Aging and asthma: pathophysiological mechanisms

Asthma is common in all age groups and emerges as significant problem for elderly people (1–5). It is often underperceived, underdiagnosed, and undertreated (6, 7). There are several reports of acute, severe asthma in this age group (8, 9). From the clinical perspective, asthma in an elderly person may be difficult to diagnose because of lower sensitivity to symptoms, nonspecific presentation, and the frequently confounding effect of comorbidity. The latter can, in turn, increase the severity of the clinical picture and make treatment more difficult (10, 11). Other important issues concerning the treatment of asthma in the elderly relate to changes in pharmacokinetics, a higher risk of untoward effects, and poorer compliance. An important aspect of this phenomenon is the limited ability of this age group to use inhalers (12). Polypharmacy is inherent in treating older people and accurate drug histories are essential for identifying those in whom concurrent treatment may induce bronchospasm or may interact with asthma medication. Morphologic and physiologic abnormalities have been observed in the aging human lung (13). A decrease in mucociliary function, dilatation of the air spaces, loss of elastic recoil, loss of elastin fibers, diminished diffusion capacity, and evidence of low grade inflammation of the respiratory tract have all been found in elderly people. These changes have superimposed effects on those induced by the asthma-related chronic inflammation of the airways, and cannot be without effect on the evolution of the remodeling process in the airways (14–21). Aging also has a profound effect on the immune system and cells that have a regulatory role in asthma (22). A decline in humoral immunity has been documented in older people (23). Advanced age has also been shown to be associated with an increased vulnerability to infectious agents (24). These specific events may depend on many age-related changes in various organ systems, such as environmental factors, nutritional status, and the frequent presence of multiple chronic debilitating diseases. However, it is still unclear whether, and to what extent, immunosenescence plays a role in the increased susceptibility to inflammatory agents involved in the pathogenesis of asthma, and in the dynamics of development of structural airway changes. Aging is associated with a decline in immune function in humans and animals. The primary defects appear to reside in the T-cell compartment (23). Progressive atrophy of the thymus gland occurs with aging, and thymic hormone activity in serum is undetectable in people over 60 years of age (22, 25, 26). Although the thymus involutes, there is little or no decline in blood T cells in older individuals (27, 28). However, the ability to generate a cell-mediated immune response has been shown to diminish with age (29, 30). T cells from aged donors have an impaired proliferative response whether they are cultured with accessory cells from young or aged donors, leading to a progressive reduction in antigen-driven lymphocyte proliferation. There are several potential causes involved in such a phenomenon. In aged individuals, the sum of CD4+ lymphocytes and CD8+ lymphocytes substantially exceeds the total number of CD3+ lymphocytes. This finding, which differs from what is observed in young individuals, implies that either CD4+ or CD8+ may be CD3−, or that CD3+ cells can be, at the same time, CD4+ and CD8+. This latter phenotype is consistent with a thymocyte-like pattern of surface marker expression, whereas the former is similar to immature cord blood cells that can be CD8+ or CD3-. It seems, therefore, that aging is associated with an expansion of the pool of undifferentiated lymphocytes. There is a potential explanation for these findings: as the thymus involutes with aging, T cells cannot undergo thymic differentiation, so they maintain a less mature phenotype that is responsible for the reduced responsiveness of T lymphocytes to inflammatory and infectious factors (Fig. 1). The potential effects of aging on lymphocyte differentiation. Thymic involution in elderly subjects leads to a decrease of differentiated and naive T cells, without major changes of memory T cells. In addition, several important T cell functions appear to be lost in aging lungs. After influenza infection, aged mice have prolonged viral shedding that is presumably due to lower anti-influenza class I-restricted CD8+ cytotoxic T lymphocyte (CTL) activity. An age-related delay in recovery from influenza virus infection has also been shown (31). Several mechanisms seem to be involved, including decreased anti-influenza class II-restricted CTL activity, pulmonary interferon(IFN)-gamma levels, and serum neutralizing antibodies. Taken together, these findings suggest a loss of CD4+ T cell function with aging, and may explain the progressive loss of immunoallergic reactions (such as in the lungs and the skin) found in elderly people. Again, an animal model has been used to study this phenomenon. Sensitized Brown Norway rats are known to develop eosinophilic bronchial inflammation and airway hyperresponsiveness after antigen exposure. However, in the past it has been shown that sensitized aged rats of the same strain fail to develop such allergic inflammation. This animal model has been used to understand the mechanisms underlying the phenomenon, showing decreased expression of Th2-type cytokine transcripts in aged animals. The age-associated changes in cytokine profile were found to be not restricted to bronchoalveolar lavage (BAL) cells, but a general feature of lymphocytes, as shown by examination of popliteal lymph nodes draining the site of sensitization. These findings suggest that decreased allergic inflammation in aged animals