The NAD ⁺ precursor nicotinamide improves diastolic dysfunction caused by aging, hypertension, or metabolic syndrome in rodents.

Lung function declines with advancing age. To improve our understanding of the structure-function relationships leading to this decline, we investigated structural alterations in the lung and their impact on micromechanics and lung function in the aging mouse. Lung function analysis was performed in 3, 6, 12, 18, and 24 months old C57BL/6 mice (n = 7–8/age), followed by lung fixation and stereological sample preparation. Lung parenchymal volume, total, ductal and alveolar airspace volume, alveolar volume and number, septal volume, septal surface area and thickness were quantified by stereology as well as surfactant producing alveolar epithelial type II (ATII) cell volume and number. Parenchymal volume, total and ductal airspace volume increased in old (18 and 24 months) compared with middle-aged (6 and 12 months) and young (3 months) mice. While the alveolar number decreased from young (7.5 × 10⁶) to middle-aged (6 × 10⁶) and increased again in old (9 × 10⁶) mice, the mean alveolar volume and mean septal surface area per alveolus conversely first increased in middle-aged and then declined in old mice. The ATII cell number increased from middle-aged (8.8 × 10⁶) to old (11.8 × 10⁶) mice, along with the alveolar number, resulting in a constant ratio of ATII cells per alveolus in all age groups (1.4 ATII cells per alveolus). Lung compliance and inspiratory capacity increased, whereas tissue elastance and tissue resistance decreased with age, showing greatest changes between young and middle-aged mice. In conclusion, alveolar size declined significantly in old mice concomitant with a widening of alveolar ducts and late alveolarization. These changes may partly explain the functional alterations during aging. Interestingly, despite age-related lung remodeling, the number of ATII cells per alveolus showed a tightly controlled relation in all age groups.

Acute lung injury (ALI) is characterized by hypoxemia, enhanced permeability of the air-blood barrier, and pulmonary edema. Particularly in the elderly, ALI is associated with increased morbidity and mortality. The reasons for this, however, are poorly understood. We hypothesized that age-related changes in pulmonary structure, function, and inflammation lead to a worse prognosis in ALI. ALI was induced in young (10 wk old) and old (18 mo old) male C57BL/6 mice by intranasal application of 2.5 mg lipopolysaccharide (LPS)/kg body wt or saline (control mice). After 24 h, lung function was assessed, and lungs were either processed for stereological or inflammatory analysis, such as bronchoalveolar lavage fluid (BALF) cytometry and qPCR. Both young and old mice developed severe signs of ALI, including alveolar and septal edema and enhanced inflammatory BALF cells. However, the pathology of ALI was more pronounced in old compared with young mice with nearly sixfold higher BALF protein concentration, twice the number of neutrophils, and significantly higher expression of neutrophil chemokine Cxcl1, adhesion molecule Icam-1, and metalloprotease-9, whereas the expression of tight junction protein occludin significantly decreased. The old LPS mice had thicker alveolar septa attributable to higher volumes of interstitial cells and extracellular matrix. Tissue resistance and elastance reflected observed changes at the ultrastructural level in the lung parenchyma in ALI of young and old mice. In summary, the pathology of ALI with advanced age in mice is characterized by a greater neutrophilic inflammation, leakier air-blood barrier, and altered lung function, which is in line with findings in elderly patients.

A chronic proinflammatory milieu (inflamm-aging) is observed in the elderly and associated with poorer prognosis in acute lung injury (ALI). Gut microbiome-derived short-chain fatty acids (SCFAs) are known to have immunomodulatory capabilities, but their function in the gut-lung axis in aging is poorly understood. Here, we analyzed the gut microbiome and its impact on inflammatory signaling in the aging lung and tested the effects of SCFAs in young (3 mo) and old (18 mo) mice that received either drinking water with a mixture of each 50 mM acetate, butyrate, and propionate for 2 wk or water alone. ALI was induced by intranasal lipopolysaccharide (LPS; n = 12/group) administration. Controls ( n = 8/group) received saline. Fecal pellets were sampled for gut microbiome analysis before and after LPS/saline treatment. The left lung lobe was collected for stereology and right lung lobes for cytokine and gene expression analysis, inflammatory cell activation, and proteomics. Different gut microbial taxa, such as Bifidobacterium, Faecalibaculum, and Lactobacillus correlated positively with pulmonary inflammation in aging, suggesting an impact on inflamm-aging in the gut-lung axis. The supplementation of SCFAs reduced inflamm-aging, oxidative stress, metabolic alteration, and enhanced activation of myeloid cells in the lungs of old mice. The enhanced inflammatory signaling in ALI of old mice was also reduced by SCFA treatment. In summary, the study provides new evidence that SCFAs play a beneficial role in the gut-lung axis of the aging organism by reducing pulmonary inflamm-aging and ameliorating enhanced severity of ALI in old mice.

The gut microbiota plays an important role in the development of asthma. With advanced age the microbiome and the immune system are changing and, currently, little is known about how these two factors contribute to the development of allergic asthma in the elderly. In this study we investigated the associations between the intestinal microbiome and allergic airway disease in young and old mice that were sensitized and challenged with house dust mite (HDM). After challenge, the animals were sacrificed, blood serum was collected for cytokine analysis, and the lungs were processed for histopathology. Fecal pellets were excised from the colon and subjected to 16S rRNA analysis. The microbial community structure changed with age and allergy development, where alterations in fecal communities from young to old mice resembled those after HDM challenge. Allergic mice had induced serum levels of IL-17A and old mice developed a greater allergic airway response compared to young mice. This study demonstrates that the intestinal bacterial community structure differs with age, possibly contributing to the exaggerated pulmonary inflammatory response in old mice. Furthermore, our results show that the composition of the gut microbiota changes with pulmonary allergy, indicating bidirectional gut-lung communications.