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Pulmonary fibrosis (PF) is a progressive and fatal lung disease with high incidence and a lack of effective treatment, which is a severe public health problem. PF has caused a huge socio-economic burden, and its pathogenesis has become a research hotspot. SIRT1 is a nicotinamide adenosine dinucleotide (NAD)-dependent sirtuin essential in tumours, Epithelial mesenchymal transition (EMT), and anti-aging. Numerous studies have demonstrated after extensive research that it is crucial in preventing the progression of pulmonary fibrosis. This article reviews the biological roles and mechanisms of SIRT1 in regulating the progression of pulmonary fibrosis in terms of EMT, oxidative stress, inflammation, aging, autophagy, and discusses the potential of SIRT1 as a therapeutic target for pulmonary fibrosis, and provides a new perspective on therapeutic drugs and prognosis prospects. [ABSTRACT FROM AUTHOR]

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors’ characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice. [ABSTRACT FROM AUTHOR]

Adult lungs present high cellular plasticity against stress and injury, mobilizing stem/progenitor populations from conducting airways to maintain tissue homeostasis and gas exchange in alveolar spaces. With aging, pulmonary functional and structural deterioration occurs, mainly in pathological conditions, which is associated with impaired stem cell activity and increased senescence in mice. However, the impact of these processes underlying lung physiopathology in relation to aging has not been explored in humans. In this work, we analyzed stem cell (SOX2, p63, KRT5), senescence (p16INK4A, p21CIP, Lamin B1) and proliferative (Ki67) markers in lung samples from young and aged individuals, with and without pulmonary pathology. We identified a reduction in SOX2+ cells but not p63+ and KRT5+ basal cells in small airways with aging. In alveoli, we revealed the presence of triple SOX2+, p63+ and KRT5+ cells specifically in aged individuals diagnosed with pulmonary pathologies. Notably, p63+ and KRT5+ basal stem cells displayed colocalization with p16INK4A and p21CIP, as well as with low Lamin B1 staining in alveoli. Further studies revealed that senescence and proliferation markers were mutually exclusive in stem cells with a higher percentage colocalizing with senescence markers. These results provide new evidence of the activity of p63+/KRT5+ stem cells on human lung regeneration and point out that regeneration machinery in human lung is activated under stress due to aging, but fails to repair in pathological cases, as stem cells would likely become senescent. [ABSTRACT FROM AUTHOR]

Aging is a major driving factor in lung diseases. Age-related lung disease is associated with downregulated expression of SIRT1, an NAD+-dependent deacetylase that regulates inflammation and stress resistance. SIRT1 acts by inducing the deacetylation of various substrates and regulates several mechanisms that relate to lung aging, such as genomic instability, lung stem cell exhaustion, mitochondrial dysfunction, telomere shortening, and immune senescence. Chinese herbal medicines have many biological activities, exerting anti-inflammatory, anti-oxidation, anti-tumor, and immune regulatory effects. Recent studies have confirmed that many Chinese herbs have the effect of activating SIRT1. Therefore, we reviewed the mechanism of SIRT1 in age-related lung disease and explored the potential roles of Chinese herbs as SIRT1 activators in the treatment of age-related lung disease.

Chronic lung disease is the third leading cause of death globally, imposing huge burden of death, disability and healthcare costs. However, traditional pharmacotherapy has relatively limited effects in improving the cure rate and reducing the mortality of chronic lung disease. Thus, new treatments are urgently needed for the prevention and treatment of chronic lung disease. It is particularly noteworthy that, multiple aging-related phenotypes were involved in the occurrence and development of chronic lung disease, such as blocked proliferation, telomere attrition, mitochondrial dysfunction, epigenetic alterations, altered nutrient perception, stem cell exhaustion, chronic inflammation, etc. Consequently, senescent cells induce a series of pathological changes in the lung, such as immune dysfunction, airway remodeling, oxidative stress and regenerative dysfunction, which is a critical issue that needs special attention in chronic lung diseases. Therefore, anti-aging interventions may bring new insights into the treatment of chronic lung diseases. In this review, we elaborate the involvement of aging in chronic lung disease and further discuss the application and prospects of anti-aging therapy. • Aging is one of the contributing factors to the development of chronic lung diseases. • Aging contributes to the formation of various pathological phenotypes in chronic lung diseases. • Anti-Aging drugs show promising prospects in the treatment of chronic lung diseases. [ABSTRACT FROM AUTHOR]

Background: The prevalence of aging-related diseases has increased significantly and this imposes a burden on both families and society. The lung is one of the few internal organs that is continuously exposed to the external environment, and lung aging is associated with a number of lung diseases. Ochratoxin A (OTA) is a toxin that is widely present in food and the environment but an effect for OTA on lung aging has not been reported. Methods: Using both cultured lung cell and in vivo model systems, we studied the effect of OTA on lung cell senescence using flow cytometry, indirect immunofluorescence, western blotting, and immunohistochemistry. Results: Results obtained showed that OTA caused significant lung cell senescence in cultured cells. Furthermore, using in vivo models, results showed that OTA caused lung aging and aging fibrosis. Mechanistic analysis showed that OTA upregulated the levels of inflammation and oxidative stress, and that this may be the molecular basis of OTA-induced lung aging. Conclusions: Taken together, these findings indicate that OTA causes significant aging damage to the lung, which lays an important foundation for the prevention and treatment of lung aging.

