The activated appearance of rTEM neutrophils resemble circulating senescent neutrophils in terms of surface expression. Neutrophils morphologically change and express lower CD62L and higher CXCR4, which are considered as senescence, in circulation and migrate back into the bone marrow and are eliminated in daily cycles in mice [58]. Senescent neutrophils were also shown to upregulate several gene pathways, including integrin and leukocyte adhesion, TLR and NOD-like receptor (NLR), and NF-κB signaling pathways, on surface in aged mice, in addition to expressing TLR4, suggesting that neutrophils in the circulation continue to be primed by signals and potentially activated with aging [59]. In aged mice, aged neutrophils highly express an Mb2 integrin under stable conditions and generate more NETs formation in response to LPS, which is a counterpart of TLR4. Additionally, depleted diversity of microbiota reduced senescent neutrophils. Taken together, senescent neutrophils constitutionally receive stimuli in the microbiome milieu and are essentially ready to expand inflammation. These substantial properties might contribute to advancing the pathology in asthma in the elderly because neutrophil counts increase in those patients. Notably, the implications of the evidence obtained on neutrophils in old mice on the pathogenesis of asthma in the elderly needs further study.

The effect of advancing age on eosinophil function is not fully understood. One study reported that IL-5-stimulated blood eosinophils reduced EDN degranulation in older patients with asthma compared to younger patients, while they spontaneously released equal EDN in older patients with asthma between in the older and the younger ones [60]. The equivalent volume of EDN content in older asthma patients compared to the younger suggests that the process of piecemeal degranulation induced by some stimuli was disturbed in the older individuals in that study. However, it is noted that blood eosinophils could be potentially upregulated toward the insufficient level to respond to additional stimulation, particularly IL-5, because these constitutionally predispose to type-2 inflammatory mediators in asthma. This eosinophil condition might resemble exhausted cells, a type of cell senescence, though senescent eosinophils remain not fully understood. Non-specifically stimulated blood eosinophils in older asthmatics also showed diminished production of superoxide anions but exhibited comparable capability of adhesion and migration compared to those in younger individuals. A small ex vivo study on older patients with mild to moderate asthma reported an equal production of LTC4 by GM-CSF-stimulated peripheral blood eosinophils compared to younger individuals [55]. Thus, eosinophils in the elderly patients with asthma seem to conserve most of their functions, except their antipathogen abilities. However, there is no evidence regarding the capacity of releasing tissue injury inducers by eosinophils in response to PAMPs and DAMPs. A study on the comparison between aged and younger adults with asthma regarding EDN and NE level in sputum demonstrated that sputum EDN levels were equivalent between both groups, whereas sputum NE levels were higher in the aged patients with asthma than in the younger, suggesting that eosinophil ability to be degranulated is preserved, whereas that of neutrophils is amplified in the aged asthma patients [61]. Further studies are needed to elucidate the alteration of eosinophils in elderly patients with asthma.

DCs act as novel antigen-presenting cells to connect between innate and adaptive immunity. The functions of DCs are compromised with age in humans, showing restricted capacity to respond to antigens and DAMP through NLR signaling, diminished capacity of antigen phagocyte and presentation, less ability to migrate to lymph nodes, and reduction of proinflammatory cytokines in response to antigens [62,63]. Nevertheless, DCs in aged individuals exhibit enhanced reactivity to self-antigen, such as human DNA and apoptotic cells, through activation of NF-κB, showing increase in IL-6 and IFN-α production by monocyte-derived DCs. Therefore, age-associated changes in DCs might potentially be primed by self-pathogens, leading to the advanced peripheral intolerance and chronic inflammation observed during aging [62].

DCs in aged individuals may affect airway epithelial cells (AECs). DCs from aged individuals chronically produce low magnitude of TNF-α and induce the production of CXCL-10, CCL-20, and CCL-26 by AECs [63] in the ordinary state, attracting T cells, CCR6-expressed AECs, and eosinophils. DCs in aged individuals also produce a disintegrin and metalloproteinase (ADAM), which exhibits degradation of the structural proteins [63]. Age-associated changes in DCs might support the progression of airway inflammation and permeability.