can be attributed to age-dependent impairment of Th2 generation in response to antigen (23). In contrast to the aforementioned studies, recent evidence has also suggested possible active involvement of T lymphocytes in the airways of elderly people. Meyer et al. performed BAL on discontinuous age groups (20–36, 45–55, and 65–78-year-olds) of clinically normal volunteer subjects. They measured immunoglobulins (IgG, IgA, IgM), albumin, and interleukins (IL-6 and IL-10). Bronchoalveolar cell profiles, cell surface antigen expression, and superoxide anion production were also measured. A significant increase in total cell concentration, neutrophils, and BAL immunoglobulin content was observed in the oldest age group compared with the youngest age group. Mean lymphocyte subset ratios (CD4+/CD8+) were significantly increased in blood, and to a greater degree in BAL, for the oldest vs youngest age groups. Similarly, BAL-derived cells displayed significantly increased phorbolmyristate acetate-stimulated release of superoxide anion for the oldest vs the youngest subject group, and mean BAL IL-6 concentrations were significantly elevated in the oldest age group compared to the youngest. Taken together these observations suggest that altered inflammatory cell profiles and low-grade inflammation exist in the lower respiratory tracts of many asymptomatic, clinically normal volunteers of advanced age. However, it is still unknown whether such age-related low-grade inflammation represents a background that favors development of exaggerated immune and inflammatory responses in elderly people affected by asthma or other chronic inflammatory diseases of the airways. The regulation of tissue mast cell numbers depends on both the rate of production of mast cell precursors from bone marrow and the length of survival of mature mast cells within tissues. In experiments with aged mice, isolated peritoneal mast cells showed a considerable decrease in Fc-gamma-RIIB/III expression and higher degranulation, as compared to peritoneal mast cells derived from young mice. Basophil-bound IgE increased rapidly and reached adult levels during childhood in atopic individuals, while it gradually increased with advancing age in parallel with serum IgE in normal controls (33). The annual change in basophil count has been directly related to change in the methacholine dose–response slope, suggesting that inflammatory mechanisms involving the basophil may be important for development of increasing nonspecific airway responsiveness during aging (34). While defects in acquired humoral and T-cell-mediated immunity may exist, increased susceptibility to infection in the elderly is more likely related to defects in the constitutive functioning of macrophages and granulocytes (35). Alveolar macrophages are the resident cellular defenders of the lung and provide first-line defence for smaller bronchioles and alveolar spaces. In the majority of studies, mononuclear phagocyte chemotaxis, adherence, and phagocytosis appear to be unaffected by aging. However, a decrease in monocyte phagocytosis of glutaraldehyde-treated red blood cells and of Candida albicans was seen when aged donors were compared with younger ones (36). Alveolar macrophages can also participate in specific immune responses, and may function as accessory cells. However, although macrophages can process and present antigen, express major histocompatibility complex (MHC), and elaborate appropriate mediators, these cells bind resting T cells rather poorly and are weak antigen-presenting cells (37, 38). It appears that by combining macrophages with nonadherent leukocytes from donors of various ages and assessing proliferation, the antigen processing and presentation to T cells is not diminished by aging (39). No difference was found in the normal proliferative response of T cells from young donors if they were cultured with adherent cells from aged donors or from young donors. Therefore, mononuclear phagocytes from normal donors are not impaired in their ability to facilitate the proliferative response to T cells. Polymorphonuclear neutrophils have long been regarded as a terminal differentiated cell, incapable of protein synthesis, and fulfilling a role in inflammation via phagocytosis. Neutrophils can release oxygen free radicals and cytokines such as IL-1, tumor necrosis factor(TNF)-α and IL-6 (40–42). They also release a wide variety of enzymes including elastase (43) which, besides degrading elastin and other extracellular matrix (ECM) proteins (44), may affect bronchial epithelium (45), activate fibroblasts, and stimulate mucous gland secretion. Neutrophils have been involved in acute and chronic injury of the lung. Many neutrophil functions appear to be altered in the elderly, including chemotaxis (46, 47) and reduced CD16 expression and phagocytosis (48). In addition, a progressive decrease in superoxide anion production associated with a decline of opsonized particles has been found (49). We recently evaluated induced sputum samples from elderly asthmatic subjects and found that the number of neutrophils significantly correlated with the levels of both active and total elastase, which were both higher than the levels measured in control nonasthmatic people. The increased ability of neutrophils isolated from elderly asthmatics to produce increased amount of elastase may play an important role in the pathogenesis of loss of elastic recoil and of elastin fibers in the aging lung. Recently the number of neutrophils in the lower respiratory tract has been evaluated in healthy, clinically normal individuals of more advanced age. Using BAL in three discontinuous age groups (group I, 19–36 years; group II, 45–55 years; group III, 64–83 years), it was found that neutrophils, IL-8, and neutrophil elastase complexed to