Globally, chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality, having a significant socioeconomic effect. Several molecular mechanisms have been related to COPD including chronic inflammation, telomere shortening, and epigenetic modifications. Nowadays, there is an increasing need for novel therapeutic approaches for the management of COPD. These treatment strategies should be based on finding the source of acute exacerbation of COPD episodes and estimating the patient's own risk. The use of biomarkers and the measurement of their levels in conjunction with COPD exacerbation risk and disease prognosis is considered an encouraging approach. Many types of COPD biomarkers have been identified which include blood protein biomarkers, cellular biomarkers, and protease enzymes. They have been isolated from different sources including peripheral blood, sputum, bronchoalveolar fluid, exhaled air, and genetic material. However, there is still not an exclusive biomarker that is used for the evaluation of COPD but rather a combination of them, and this is attributed to disease complexity. In this review, we summarize the clinical significance of COPD-related biomarkers, their association with disease outcomes, and COPD patients' management. Finally, we depict the various samples that are used for identifying and measuring these biomarkers. [ABSTRACT FROM AUTHOR]

Lung fibrosis is increasingly detected with aging and has been associated with poor outcomes in acute lung injury or infection. However, the molecular programs driving this pro-fibrotic evolution are unclear. Here we profile distal lung samples from healthy human donors across the lifespan. Gene expression profiling by bulk RNAseq reveals both increasing cellular senescence and pro-fibrotic pathway activation with age. Quantitation of telomere length shows progressive shortening with age, which is associated with DNA damage foci and cellular senescence. Cell type deconvolution analysis of the RNAseq data indicates a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts with age. Consistent with this pro-fibrotic profile, second harmonic imaging of aged lungs demonstrates increased density of interstitial collagen as well as decreased alveolar expansion and surfactant secretion. In this work, we reveal the transcriptional and structural features of fibrosis and associated functional impairment in normal lung aging. Age is associated with increasing vulnerability to both acute and chronic lung diseases. Employing genomic analysis and live lung imaging, this study reveals a profile of increased cellular senescence, telomere shortening, and fibrosis-induced impaired alveolar function in the natural history of human lung aging. [ABSTRACT FROM AUTHOR]

Aging is often viewed as a progressive decline in fitness due to cumulative deleterious alterations of biological functions in the living system. Recently, our understanding of the molecular mechanisms underlying aging biology has significantly advanced. Interestingly, many of the pivotal molecular features of aging biology are also found to contribute to the pathogenesis of chronic lung disorders such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, for which advanced age is the most crucial risk factor. Thus, an enhanced understanding of how molecular features of aging biology are intertwined with the pathobiology of these aging-related lung disorders has paramount significance and may provide an opportunity for the development of novel therapeutics for these major unmet medical needs. To serve the purpose of integrating molecular understanding of aging biology with pulmonary medicine, in this review, recent findings obtained from the studies of aging-associated lung disorders are summarized and interpreted through the perspective of molecular biology of aging.

Lung aging is characterized by lung function impairment, ECM remodeling and airspace enlargement. Tenascin-C (TNC) is a large extracellular matrix (ECM) protein with paracrine and autocrine regulatory functions on cell migration, proliferation and differentiation. This matricellular protein is highly expressed during organogenesis and morphogenetic events like injury repair, inflammation or cancer. We previously showed that TNC deficiency affected lung development and pulmonary function, but little is known about its role during pulmonary aging. In order to answer this question, we characterized lung structure and physiology in 18 months old TNC-deficient and wild-type (WT) mice. Mice were mechanically ventilated with a basal and high tidal volume (HTV) ventilation protocol for functional analyses. Additional animals were used for histological, stereological and molecular biological analyses. We observed that old TNC-deficient mice exhibited larger lung volume, parenchymal volume, total airspace volume and septal surface area than WT, but similar mean linear intercept. This was accompanied by an increase in proliferation, but not apoptosis or autophagy markers expression throughout the lung parenchyma. Senescent cells were observed in epithelial cells of the conducting airways and in alveolar macrophages, but equally in both genotypes. Total collagen content was doubled in TNC KO lungs. However, basal and HTV ventilation revealed similar respiratory physiological parameters in both genotypes. Smooth muscle actin (α-SMA) analysis showed a faint increase in α-SMA positive cells in TNC-deficient lungs, but a marked increase in non-proliferative α-SMA + desmin + cells. Major TNC-related molecular pathways were not up- or down-regulated in TNC-deficient lungs as compared to WT; only minor changes in TLR4 and TGFβR3 mRNA expression were observed. In conclusion, TNC-deficient lungs at 18 months of age showed exaggerated features of the normal structural lung aging described to occur in mice between 12 and 18 months of age. Correlated to the increased pulmonary function parameters previously observed in young adult TNC-deficient lungs and described to occur in normal lung aging between 3 and 6 months of age, TNC might be an advantage in lung aging. [ABSTRACT FROM AUTHOR]