NK cells also present age-associated changes on behavior, including reduction of cytokine secretion and decrease in cytotoxicity on target cells such as damaged cells and senescent cells [64]. This alteration is contributed by a change in the NK cell phenotype, for instance, decrease in CD56⁺ bright cells and increase in CD56⁺ dim cells. NK cells are less capable of producing IFN-γ and express perforin, granzyme, and NK cell cytotoxicity with aging [64,65]. Some NK cells with aging showed a reduced ability to eliminate tumor cells or damaged cells, which is attributed to the expression of the inhibitory receptor KLRG1, particularly in CD56⁺ dim NK cells, and both NKG2A and KLRG1 [64]. Reduction of inflammatory mediator production of NK cells promote a defective innate immune response in older humans. Additionally, restriction of eliminating damaged cells preserves the production of inflammatory cytokine and DAMPs and leads to inflammaging.

Monocyte- and macrophage-altered magnitude of TLRs expression with aging depend on the TLRs, showing reduced expression of TLR1 and upregulation of TLR3 mRNA in old human monocytes and no change of TLR2 and TLR4 upregulation in human macrophages [23,30,32,38,39,40,66]. Reduction of TLRs could lead to diminished production TLR-induced cytokines such as IL-6 and TNF-α by monocytes or macrophages in old people [23,30,32,38,39,40].

Along with aging, macrophages in the lungs of mice were reported to decrease and to exhibit downregulation of pathways involved in the cell cycle but upregulation of certain inflammatory pathways, including substance P, PGE₂, macrophage inhibitory factor, oxidative burst and IL-8, and vascular endothelial growth factor signaling in the transcriptional profile [67]. Lung-resident macrophages impaired phagocytosis and scavenging capacity in old mice [67]. Activated macrophages in the lung were shown to be increased and to poorly respond to further stimulation by IFN-γ in old mice, though those cells released more proinflammatory cytokines in response to mycobacterium tuberculosis infection than those from young mice [68]. Macrophages from old murine lungs reduced production of ATP, accelerated generation of ROS, and decreased antioxidant reflection in response to streptococcus pneumoniae infection [69]. This phenomenon was abolished by improvement of mitochondrial function and reduction of oxidative stress, suggesting pulmonary-resident macrophages impaired mitochondrial function with aging [69].

A decline of thymic activity compromises the T cell compartment, mainly depending on the involution of the thymus [18,26,27]. Thymus involution starts in early life in human subjects, showing that the thymopoietic space is reconstituted with fatty tissue [26,27]. The replacement result in consequences, showing a decrease in greater than 95% of CD4⁺ CD45RO⁺ cells of the thymic output and a 10-fold decrease in TCR diversity in aged humans [73]. However, the naïve T cell compartment is still maintained in humans [26]. The reduction of magnitude of the thymic ability of the peripheral naïve T cell pool is estimated at up to 16% throughout the adult lifetime [26,74].

In aged mice, thymic function rapidly diminishes during adolescence and early adulthood, confirming that new thymic emigrants produced by the thymus of aged mice attenuated the expression of activation markers, their proliferation, TCR function defect, and IL-2 production [20,75].

The naïve T cell compartment maintains its own size, where the naïve cells homeostatically proliferate [26,27]. Along with aging, homeostatic proliferation is impaired by the following processes: (1) depletion of cell compartment size by loss of fibroblastic reticular cell niches, reduction of IL7R gene expression, telomere defect, and cellular senescence; (2) progression of memory cell differentiation by reduced self-renewal and virtual memory T cells, which are cytokine-activated naïve CD8⁺ T cells and are marked in mouse CD8⁺ T cells [26,27]; (3) clonal expansion with some evidence regarding a contraction of the TCR repertoire; and (4) phenotypically central memory T cells infiltration, mainly for CD8⁺ T cells [26,27].

A single-cell RNA sequencing and multidimensional protein analysis to characterize CD4⁺ T cells in mice revealed that exhausted, cytotoxic, and activated regulatory T cells were predominant in old mice, showing pro- and anti-inflammatory attributes [76]. In this study, cytotoxic CD4⁺ T cells were predominantly composed of TH1 and TH17 cells and produced IFN-γ, IL-17, and IL-21.

