Age-related Changes In Lung Function Research Articles

A genomic perspective of the aging human and mouse lung with a focus on immune response and cellular senescence

BackgroundThe aging lung is a complex process and influenced by various stressors, especially airborne pathogens and xenobiotics. Additionally, a lifetime exposure to antigens results in structural and functional changes of the lung; yet an understanding of the cell type specific responses remains elusive. To gain insight into age-related changes in lung function and inflammaging, we evaluated 89 mouse and 414 individual human lung genomic data sets with a focus on genes mechanistically linked to extracellular matrix (ECM), cellular senescence, immune response and pulmonary surfactant, and we interrogated single cell RNAseq data to fingerprint cell type specific changes.ResultsWe identified 117 and 68 mouse and human genes linked to ECM remodeling which accounted for 46% and 27%, respectively of all ECM coding genes. Furthermore, we identified 73 and 31 mouse and human genes linked to cellular senescence, and the majority code for the senescence associated secretory phenotype. These cytokines, chemokines and growth factors are primarily secreted by macrophages and fibroblasts. Single-cell RNAseq data confirmed age-related induced expression of marker genes of macrophages, neutrophil, eosinophil, dendritic, NK-, CD4+, CD8+-T and B cells in the lung of aged mice. This included the highly significant regulation of 20 genes coding for the CD3-T-cell receptor complex. Conversely, for the human lung we primarily observed macrophage and CD4+ and CD8+ marker genes as changed with age. Additionally, we noted an age-related induced expression of marker genes for mouse basal, ciliated, club and goblet cells, while for the human lung, fibroblasts and myofibroblasts marker genes increased with age. Therefore, we infer a change in cellular activity of these cell types with age. Furthermore, we identified predominantly repressed expression of surfactant coding genes, especially the surfactant transporter Abca3, thus highlighting remodeling of surfactant lipids with implications for the production of inflammatory lipids and immune response.ConclusionWe report the genomic landscape of the aging lung and provide a rationale for its growing stiffness and age-related inflammation. By comparing the mouse and human pulmonary genome, we identified important differences between the two species and highlight the complex interplay of inflammaging, senescence and the link to ECM remodeling in healthy but aged individuals.Graphical

Age-related changes in lung function in National Center for Geriatrics and Gerontology Aging Farm C57BL/6N mice.

Aging is an extremely complex biological process, and various models, from unicellular organisms to mammals, have been used in its research. The mouse is the most widely used model for studying human aging and diseases due to its high homology and well-established strategies for genetic manipulation. Despite these advantages, the maximum lifespan of laboratory mice is nearly three years, which makes it time-consuming to obtain animals of the desired age. To avoid this issue and efficiently conduct aging research, the National Center for Geriatrics and Gerontology operates its "Aging Farm", a system that supplies aged animals in response to researchers' requests. In the present study, as part of the Aging Farm project, we examined changes in the physiological functions of the lungs and gene expression in lung tissues of Aging Farm animals as they aged. A decline in the physiological function of the lungs was already apparent before 6 months of age, and it continued until at least 1 year of age. On the other hand, gene expression profiling by RNA sequencing showed small changes in the early stages of aging but more pronounced changes at 12 and 24 months of age than at 3 months of age. Age-related lung tissue changes are considered to be involved in the pathogenesis of various chronic respiratory diseases, and the characterization of animals as they age will ensure the quality of the Aging Farm as a resource for aging research.

The effect of manual therapy and exercise on age-related lung function: study protocol for a randomised controlled trial