Lung aging alters the intrinsic structure of the lung and pulmonary surfactant system and increases the mortality and morbidity due to respiratory diseases in elderly individuals. We hypothesized that lung aging results from an insufficiency of type II alveolar epithelial cells (AECIIs) in the lung tissue. Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased SIRT3 expression has been linked to an extended life span in humans. Hence, we speculated that the overexpression of SIRT3 may help to ameliorate lung senescence and improve AECII function. AECIIs were isolated from young and old patients with pneumothorax caused by pulmonary bullae. The expression of SIRT3, manganese superoxide dismutase, and catalase, as well as cell function and senescence indicators of young and old AECIIs, was measured before and after SIRT3 overexpression. After SIRT3 overexpression, the aged state of old AECIIs improved, and antiapoptotic activity, proliferation, and secretion were dramatically enhanced. Surfactant protein C (SPC), which is secreted by AECIIs, reduces alveolar surface tension, repairs the alveolar structure, and regulates inflammation. SPC deficiency in patients is associated with increased inflammation and delayed repair. SIRT3 deacetylated forkhead box O3a, thereby protecting mitochondria from oxidative stress and improving cell function and the senescent state of old AECIIs. These findings provide a possible direction for aging-delaying therapies and interventions for diseases of the respiratory system. [ABSTRACT FROM AUTHOR]

Aging is the predominant risk factor for most degenerative diseases, including chronic obstructive pulmonary disease (COPD). This process is however very heterogeneous. Defining the biological aging of individual tissues may contribute to better assess this risky process. In this study, we examined the biological age of induced sputum (IS) cells, and peripheral blood leukocytes in the same subject, and compared these to assess whether biological aging of blood leukocytes mirrors that of IS cells. Biological aging was assessed in 18 COPD patients (72.4 ± 7.7 years; 50% males). We explored mitotic and non-mitotic aging pathways, using telomere length (TL) and DNA methylation-based age prediction (DNAmAge) and age acceleration (AgeAcc) (i.e., difference between DNAmAge and chronological age). Data on demographics, life style and occupational exposure, lung function, and clinical and blood parameters were collected. DNAmAge (67.4 ± 5.80 vs. 61.6 ± 5.40 years; p = 0.0003), AgeAcc (−4.5 ± 5.02 vs. −10.8 ± 3.50 years; p = 0.0003), and TL attrition (1.05 ± 0.35 vs. 1.48 ± 0.21 T/S; p = 0.0341) are higher in IS cells than in blood leukocytes in the same patients. Blood leukocytes DNAmAge (r = 0.927245; p = 0.0026) and AgeAcc (r = 0.916445; p = 0.0037), but not TL, highly correlate with that of IS cells. Multiple regression analysis shows that both blood leukocytes DNAmAge and AgeAcc decrease (i.e., younger) in patients with FEV1% enhancement (p = 0.0254 and p = 0.0296) and combined inhaled corticosteroid (ICS) therapy (p = 0.0494 and p = 0.0553). In conclusion, new findings from our work reveal a differential aging in the context of COPD, by a direct quantitative comparison of cell aging in the airway with that in the more accessible peripheral blood leukocytes, providing additional knowledge which could offer a potential translation into the disease management.

Infants suffering from neonatal chronic lung disease, i.e., bronchopulmonary dysplasia, are facing long-term consequences determined by individual genetic background, presence of infections, and postnatal treatment strategies such as mechanical ventilation and oxygen toxicity. The adverse effects provoked by these measures include inflammatory processes, oxidative stress, altered growth factor signaling, and remodeling of the extracellular matrix. Both, acute and long-term consequences are determined by the capacity of the immature lung to respond to the challenges outlined above. The subsequent impairment of lung growth translates into an altered trajectory of lung function later in life. Here, knowledge about second and third hit events provoked through environmental insults are of specific importance when advocating lifestyle recommendations to this patient population. A profound exchange between the different health care professionals involved is urgently needed and needs to consider disease origin while future monitoring and treatment strategies are developed.