In contrast to CD4⁺ T cells in mice, maintenance of a naïve CD4⁺ T cells compartment receives sufficient benefit from homeostatic proliferation, partly because this process might be supported by IL-2 through expression of CD25 on CD4⁺ T cells and less epigenetic alteration of CD4⁺ T cells with aging in humans [77]. In contrast to the naïve CD4⁺ T cells, the reduction of circulating naïve CD8⁺ T cells is prominent as a consequence of damage of homeostatic proliferation with aging due to epigenetic changes including dysfunction associated with IL-7 [26,77,78,79]. As a result, naïve T cells decline, and therefore, the TCR repertoire results in contraction. Deterioration of TCR diversity with aging is promoted by other factors, including clonal hematopoiesis, independent of antigen specificity, continuous explosion of antigens causing memory inflation, and T cell senescence due to clonal expansion in humans [80]. T effector memory CD45RA cells (TEMRA cells) present mostly loss of TCR diversity, expand under chronic viral infection, such as cytomegalovirus (CMV), sustain effector functionality, enhance inflammatory mediator production, and exhibit aspects of cellular senescence, including cell cycle arrest, expression of DNA damage foci, and production of the senescence-associated secretory phenotype (SASP) [81,82].

The decrease in the naïve T cells population affected by destruction of homeostatic proliferation reflects on the abundant memory T cells, exhibiting the deteriorated feature of memory function. Failure to maintain quiescence engages advanced differentiation pathways in T cell aging, resulting in a terminal differentiated condition. This transition is likely to alter cell performance without cell senescence. A study on microRNA demonstrated that miR-21^hi-expressed naïve CD4⁺ T cells in old individuals sustained diminishment of several negative regulators of signal pathways and tended to generate inflammatory effector T cells rather than differentiation into memory T cells [83].

There exists a subset of memory CD8⁺ T cells activated by cytokines without experiencing antigen stimulation, named virtual memory T cells. These cells were reported to be accumulated and to present characters like memory T cells in response to exposure to specific antigens in old mice [26,27]. Virtual memory CD8⁺ T cells exhibit high affinity for self-antigens and innate-like effector functions, expressing IL-12R, IL-18R, and IFN-γ, in response to IL-15 in mice; populations of those like virtual memory CD8⁺ T cells in humans accumulate with age and exhibit similar function to those cells in mice [84]. These cells contribute to developing the aspects of cellular senescence in humans and mice [85]. Although differentiation to virtual memory CD8⁺ T cells seems beneficial for innate defense, their loss of proliferative potential results in the disturbance of responses in primary CD8⁺ T cells with aging.

Taken together, based upon age-related alteration in T cell homeostasis, differentiated subsets of memory T cells compromise innate immune response and act with similar properties as senescent cells, leading to chronicity of infection, dysbiosis, and elevation of proinflammatory cytokines, chemokines, and SASP in old people. Although prompt proinflammatory molecules delivered from subsets of memory T cells support the repair of tissue injury, the violent loop between T cell dysfunction, excessive inflammation, and persistence of stimuli by pathogens promote inflammaging in old people.

Cell senescence enhances age-associated dysfunction. Senescent cells irreversibly arrest their growth, while DNA damage response is promoted by induction of telomere shortening or continuous response to various stresses [82,86,87,88]. Shortened telomeres are observed in the homeostatic proliferation of naïve T cells and continuous cell replication of memory T cells [26]. Senescent T cells impair their proliferation induced by TCR stimulation and present low telomerase activity and short telomeres and DNA damage signs including γH2AX foci, apoptosis resistance, and β-galactosidase activity [27]. Additionally, senescent T cells fail to express CD27 and CD28 and activate the expression of KLRG1, a terminal differentiation marker [82].

Though senescent T cells are involved in the progression of age-related disease, such as cardiovascular, metabolic, and neurodegenerative diseases, the mechanism though which these cells modify the pathophysiology of asthma remain poorly understood.