BackgroundAgeing is associated with a range of anatomical and physiological changes. Establishing whether a change is part of ‘normal’ ageing or the early signs of disease will affect management strategies. Progressive stiffening of the thoracic spine, decreasing chest wall compliance and declining lung function begin as early as 40 years of age. Administering an intervention such as manual therapy, which has the potential to mitigate age-related changes in the thoracic spine and chest wall, has the potential to improve thoracic compliance and lung function. The aims of this trial are to investigate whether manual therapy can mitigate the effects of age-related changes in lung function and whether there is a difference in effect between different forms of manual therapy.MethodsThe study design is a randomised controlled trial of 372 people with no history of respiratory disease between the ages of 50 and 65 years. The cohort will be divided into three equal groups. The first group will receive a simple 10-min treadmill walking program (Ex). The second group will receive joint mobilisation (MB) of the thoracic spine and ribs plus the same walking program (MB + Ex). The third group will receive joint manipulation (MT) of the thoracic spine and ribs plus the same walking program (MT + Ex). All interventions will be administered a total of six times over a 3-week period. The primary outcome measure is lung function: forced expiratory volume in the 1st second and forced vital capacity. The secondary outcome measures include chest wall expansion (tape measurements) and quality of life measurements (36-Item Short Form Health Survey). Outcome measurements will be taken by blinded assessors on four occasions over a 9-week period. Adverse event data will be gathered at the beginning of each intervention session.DiscussionThis randomised controlled trial is designed to investigate whether manual therapy can mitigate the effects of age-related changes in lung function and whether there is a difference in effect between different forms of manual therapy. This is the first fully powered trial designed to test this hypothesis on healthy males and females in this age range.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR), 12616001317482. Registered on 20 September 2016.

Spirometric impairments, cardiovascular outcomes, and noncardiovascular death in older persons.

In prior work involving older persons, the reported associations of spirometric impairments with cardiovascular outcomes may have been confounded by age-related changes in lung function. Hence, using more age-appropriate spirometric criteria from the Global Lung Function Initiative (GLI), we have evaluated the associations of spirometric impairments, specifically restrictive-pattern and airflow-obstruction, with cardiovascular death (CV-death) and hospitalization (CV-hospitalization). In these analyses, we also evaluated the competing outcome of noncardiovascular death (nonCV-death) and calculated measures of relative and absolute risk. Our study sample was drawn from the Cardiovascular Health Study (CHS), including 4232 community-dwelling white persons aged ≥65 years. Multivariable regression models included the following baseline predictors: GLI-defined restrictive-pattern and airflow-obstruction, age, male gender, obesity, waist circumference, current smoker status, ≥10 pack-years of smoking, hypertension, dyslipidemia, diabetes, and cardiovascular and cerebrovascular disease. Outcomes included adjudicated CV-death, CV-hospitalization, and nonCV-death, ascertained over 10 years of follow-up. Measures of association included hazard ratios (HRs), rate ratios (RRs), and average attributable fraction (AAF), each with 95% confidence intervals. Restrictive-pattern and airflow-obstruction were associated with CV-death (adjusted HRs: 1.57 [1.18, 2.09] and 1.29 [1.04, 1.60]) and with nonCV-death (adjusted HRs: 2.10 [1.63, 2.69] and 1.79 [1.51, 2.12]), respectively. Airflow-obstruction, but not restrictive-pattern, was also associated with CV-hospitalization (adjusted RRs: 1.18 [1.02, 1.36] and 1.20 [0.96, 1.50], respectively). The adjusted AAFs of restrictive-pattern and airflow-obstruction were 1.68% (0.46, 3.06) and 2.35% (0.22, 4.72) for CV-death, and 3.44% (1.97, 5.08) and 7.77% (5.15, 10.60) for nonCV-death, respectively. Assessment of GLI-defined spirometric impairments contributes to broad geriatric risk stratifications for both cardiovascular and non-cardiovascular outcomes.