Lung function declines as people age and their lungs become stiffer. With an increasing elderly population, understanding mechanisms that contribute to these structural and functional changes in the aging lung is important. Part of the aging process is characterized by thicker, more fibrotic airways, and senile emphysema caused by changes in lung parenchyma. There is also senescence, which occurs throughout the body with aging. Here, using human airway smooth muscle (ASM) cells from patients in different age groups, we explored senescence pathways and changes in intracellular calcium signaling and extracellular matrix (ECM) deposition to elucidate potential mechanisms by which aging leads to thicker and stiffer lungs. Senescent markers p21, γH2AX, and β-gal, and some senescence-associated secretory proteins (SASP) increased with aging, as shown by staining and biochemical analyses. Agonist-induced intracellular Ca2+ responses, measured using fura-2 loaded cells and fluorescence imaging, increased with age. However, biochemical analysis showed that expression of the following markers decreased with age: M3 muscarinic receptor, TRPC3, Orai1, STIM1, SERCA2, MMP2 and MMP9. In contrast, collagen III, and fibronectin deposition increased with age. These data show that senescence increases in the aging airways that is associated with a stiffer but surprisingly greater intracellular calcium signaling as a marker for contractility. ASM senescence may enhance fibrosis in a feed forward loop promoting remodeling and altered calcium storage and buffering. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction has long been implicated to have a causative role in organismal aging. A mitochondrial molecule, nucleotide‐binding domain and leucine‐rich‐repeat‐containing protein X1 (NLRX1), represents the only NLR family member that targets this cellular location, implying that NLRX1 probably establishes a fundamental link between mitochondrial functions and cellular physiology. However, the significance of NLRX1 function in cellular senescence, a key conceptual constituent in aging biology, is yet to be defined. Here, we demonstrate that molecular hallmarks involved in aging biology including NAD+ decline, and activation of mTOR, p53, and p16INK4A are significantly enhanced in NLRX1 deficiency in vitro. Mechanistic studies of replicative cellular senescence in the presence or absence of NLRX1 in vitro reveal that NLRX1‐deficient fibroblasts fail to maintain optimal NAD+/NADH ratio, which instigates the decline of SIRT1 and the activation of mTOR, p16INK4A, and p53, leading to the increase in senescence‐associated beta‐galactosidase (SA‐β‐gal)‐positive cells. Importantly, the enhanced cellular senescence response in NLRX1 deficiency is significantly attenuated by pharmacological inhibition of mTOR signaling in vitro. Finally, our in vivo murine studies reveal that NLRX1 decreases with age in murine lungs and NLRX1 deficiency in vivo accelerates pulmonary functional and structural changes that recapitulate the findings observed in human aging lungs. In conclusion, the current study provides evidence for NLRX1 as a crucial regulator of cellular senescence and in vivo lung aging. [ABSTRACT FROM AUTHOR]

Beyond the structural changes, features including the dysregulation of endoplasmic reticulum (ER) stress response and increased senescence characterize the lung aging. ER stress response and senescence have been reported to be induced by factors like cigarette smoke. Therefore, deciphering the mechanisms underlying ER and senescent pathways interaction has become a challenge. In this review we highlight the known and unknown regarding ER stress response and senescence and their cross talk in aged lung. [ABSTRACT FROM AUTHOR]

The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age. Recent cellular and molecular studies have given insight into why the incidence and/or severity of many lung diseases, from lung cancer to COVID-19, increase with age. [ABSTRACT FROM AUTHOR]

Oxidative stress is one of the major causes of cellular senescence in mammalian cells. The excess amount of reactive oxygen species generated by oxygen metabolism is pathogenic and facilitates tissue aging. Lung tissue is more susceptible to oxidative stress than other organs because it is directly exposed to environmental stresses. The aging of lung tissues increases the risk of chronic diseases. Senescent cells accumulate in tissues during aging and contribute to aging-associated morbidity; however, the roles of cellular senescence in lung aging and diseases have not yet been elucidated in detail. To clarify the physiological role of oxidative stress-induced cellular senescence in aging-associated declines in pulmonary function, we herein investigated the effects of the antioxidant N -acetyl-L-cysteine (NAC) on lung cellular senescence and aging in mice. The administration of NAC to 1-year-old mice reduced the expression of senescence-associated genes in lung tissue. Pulmonary function and lung morphology were partly restored in mice administered NAC. Collectively, these results suggest that oxidative stress is a major inducer of cellular senescence in vivo and that the control of oxidative stress may prevent lung aging and diseases. • The effects of NAC on lung cellular senescence were monitored by in vivo imaging. • Senescence-associated genes were down-regulated in the lung tissues of NAC-fed mice. • NAC feeding restored pulmonary function in aged mice. [ABSTRACT FROM AUTHOR]