An increase in T helper 17 (TH17) cells has been observed in aged humans and aged mice, with more production of IL-17, a representative proinflammatory cytokine derived from TH17 [78,89]. Difference of TH17 cells from naïve T cells is induced by IL-6 and TGF-β, members of SASP. Increment of these cytokines promoted by age-related change in the immune system might be involved in the increase in TH17 cells with aging. Studies on aged individuals and mice demonstrated that regulatory T cells (Tregs) also increased, of which natural Tregs particularly increased, while induced Tregs were reduced [90,91,92]. Additionally, the TH17/Treg imbalance could be advanced in healthy aged persons [89]. The skew toward TH17 cells in healthy aged individuals might enhance neutrophilic inflammation in asthma in the elderly, as observed with severe neutrophilic asthma. In keeping with this, IL-17 and IL-10 were shown to be increased in the older asthma patients compared to the younger [93]. On the other hand, a study on asthmatics demonstrated that IL-17 amplified the production of SASP cytokines by bronchial fibroblasts, including GM-CSF, TNF-α, IL-1β, and IL-6 [94]. These progressive interactions between CD4+ T cells and proinflammatory cytokines might evolve to inflammaging in aged patients with asthma.

B cells undergo alteration related to senescence [75,95]. In contrast to the maintenance of total T cells percentage, B cells percentage and numbers decrease with aging in humans. Additionally, there is alteration in the distribution of B cell differentiation from naïve to memory B cells with aging. Memory B cells circulating in blood are composed of IgM memory B cells and switched memory B cells. Under B cell senescence, the percentage that switch to memory B cells decrease without change in IgM memory, while the percentage of naive and the subset called double negative (DN) B cells increase. DN B cells are shown as naïve B cells through stimulation of TLRs. Observational studies have demonstrated that DN B cells increase in blood in autoimmune and infectious disease in humans, suggesting that these cells could accumulate in chronic inflammatory disease and are continuously exposed to self-antigens or noxious pathogens [96,97]. Given such evidence, DN B cells are likely a terminal B cell differentiation form with class switch, resulting in the inability to be reactivated by chronic stimuli. Factors other than the alteration in B cells subclass distribution include the decline in the generation of specific protective antibodies and the prolonged survival of plasma cells in older humans [98,99]. The affinity and avidity of antibodies for antigens diminish, likely due to deficiency in the expression of molecules involved in somatic hypermutation (SHM) and Ig class switch recombination (CSR) [100,101] in the germinal center in mice. Evidence on B cell senescence in humans and mice suggests that advancing age compromises B cell differentiation and production of antigen-specific antibodies, leading to impairment of humoral immunity in the elderly.

Memory B cells in aged humans are likely involved in the secretion of SASP, as blood B cells derived from old individuals were reported to highly express TNF-α mRNA. These levels were inversely correlated with serum TNF-α and the expression of activation-induced cytidine deaminase, the enzyme that regulates CSR and SHM in B cells [102]. These complicated functions of B cells might contribute to inflammaging.

Immunosenescence and inflammaging are engaged and sustained by numerous external and internal stimuli, including allergens, PAMPs derived from pathobionts, fungi and viruses, pollutants, the microbiome, DAMPs derived from impaired cells, abandoned cell debris, and senescent cells (Figure 1).

The microbiota are recognized as symbiotic communities of various microbes with an equilibrium between the commensal favorable microbes and the potentially harmful ones in various anatomical locations of the body. Along with aging, heterogeneous microbiota, due to increasing pathobionts and opportunistic proinflammatory bacteria, evolves and compromises the immune system, especially in the intestinal tract [51,124]. The cumulative exposure to pathobionts induces the release of inflammatory mediators from chronically activated immune cells, resulting in inflammaging. There have been studies regarding involvement of the microbiota in inflammaging in old mice [125,126,127]. In old mice, the intestinal mucosa develops higher permeability, and gut substances leak into the blood flow, resulting in an increase in bacterial components in the blood [125,126]. Furthermore, circulating monocytes are activated by bacterial components including LPS and produce proinflammatory cytokines such as TNF-α and IL-6 [125]. Circulating neutrophils can be potentially primed by signals and turn into senescent cells in response to the intestinal microbiota in old mice [60].