alpha1-antiprotease were significantly elevated in the oldest vs the youngest age group. This cross-sectional investigation suggests that low-grade inflammation exists in the air spaces of many clinically normal, older people (50) (Fig. 2). The figure shows that the number of neutrophils and levels of interleukin-8 are significantly elevated in the oldest vs youngest age group (51). Evidence obtained using an animal model has shown that aging is associated with a defect in eosinophil accumulation in sites exposed to antigen, probably because of an age-dependent alteration in T cells, leading to reduced IL-5 production (52). For many years bronchial epithelial cells were considered to act mainly as a barrier, participating in mucociliary clearance, and the removal of noxious agents. More recently, epithelial cells were found to participate in inflammatory reactions also by releasing eicosanoids, peptidases, matrix proteins, cytokines and nitric oxide (NO), as well as by performing an immune function through their capacity to express human leukocyte antigen HLA-DR and to present antigen. There are many studies evaluating morphological and functional abnormalities of bronchial epithelial cells in elderly asthmatic people. However, a prominent feature seems to be a progressive reduction in mucociliary clearance rate in the healthy aged population, compared with that found in the young (53). Although not yet explored, it is likely that this specific function is further reduced in elderly people suffering from chronic inflammation of the airways. If so, this may lead to increased accumulation of mucus in the airways, leading to reduced airway baseline caliber, and to greater susceptibility to viral and/or bacterial infections. is a of immune function that to the increased susceptibility to infection in the elderly during aging are complex and of remodeling or altered rather than immune The age-related changes within the T cell the of the immune system that and However, there is no evidence to that these changes are directly to the common seen in the aged (24). the of defence that the T and cell responses, also changes with age (48). of the immune effects associated with aging are to changes of the such as in the of cell and cellular tract are a leading of in years or older in both and many of immunity with advancing the elderly may be more to respiratory if they appear to be in A decline in the ability of to an response to specific such as the influenza virus or is to be an important in increasing susceptibility to respiratory tract infection with advancing age. However, abnormalities in immunity may also to increased susceptibility to respiratory and have been poorly in the elderly serum levels of inflammatory are of aging either of regulatory or of an on or infection There is evidence that advanced age is associated with of Several studies have shown age-related changes in the levels of proteins and factors that response in the airways of elderly asthma has not been to However, on evidence in healthy individuals, can be of the of the immune and of in is a that may the airways of asthmatic people to viral and/or bacterial infections. which also be by changes in bronchial epithelium of elderly may to of the inflammatory response in the airways of asthmatic subjects. The development of an exaggerated inflammatory process in the airways may also be by the increased of neutrophils that the aging lung. This may lead to increased neutrophil and to the release of mediators, such as elastase and free that have the potential to airway and to their it may be suggested that in the elderly low-grade mainly by a the development of more severe clinical asthma (Fig. This explain elderly people with asthma have more severe airway than those with recently acquired of in elderly asthmatic people. may have important in the airways of asthmatic such as increased susceptibility to and neutrophil The of this be the release of and oxygen free leading to airway inflammation and diseases by such as allergic asthma, allergic and allergic atopic in childhood or of less frequent with and to decrease Aging may an in model for the of allergic diseases. age-dependent is IgE levels and IgE production both decline which may explain the age-dependent decline in allergic diseases. The reduction in total IgE levels in aged people may be associated with reduced basophil reports have with age-related changes in the cytokine profile of T cells with nonspecific in a variety of in of functional cytokine responses was found in aged mice to also with age However, if may be in elderly may be a common and can be present in of adult asthma is often associated with an increase in the rate of decline in in (14–21). However, may while lung function In and elderly it is in individuals, to chronic and asthma by of and by response to hyperresponsiveness appears to be associated with an increased rate of decline of lung function and with (34). It is likely that airway remodeling may be responsible for of the functional abnormalities found in elderly asthmatic people. In of may to progressive reduction of the airway baseline levels are by a and It is known that these have in young but little evidence has been as yet for aging lungs. et al. age-related changes in lung and in rats at from to They showed that lung and and that may play important in production during during aging. The of lung and in individuals with asthma is still poorly appears to be normal in with asthma, but is reduced childhood and in those with severe and It is not known whether this a to in to or lungs is known the of the degree of bronchial and the of asthma in of with asthma still have respiratory in adult Although there are no studies in it is that decline in lung function may at a in the of the An increase in the rate