Physiological lung ageing is associated with a gradual decline in dynamic lung volumes and a progressive increase in residual volume due to diminished elastic recoil of the lung, loss of alveolar tissue, and lower chest wall compliance. However, the effects of ageing on the small airways (ie, airways <2·0 mm in diameter) remain largely unknown. By using a combination of ex-vivo conventional CT (resolution 1 mm), whole lung micro-CT (resolution 150 μm), and micro-CT of extracted cores (resolution 10 μm), we aimed to provide a multiresolution assessment of the small airways in lung ageing in a large cohort of never smokers. For this cross-sectional study, we included donor lungs collected from 32 deceased never-smoking donors (age range 16–83 years). Ex-vivo CT and whole lung high-resolution CT (micro-CT) were used to determine total airway numbers, stratified by airway diameter. Micro-CT was used to assess the number, length, and diameter of terminal bronchioles (ie, the last generation of conducting airways); mean linear intercept; and surface density in four lung tissue cores from each lung, extracted using a uniform sampling approach. Regression β coefficients are calculated using linear regression and polynomial models. Ex-vivo CT analysis showed an age-dependent decrease in the number of airways of diameter 2·0 mm to less than 2·5 mm (β coefficient per decade −0·119, 95% CI −0·193 to −0·045; R 2=0·29) and especially in airways smaller than 2·0 mm in diameter (−0·158, −0·233 to −0·084; R 2=0·47), between 30 and 80 years of age, but not of the larger (≥2·5 mm) diameter airways (−0·00781, −0·04409 to 0·02848; R 2=0·0007). In micro-CT analysis of small airways, the total number of terminal bronchioles per lung increased until the age of 30 years, after which an almost linear decline in the number of terminal bronchioles was observed (β coefficient per decade −2035, 95% CI −2818 to −1252; R 2=0·55), accompanied by a non-significant increase in alveolar airspace size (6·44, −0·57 to 13·45, R 2=0·10). Moreover, this decrease in terminal bronchioles was associated with the age-related decline of pulmonary function predicted by healthy reference values. Loss of terminal bronchioles is an important structural component of age-related decline in pulmonary function of healthy, non-smoking individuals. Research Foundation—Flanders, KU Leuven, Parker B Francis Foundation, UGent, Canadian Institutes for Health. [ABSTRACT FROM AUTHOR]

COVID-19 is prevalent in the elderly. Old individuals are more likely to develop pneumonia and respiratory failure due to alveolar damage, suggesting that lung senescence may increase the susceptibility to SARS-CoV-2 infection and replication. Considering that human coronavirus (HCoVs; SARS-CoV-2 and SARS-CoV) require host cellular factors for infection and replication, we analyzed Genotype-Tissue Expression (GTEx) data to test whether lung aging is associated with transcriptional changes in human protein-coding genes that potentially interact with these viruses. We found decreased expression of the gene tribbles homolog 3 (TRIB3) during aging in male individuals, and its protein was predicted to interact with HCoVs nucleocapsid protein and RNA-dependent RNA polymerase. Using publicly available lung single-cell data, we found TRIB3 expressed mainly in alveolar epithelial cells that express SARS-CoV-2 receptor ACE2. Functional enrichment analysis of age-related genes, in common with SARS-CoV-induced perturbations, revealed genes associated with the mitotic cell cycle and surfactant metabolism. Given that TRIB3 was previously reported to decrease virus infection and replication, the decreased expression of TRIB3 in aged lungs may help explain why older male patients are related to more severe cases of the COVID-19. Thus, drugs that stimulate TRIB3 expression should be evaluated as a potential therapy for the disease. [ABSTRACT FROM AUTHOR]

People worldwide are living longer, and it is estimated that by 2050, the proportion of the world's population over 60 years of age will nearly double. Natural lung aging is associated with molecular and physiological changes that cause alterations in lung function, diminished pulmonary remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. As the aging population rapidly grows, it is essential to examine how alterations in cellular function and cell-to-cell interactions of pulmonary resident cells and systemic immune cells contribute to a higher risk of increased susceptibility to infection and development of chronic diseases, such as chronic obstructive pulmonary disease and interstitial pulmonary fibrosis. This review provides an overview of physiological, structural, and cellular changes in the aging lung and immune system that facilitate the development and progression of disease. [ABSTRACT FROM AUTHOR]

Healthy ageing of the lung involves structural changes but also numerous cell-intrinsic and cell-extrinsic alterations. Among them are the age-related decline in central cellular quality control mechanisms such as redox and protein homeostasis. In this review, we would like to provide a conceptual framework of how impaired stress responses in the ageing lung, as exemplified by dysfunctional redox and protein homeostasis, may contribute to onset and progression of COPD and idiopathic pulmonary fibrosis (IPF). We propose that age-related imbalanced redox and protein homeostasis acts, amongst others (e.g. cellular senescence), as a "first hit" that challenges the adaptive stress-response pathways of the cell, increases the level of oxidative stress and renders the lung susceptible to subsequent injury and disease. In both COPD and IPF, additional environmental insults such as smoking, air pollution and/or infections then serve as "second hits" which contribute to persistently elevated oxidative stress that overwhelms the already weakened adaptive defence and repair pathways in the elderly towards non-adaptive, irremediable stress thereby promoting development and progression of respiratory diseases. COPD and IPF are thus distinct horns of the same devil, "lung ageing". [ABSTRACT FROM AUTHOR]