Notably, constant and systematic low-grade inflammation promoted by dysbiosis, in turn, possibly promote the increase in pathobionts. Similar to dysbiosis, restriction of the lung microbiome diversity has been observed, associated with aging in addition to advanced severity of lung disease, antibiotics administration, and environmental exposure to air pollution and smoking in adults [51,52,53,54]. Studies on airway microbiota in asthma demonstrated the predominance of certain bacteria, and the differences in the lung microbiota among bronchial inflammation types were observed [127,128,129,130,131,132,133,134] and associated with older adults with asthma [128]. In turn, an impaired immune system with aging has also been shown to affect the lung microbiome [53,54].

Oxidative stress has been recognized as an inducible factor of tissue homeostatic dysfunction, such as premature cell senescence and chronic inflammation with aging. Imbalance of oxidation due to excessive ROS production in relation to the antioxidant capacity results in lipid peroxidation, protein carbonylation, and DNA damage within cells with aging [18]. Intracellular ROS is easily produced in response to endogenous and exogenous stimuli, including mitochondrial metabolism, respiratory burst, and exposure to environmental pollutants, such as cigarette smoke, particulate matter, noxious gases, and O3. Excessive amounts of ROS can be released from activated immune cells under oxidative stress during chronic inflammation, leading to the progression of cell damage and further tissue inflammation in an autocrine and paracrine manner. This aggravated process keeps the cells under stress, activating nucleotide-binding domain, leucine-rich repeat-containing family protein-3, and subsequently producing inflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-18, namely SASP [19,20]. Evidence on oxidative stress demonstrated its contribution to the pathogenesis of asthma and age-related pulmonary disorders [18].

While DAMPs are usually stored within cells as endogenous components, they are released from stressed or damaged cells and dead cells in response to environmental pathogens and injury signals [135]. DAMPs consist of ATP, uric acid, high mobility group box 1 (HMGB-1), S100 calcium-binding protein, histones, DNA, and IL-1 family cytokines. DAMPs activate immune cells and lung-resident cells in autocrine and paracrine manners and are involved in the release of proinflammatory cytokines, accumulation of leukocytes, and allergic airway inflammation in mice [136,137,138]. ATP was reported to induce effector functions of human peripheral blood eosinophils and to be involved in eosinophilic asthma [139,140]. Persistent DAMP stress may promote cell senescence and be involved in immunosenescence and inflammaging [17,18]. Studies on aged mice have demonstrated elevation of HMGB-1 and NALP3 inflammasome—which is activated in response to DAMPs—in old mice [141,142]. Additionally, elimination of the NALP3 gene decreased aged-related inflammation in old mice [142].

Mitochondrial dysfunction exists in most tissues and cell types with aging, including incremented mutation and deletions of mtDNA, accelerated oxidation of constructive and functional proteins of mitochondria, changes of lipid composition of mitochondrial membranes, permeabilization of mitochondrial membranes induced by stress, and defects in electron transport chain complexes (ETC) [18]. Change in mTOR/PGC-1 α/β signaling is observed in senescent epithelial cells of the murine lung [143]. Telomere dysfunction, a cause of cell senescence, promotes abrogation of PGC-1α/ERRα transcriptional programs, reduced expression of ETC genes, decreased ATP, and increased ROS in alveolar macrophages, resulting in an extensive innate immune response [144]. Enhanced production of mitochondrial ROS by CD8⁺ T cell has been associated with advancing age in humans [145]. Mitochondrial dysfunction may contribute to inflammaging [146,147].