Clinical Pearls for Treating COPD

Exacerbations of chronic obstructive pulmonary disease (COPD) in the elderly and in the post-acute and long-term care populations “tend to present very atypically,” with symptoms such as dizziness, weakness, chest pain, and confusion, Milta Little, DO, CMD, said at the Annual Conference of AMDA — the Society for Post-Acute and Long-Term Care Medicine. “We need to help our staff understand this,” she said. “We need to make sure that changes are identified and exacerbations are brought to our attention so that we can institute therapy early and prevent decline and hospitalization.” COPD is prevalent in nursing homes, yet there are high rates of exacerbation and high rates of undermedication. In a retrospective analysis of more than 126,000 nursing home residents published 5 years ago, 17% of residents with COPD received no respiratory medication, 60% were not prescribed long-acting bronchodilators or inhaled corticosteroids, and 20% had two or more exacerbations in 1 year (J Manag Care Pharm 2012;18:598–606). “We need to follow the GOLD [Global Initiative for Chronic Obstructive Lung Disease] guidelines for management of COPD,” she urged. The guidelines form the basis of other published COPD guidelines, including the Society’s clinical practice guideline on managing this progressive lung disorder in the post-acute and long-term care setting. The Society recently came out with a pocket version of its COPD guidelines. “We don’t have much data from the long-term care setting, but the data that exist suggest that people generally receive the same benefits [from management per the GOLD guidelines] in those settings and age groups as do younger community-dwelling populations,” she said. Per the GOLD guidelines, regardless of COPD stage, “you want to start with non-pharmacologic interventions” — mainly smoking cessation, exercise, and a “good vaccination protocol,” she said, noting that quality of life and relief from dyspnea are management goals that are just as important as reduced mortality and hospitalization. The optimization of drug therapies is at the heart of management, however. On this front, Dr. Little stressed two key points. First, age-related changes in lung function can limit older residents’ responsiveness to drugs. Second, age can also increase their susceptibility to adverse drug reactions. “Doubling the dose [of a drug] in an older person is not the answer [to decreased responsiveness] because that person is also at higher risk of adverse drug events,” she said. “Combination therapy is better.” For GOLD stages II–IV (moderate to very severe), and particularly in advanced stages, “combining the long-acting muscarinic antagonists [LAMAs] and long-acting beta-agonists (LABAs) can help improve lung function,” she said. LAMAs, or anticholinergics, are the first-line therapy for GOLD stages II–IV. She pointed out that systematic reviews and meta-analyses published in the last 5 to 10 years have shown that, within the main classes of drugs, medications have similar efficacy and safety. Among Dr. Little’s other clinical pearls on pharmacologic management: •Dry powder inhalers require a relatively high force of inspiration to deliver enough drug to the lungs and ward off the risk of systemic side effects, but “interestingly, people with mild to moderate cognitive impairment in long-term care can be educated to use these devices properly.”•Nebulizers are more staff-intensive to use but only require normal tidal respiration and are “really good for those patients who have a lot of functional or cognitive impairment.”•Spacers are sometimes used with metered dose inhalers, but “there is some evidence that even applying the spacer in our older adult population doesn’t really help to deliver the drug any better.”•Inhaled corticosteroids (ICS) should be reserved for more advanced illness and frequent exacerbations. (Short-acting bronchodilators are the mainstay treatment for acute COPD exacerbations.) However, there is evidence that starting an ICS/long-acting beta-agonist combination early on in older patients who have an asthma component to their COPD (asthma–COPD overlap syndrome) decreases death and hospitalization. To identify an asthma component, “look for some reversibility on spirometry and an eosinophilic rather than a neutrophilic type of patient.”•Regarding bronchodilators, “the literature suggests that you have fewer side effects with long-acting beta-agonists than with the short-acting. That’s one reason why you want to move them to the long-acting if they have GOLD stage II or above.” Research is showing, Dr. Little said, that continuous oxygen therapy is better than nocturnal-only for residents with hypoxia at night. “They may be having symptoms during the day that we’re not catching,” she said. “So we may want to encourage … our residents to wear that oxygen continuously.” Christine Kilgore is a freelance writer in Falls Church, VA.

Novel Predictors of Age-Related Changes in Lung Function

Novel Predictors of Age-Related Changes in Lung Function

Ethnic differences in respiratory impairment

ObjectiveSpirometric Z scores by lambda-mu-sigma (LMS) rigorously account for age-related changes in lung function. Recently, the Global Lung Function Initiative (GLI) expanded LMS spirometric Z scores to multiple ethnicities. Hence,...

Effect of coexisting chronic obstructive pulmonary disease and cognitive impairment on health outcomes in older adults.