Abstract Life expectancy is increasing worldwide. Lung aging is a process marked by changes in multiple morphological, physiological and age-related biomarkers (e.g., sirtuins) and is influenced by external factors, such as air pollution. Hence, the elderly are considered more vulnerable to the air pollution hazards. We hypothesized that diesel exhaust (DE) exposure intensifies changes in lung inflammatory and structural parameters in aging subjects. Two- and fifteen-month-old mice were exposed to DE for 30 days. Lung function was measured using the forced oscillation method. The inflammatory profile was evaluated in the bronchoalveolar lavage fluid (BALF) and blood, and lung volumes were estimated by stereology. Antioxidant enzyme activity was evaluated by spectrophotometry, sirtuin 1 (SIRT1), sirtuin 2 (SIRT2) and sirtuin 6 (SIRT6) expression was assessed by reverse transcription polymerase chain reaction (RT-PCR), and levels of the sirtuin proteins were evaluated by immunohistochemical staining in lung tissues. Older mice presented decreased pulmonary resistance and elastance, increased macrophage infiltration and decreased tumor necrosis factor (TNF) and interleukin 10 (IL-10) levels in the BALF, reduced activities of the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR), and increased activity glutathione S-transferase (GST); increased lung volumes with decreased elastic fiber and increased airway collagen content. SIRT1 gene expression was decreased in older animals, but protein levels were increased. DE exposure increased macrophage infiltration and oxidative stress in the lungs of animals of both ages. SIRT6 gene expression was decreased by DE exposure, with increased protein levels. In older animals, DE affected lung structure and collagen content. Lung aging features, such as decreased antioxidant reserves, lower IL-10 expression, and decreased SIRT1 levels may predispose subjects to exacerbated responses after DE exposure. Our data support the hypothesis that strategies designed to reduce ambient air pollution are an important step towards healthy aging. Graphical abstract fx1 Highlights • DE exposure accelerates lung aging in mice. • DE exposure decreases the mRNA expression and increases protein expression of SIRT6 in the lung regardless of the mice age. • Anti-oxidant enzymes imbalance occurred due to DE exposure in old and young mice. • Morphological/structural changes and increased collagen content occurred due to DE exposure only in the lungs of aged mice. [ABSTRACT FROM AUTHOR]

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)-induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)-treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain- containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor g coactivator-1b-mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling. [ABSTRACT FROM AUTHOR]

Background: Smoking is the main risk factor for most of the leading causes of death. Cessation is the single most important step that smokers can take to improve their health. With the aim of informing policy makers about decisions on future tobacco control strategies, we estimated time and age trends in smoking cessation in Europe between 1980 and 2010. Methods: Data on the smoking history of 50,228 lifetime smokers from 17 European countries were obtained from six large population-based studies included in the Ageing Lungs in European Cohorts (ALEC) consortium. Smoking cessation rates were assessed retrospectively, and age trends were estimated for three decades (1980–1989, 1990–1999, 2000–2010). The analyses were stratified by sex and region (North, East, South, West Europe). Results: Overall, 21,735 subjects (43.3%) quit smoking over a total time-at-risk of 803,031 years. Cessation rates increased between 1980 and 2010 in young adults (16–40 years), especially females, from all the regions, and in older adults (41–60 years) from North Europe, while they were stable in older adults from East, South and West Europe. In the 2000s, the cessation rates for men and women combined were highest in North Europe (49.9 per 1,000/year) compared to the other regions (range: 26.5–32.7 per 1,000/year). A sharp peak in rates was observed for women around the age of 30, possibly as a consequence of pregnancy-related smoking cessation. In most regions, subjects who started smoking before the age of 16 were less likely to quit than those who started later. Conclusions: Our findings suggest an increasing awareness on the detrimental effects of smoking across Europe. However, East, South and West European countries are lagging behind North Europe, suggesting the need to intensify tobacco control strategies in these regions. Additional efforts should be made to keep young adolescents away from taking up smoking, as early initiation could make quitting more challenging during later life. [ABSTRACT FROM AUTHOR]

Objective: To determine and explain the effect of age on exhaled nitric oxide values in North African healthy subjects aged from 5 to 83 years.Design: Prospective cross-sectional study.Methods: Volunteer children adults and elderly healthy subjects were included. A medical questionnaire was used to assess several subject characteristics. The levels of exhaled fraction of nitric oxide (FeNO) were measured by Medisoft HypAir FeNO method. Spirometry function test was done after the FeNO measurement. The following parameters were measured: forced vital capacity (FVC, L); 1st second forced expiratory volume (FEV1, L); FEV1/FVC ratio (absolute value); maximal mid expiratory flow (MMEF, L/s); Mid expiratory flow from 25 to 75% (MEF25%, MEF50%, and MEF75%). Statistical analyses were carried out using Statistica software with a significance set at the 0.05 level.Results: A significant increase in FeNO is noted between groups with respective age ranges of (5, 17) and (17, 25) years with a breakpoint at 1,397,034 years. A significant decrease of FeNO is noted between groups with respective age ranges of (45, 55) and (55, 65) years with a breakpoint at 6,366,052 years. No statistical significant difference was found between females' and males' means FeNO data. Finally, SEL, obesity status, and hypertension contribute significantly in the variations of FeNO values.Conclusion: The development and aging of the lung touched non-respiratory functions and so modified FeNO values in healthy North African subjects. [ABSTRACT FROM AUTHOR]