Cell senescence is a terminal state of replication of cells in which the irreversible restriction of cell division occurs. Studies on cell senescence demonstrated that various aspects of senescence were observed in diverse cells, including lung structural cells and immune cells. Various stimuli generate senescent cells, involving telomere shortening due to exhausted replication, DNA damage, epigenetic modifications, mitochondrial dysfunction, oxidative stress, cytokines, and lost tumor suppressors (Figure 1) [133]. Senescent cells exhibit long survival ability and resistance to apoptosis. Despite replication arrest, senescent cells preserve their metabolic activity and produce various inflammatory agents specified by cell types, named SASPs, including inflammatory cytokines, chemokines, growth factors, matrix metalloproteinase, and DAMPs. SASPs are recognized as a main contributor of inflammaging and can increase inflammation and remodeling in tissues, susceptibility to infection, angiogenesis, and immune cell proliferation, leading to dilation of tissue repair and regeneration. Involvement of SASPs has been observed in older asthmatics and mice using an allergic airway inflammation model [1,61,75,93,123].

Macrophages and neutrophils in aged individuals show a decline in their phagocytotic capability, including increase in susceptibility to pathogens and reduced production of cytotoxic enzymes and radicals [31,32,33]. This age-related impairment delays pathogen elimination and could contribute to the colonization of alternative pathogens and changes in microbiota in the airway, leading to chronic airway inflammation and remodeling in aged adults with and without asthma [127,128,129,131,132]. However, association between airway or gut bacterial dysbiosis and clinical manifestations in asthma is not fully understood. The bacterial diversity is shown to be inconsistent among observational studies, depending on samples, generations of objective, airway inflammatory phenotype, asthma phenotype and severity, and medication [131]. Proteobacteria was reported to be predominant in the airway of asthmatics compared to healthy individuals [131]. Patients with severe asthma, which is frequently observed in older patients [10,11], enriched an Actinobacteria and a Klebsiella genus member [127]. Adult asthma patients who are C. pneumoniae IgG- and IgA-positive exhibited characteristics manifested by the elderly and in severe asthma, showing higher dose of ICS, more fixed airflow, and air trapping [128].

Patients with neutrophilic asthma have reduced bacterial diversity and have abundant Proteobacteria phylum [127,129,131]. Age-related alteration in airway bacterial diversity can continuously engage a type-1 immune response with neutrophilic inflammation and complementary eosinophilic inflammation in asthma. Even with enhanced neutrophil dysfunction in aged asthma patients, excessive neutrophil infiltration induces redundant mucus secretion, abundant bronchial damage, and bronchial remodeling, accompanied with eosinophilic inflammation. This noxious loop between infiltrated neutrophils and eosinophils and heterogeneous diversity of bacteria in airways may promote chronic low-grade inflammation and SARP production in aged asthmatics.

Despite little evidence on airway bacterial diversity in type-2 inflammatory asthma, one study demonstrated that an increase in eosinophil counts in the airway might be associated with increases in bacterial taxa, such as Actinobacteria phylum [132], Neisseria, Bacteroides, and Rothia species [130]. Notably, latent Chlamydia pneumoniae and Mycoplasma pneumoniae infections have been reported to contribute to the pathogenesis of asthma, showing an increase in IgE, IL-4, IL-5, IL-8, and IFN-γ in asthma [128]. Increases in IL-13 level and neutrophil ratios in BAL were moderately correlated with the abundance of bacteria in BAL in patients with asthma, suggesting involvement of IL-13 in the remodeling of airways under inflammation due to bacteria [134].

Additionally, gut dysbiosis was reported to enhance the allergic airway inflammation in HDM-sensitized old mice with exposure to HDM [148]. Age-related change of the gut microbiome, accompanied with intestinal dysbiosis, could promote higher mucosa permeability and the leakage of bacterial components and SASP into the blood in mice [125,126]. Considering evidence on age-related alteration in airway bacterial diversity in =adults with asthma and aged individuals, in addition to the involvement of gut dysbiosis in inflammation in aged mice, the cumulative exposure to pathobionts induces release of inflammatory mediators from persistently activated immune cells, resulting in unique inflammaging composed of type-1 and -2 inflammations in asthma in the elderly.

As the deteriorated capacity of phagocytes due to aging can promote inflammaging with type-2-high and -low (type-1) inflammations in elderly patients with asthma, the adaptive immunosenescence process observed in elderly individuals could compromise it.

Data sharing not applicable.