To determine the extent to which the co-occurrence of chronic obstructive pulmonary disease (COPD) and cognitive impairment affect adverse health outcomes in older adults. Multicenter longitudinal cohort study. California, Pennsylvania, Maryland, and North Carolina. Three thousand ninety-three community-dwelling adults aged 65 and older from the Cardiovascular Health Study. Four hundred thirty-one had chronic obstructive pulmonary disease (COPD) at study baseline. Follow-up began at the second CHS visit and continued for 3years. Spirometric criteria for airflow limitation served to establish COPD using the Lambda-Mu-Sigma method, which accounts for age-related changes in lung function. Cognitive impairment was evaluated using the modified Mini-Mental State Examination and claims data. Outcomes were respiratory-related and all-cause hospitalizations and death. Participants with coexisting COPD and cognitive impairment had the highest rates of respiratory-related (adjusted hazard ratio (aHR)=4.10, 95% confidence interval (CI)=1.86-9.05) and all-cause hospitalizations (aHR=1.34, 95% CI=1.00-1.80) and death (aHR= 2.29, 95% CI=1.18-4.45). In particular, individuals with both conditions had a 48% higher rate of all-cause hospitalizations (adjusted synergy index (aSI)=1.48, 95% CI=0.19-11.31) and a rate of death nearly three times as high (aSI=2.74, 95% CI=0.43-17.32) as the sum of risks for each respective outcome associated with having COPD or cognitive impairment alone. Nevertheless, tests for interaction were not statistically significant for the presence of synergism between the two conditions contributing to each of the outcomes. Therefore, it cannot be concluded that the combined effect of COPD and cognitive impairment is greater than additive. Coexisting COPD and cognitive impairment have an additive effect on respiratory-related and all-cause hospitalizations and death. Optimizing outcomes in older adults with COPD and cognitive impairment will require that how to improve concurrent management of both conditions be determined.

Short-term modulation of the exercise ventilatory response in older men

During exercise with added dead space (DS), the exercise ventilatory response (DeltaV(E)/ DeltaV(CO(2))) is augmented in younger men, via short-term modulation (STM) of the exercise ventilatory response. We hypothesized that STM would be diminished or absent in older men due to age-related changes in respiratory function and ventilatory control. Men were studied at rest and during cycle exercise with and without added DS. DeltaV(E)/ DeltaV(CO(2)) increased progressively with increasing DS volume (p<0.01), such that CO(2) was not retained with added DS versus without. Hence, the increase in DeltaV(E)/ DeltaV(CO(2)) was not due to increased chemoreceptor feedback from rest to exercise. Increasing exercise intensity diminished the DeltaV(E)/ DeltaV(CO(2)) (p<0.01), and the size of this effect varied by DS volume (p<0.05). We conclude that STM of the exercise ventilatory response is robust in older men; hence, despite age-related changes in lung function and ventilatory control, the exercise ventilatory response can still adapt to increased DS, in order to maintain isocapnia during exercise relative to rest.

Diagnosis and Management of Asthma in Older Adults

Despite comprehensive guidelines established by the European Global Initiative for Asthma and the U.S. National Asthma Education and Prevention Program on the diagnosis and management of asthma, its mortality in older adults continues to rise. Diagnostic and therapeutic problems contribute to older patients being inadequately treated. The diagnosis of asthma rests on the history and characteristic pulmonary function testing (PFT) with the demonstration of reversible airway obstruction, but there are unique problems in performing this test in older patients and in its interpretation. This review aims to address the difficulties in performing and interpreting PFT in older patients because of the effects of age-related changes in lung function on respiratory physiology. The concept of "airway remodeling" resulting in "fixed obstructive" PFT and the relevance of atopy in older people with asthma are assessed. There are certain therapeutic issues unique to older patients with asthma, including the increased probability of adverse effects in the setting of multiple comorbidities and issues surrounding effective drug delivery. The use of beta 2-agonist, anticholinergic, corticosteroid, and anti-immunoglobulin E treatments are discussed in the context of these therapeutic issues.