Lung aging results in altered lung function, reduced lung remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. The molecular and physiological underlying mechanisms of lung aging remain unclear. Mounting evidence suggests that deubiquitinating enzymes (DUBs) play a critical role in tissue aging and diseases through regulation of cellular signaling pathways. Here we investigate the role of Ubiquitin-Specific Protease 13 (USP13) in cell senescence and lung aging and its underlying mechanisms. Protein levels of USP13 and MDM2 in lung tissues from aged and young mice were compared. Gene silencing and overexpression of USP13 in human cell lines were performed. MDM2 levels were examined by Quantitative Real-Time PCR and Western blotting analysis. The cell senescence levels of human cells were checked by the β-galactosidase staining. Lung tissues from aged mice showed higher levels of USP13 compared to younger mice. We found a negative correlation between USP13 and MDM2 expression in lung tissues of aged mice. The increased protein levels of MDM2 were detected in lung tissues of USP13 deficient mice. Furthermore, overexpression of USP13 promoted cell senescence. Knockdown of USP13 increased MDM2 levels in lung cells, while overexpression of USP13 reduced it. The degradation of MDM2 caused by USP13 was prevented by the proteasome inhibitor MG132. Furthermore, we showed that USP13 targeted and reduced K63-linked polyubiquitination of MDM2. These results demonstrate that USP13 is involved in the aging signaling pathway in lungs through regulation of MDM2. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis is a chronic and progressive lung disease characterized by the activation of fibroblasts and the irreversible deposition of connective tissue matrices that leads to altered pulmonary architecture and physiology. Multiple factors have been implicated in the pathogenesis of lung fibrosis, including genetic and environmental factors that cause abnormal activation of alveolar epithelial cells, leading to the development of complex profibrotic cascade activation and extracellular matrix (ECM) deposition. One class of proteinases that is thought to be important in the regulation of the ECM are the matrix metalloproteinases (MMPs). MMPs can be up- and down- regulated in idiopathic pulmonary fibrosis (IPF) lungs and their role depends upon their location and function. Furthermore, alterations in the ubiquitin-proteosome system (UPS), a major intracellular protein degradation complex, have been described in aging and IPF lungs. UPS alterations could potentially lead to the abnormal accumulation and deposition of ECM. A better understanding of the specific roles MMPs and UPS play in the pathophysiology of pulmonary fibrosis could potentially drive to the development of novel biomarkers that can be as diagnostic and therapeutic targets. In this review, we describe how MMPs and UPS alter ECM composition in IPF lungs and mouse models of pulmonary fibrosis, thereby influencing the alveolar epithelial and mesenchymal cell behavior. Finally, we discuss recent findings that associate MMPs and UPS interplay with the development of pulmonary fibrosis.

Inhalation of noxious gasses induces oxidative stress in airway epithelial cells (AECs), which may lead to cellular senescence and contribute to the development of chronic obstructive pulmonary disease (COPD). FAM13A, a well-known COPD susceptibility gene, is highly expressed in airway epithelium. We studied whether its expression is associated with aging and cellular senescence and affects airway epithelial responses to paraquat, a cellular senescence inducer. The association between age and FAM13A expression was investigated in two datasets of human lung tissue and bronchial brushings from current/ex-smokers with/without COPD. Protein levels of FAM13A and cellular senescence marker p21 were investigated using immunohistochemistry in lung tissue from patients with COPD. In vitro, FAM13A and P21 expression was assessed using qPCR in air-liquid-interface (ALI)-differentiated AECs in absence/presence of paraquat. In addition, FAM13A was overexpressed in human bronchial epithelial 16HBE cells and the effect on P21 expression (qPCR) and mitochondrial reactive oxygen species (ROS) production (MitoSOX staining) was assessed. Lower FAM13A expression was significantly associated with increasing age in lung tissue and bronchial epithelium. In airway epithelium of patients with COPD, we found a negative correlation between FAM13A and p21 protein levels. In ALI-differentiated AECs, the paraquat-induced decrease in FAM13A expression was accompanied by increased P21 expression. In 16HBE cells, the overexpression of FAM13A significantly reduced paraquat-induced P21 expression and mitochondrial ROS production. Our data suggest that FAM13A expression decreases with aging, resulting in higher P21 expression and mitochondrial ROS production in the airway epithelium, thus facilitating cellular senescence and as such potentially contributing to accelerated lung aging in COPD. NEW & NOTEWORTHY To our knowledge, this is the first study investigating the role of the COPD susceptibility gene FAM13A in aging and cellular senescence. We found that FAM13A negatively regulates the expression of the cellular senescence marker P21 and mitochondrial ROS production in the airway epithelium. In this way, the lower expression of FAM13A observed upon aging may facilitate cellular senescence and potentially contribute to accelerated lung aging in COPD.