of decline in can also during adult in in and elderly a chronic and asthma by of decreased lung shown by which has been shown to change in individuals with chronic pulmonary has recently been shown to with aging in a for functional and structural changes in the lungs this decline appears to be in and in and similar to those with of pulmonary function during a not seem to increase but The decline in with aging is by other factors, such as or levels in the which has been shown to be an risk for impairment in Aging is associated with important changes in turn, lead to a decrease in lung in pulmonary respiratory and airway responsiveness have been in elderly and to the of the asthma phenotype for this age. In age-related changes that may have important the of may be three decrease in of respiratory decrease in lung recoil, and increase in of the (Fig. changes can be three decrease in of respiratory decrease in lung recoil, and increased of the The of the has been shown to be reduced in elderly people as a of age-associated in function The nutritional often seen in the elderly also explain impaired of respiratory et al. showed that and and which are of respiratory significantly correlated with and This study also in the elderly population, normal and were the clinical for of respiratory in the of the and the of the may affect the capacity of the The loss of elastic recoil in the lung is mainly due to structural changes in the elastic of the lungs Aging have been shown to induce a rather than an in the which is more prominent the alveolar spaces. This phenomenon in dilatation of the alveolar similar to so leading to the of issues the aforementioned are from the of air associated with in of and together with changes in the of the related to increased of the to a with age. elastic recoil and of the with age have a profound on lung of the that the airways is responsible for the to with of the airways, in a occurs with increase in which is also by the reduced and the diminished of the respiratory total lung capacity not change capacity to of In addition, diminished elastic recoil for in functional capacity which represents the at which the lung elastic recoil is by the elastic recoil of the The in the that elderly people at higher lung than younger an to respiratory The age-related changes in with of terminal airways, mainly affect the of with to with reduction of the This is of the major factors responsible for diminished oxygen and reduced capacity of the lungs for of the alveolar surface is also to explain reduction in Although difficult with aging, is in of the elderly and control has been shown to in the majority of subjects and may be by reduction in to greater extent, by decreased lung elastic recoil, which the An functional pattern in the elderly is by the development of at lung This is to be to the of the airways, limited by by lung elastic In older elastic recoil is the in the with of airways and hyperresponsiveness is a feature of asthma and a potential risk for the development and of the In the Aging nonspecific airway responsiveness was shown to increase with advancing as suggested by observations the of pulmonary function was shown to the response to suggesting that factors, rather than be responsible for the increased airway responsiveness in this age. the other there is evidence that bronchial not diminish with age An important to the and of is by the of for older as a the age and airway responsiveness to be further Aging has been associated with a reduced acute response to likely attributed to age-related decline in function or loss of with aging The reduced sensitivity to in the elderly has been shown to after for levels The aforementioned changes of aging have a significant on the clinical of asthma in the elderly and to the and treatment of the at this age. are the other factors to the of asthma in the elderly, including of and the reduced responsiveness of to and the of of airway function The of physiologic age-related alteration of lung in the that of asthma are by a complex of multiple of which are yet to be The clinical of asthma is that clinically and to a This pattern is less in the elderly, it to from other diseases such as chronic and of these diseases is the in appropriate to elderly asthma the clinical phenotype of asthma in the elderly is not from that of younger although observations have that elderly asthmatics seem to more severe to when evaluating asthma in the elderly is the of the In this the aged lung is affected by factors, such as and are and the groups are clinically of asthma is associated with the degree of and and these abnormalities can over time, airway and/or changes as well as airway remodeling is a with to people suffering from asthma In many elderly asthmatic is associated with Asthma is common in all age groups and emerges as a significant problem for Morphologic and physiologic abnormalities have been observed in the aging human such as a decreased mucociliary function, dilatation of the air spaces, loss of elastic recoil and of elastin fibers, diminished diffusion capacity, and evidence of low-grade inflammation of the respiratory These changes may their effects those induced by asthma-related chronic inflammation of the airways, and cannot be without the evolution of the remodeling process within the airways. Aging also has a profound effect on the immune system and the cells that have a regulatory role in asthma, such as T lymphocytes, neutrophils and epithelial cells. these changes may be responsible for the development of specific airway responsiveness and reduced responsiveness to Taken together, these observations that asthma in the elderly is a complex phenomenon because the in lung function the at this age. This the that a functional of asthma in the elderly be to and to provide the