Lung function is inherently mechanical in nature and depends on the capacity to conduct air and blood to and from the gas exchange regions. Variations in the elastic properties of the human lung across anatomical compartments and with aging are likely important determinants of lung function but remain relatively poorly characterized. Here we applied atomic force microscopy microindentation to characterize human lung tissue from subjects ranging in age from 11 to 60 yr old. We observed striking anatomical variations in elastic modulus, with the airways (200- to 350-μm diameter) the stiffest and the parenchymal regions the most compliant. Vessels (diameter < 100 μm) represented an intermediate mechanical environment and displayed diameter-dependent trends in elastic modulus. Binning our samples into younger (11-30 yr old) and older (41-60 yr old) groups, we observed significant age-related increases in stiffness in parenchymal and vessel compartments, with the most pronounced changes in the vessels. To investigate cellular mechanisms that might contribute to vascular stiffening with aging, we studied primary human pulmonary artery smooth muscle cells from subjects ranging in age from 11 to 60 yr old. While we observed no change in the mechanical properties of the cells themselves, we did observe trends toward increases in traction forces and extracellular matrix deposition with aging. These results demonstrate age-related changes in tissue mechanical properties that likely contribute to impaired lung function with aging and underscore the potential to identify mechanisms that contribute to mechanical tissue remodeling through the study of human cells and tissues from across the aging spectrum. [ABSTRACT FROM AUTHOR]

Summary: PINK1 (PTEN‐induced putative kinase 1) is a key regulator of mitochondrial homeostasis that is relatively depleted in aging lungs and in lung epithelial cells from patients with idiopathic pulmonary fibrosis (IPF), a disease linked with aging. Impaired PINK1 expression and accumulation of damaged mitochondria in lung epithelial cells from fibrotic lungs were associated with the presence of ER stress. Here, we show that ATF3 (activating transcription factor 3), a member of the integrated stress response (ISR), negatively regulates transcription of the PINK1 gene. An ATF3 binding site within the human PINK1 promoter is located in the first 150 bp upstream of the transcription start site. Induction of ER stress or overexpression of ATF3 inhibited the activity of the PINK1 promoter. Importantly, overexpression of ATF3 causes accumulation of depolarized mitochondria, increased production of mitochondrial ROS, and loss of cell viability. Furthermore, conditional deletion of ATF3 in type II lung epithelial cells protects mice from bleomycin‐induced lung fibrosis. Finally, we observed that ATF3 expression increases in the lung with age and, specially, in lung epithelial cells from IPF lungs. These data provide a unique link between ATF3 and PINK1 expression suggesting that persistent stress, driven by ATF3, can dysregulate mitochondrial homeostasis by repression of PINK1 mRNA synthesis. [ABSTRACT FROM AUTHOR]

The rapid expansion of the elderly population has led to the recent epidemic of age-related diseases, including increased incidence and mortality of chronic and acute lung diseases. Numerous studies have implicated aging and oxidative stress in the pathogenesis of various pulmonary diseases; however, despite recent advances in these fields, the specific contributions of aging and oxidative stress remain elusive. This review will discuss the consequences of aging on lung morphology and physiology, and how redox imbalance with aging contributes to lung disease susceptibility. Here, we focus on three lung diseases for which aging is a significant risk factor: acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Preclinical and clinical development for redox- and senescence-altering therapeutic strategies are discussed, as well as scientific advancements that may direct current and future therapeutic development. A deeper understanding of how aging impacts normal lung function, redox balance, and injury-repair processes will inspire the development of new therapies to prevent and/or reverse age-associated pulmonary diseases, and ultimately increase health span and longevity. This review is intended to encourage basic, clinical, and translational research that will bridge knowledge gaps at the intersection of aging, oxidative stress, and lung disease to fuel the development of more effective therapeutic strategies for lung diseases that disproportionately afflict the elderly. [ABSTRACT FROM AUTHOR]

Cellular senescence, the irreversible loss of replicative capacity in somatic cells, plays a causal role in the development of age-related pathology and in a number of age-related chronic inflammatory diseases. The ageing lung is marked by an increasing number of senescent cells, and evidence is mounting that senescence may directly contribute to a number of age-related respiratory diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Telomere dysfunction and alterations in mitochondrial homeostasis frequently occur in cellular senescence and are important to the development of the often detrimental senescence-associated secretory phenotype (SASP). The roles of telomeres, the mitochondria and cellular senescence in lung ageing and disease are discussed. Therapeutic interventions targeting cellular senescence are considered for delaying or potentially reversing age-related respiratory disease. [ABSTRACT FROM AUTHOR]

Aging is the leading risk factor for diminishing lung function, as well as injury and lung disorder. The target of our research was to examine the potential protective effect of naringin and the possible role of SIRT1 in mice with D-galactose-induced lung aging, by evaluating its effects on antioxidant systems, mitochondrial biogenesis, autophagy, and apoptosis, by referring to the potential involvement of Nrf2/NQO1, LKB1/AMPK/PGC-1α, FOXO1, and P53/caspase-3 signaling. The mice were randomly sorted into 5 groups (10 each): 1st: normal group received subcutaneous normal saline and intragastric distilled water, 2nd: naringin 300 mg/kg orally, 3rd: D-galactose (200 mg/kg/day) was administered subcutaneously into mice for eight weeks, to accelerate aging, 4th & 5th: oral naringin (150, 300 mg/kg) was given daily concurrently with D-galactose injection for 8 weeks. In silico investigation revealed that naringin substantially stimulates the SIRT1 and AMPK molecules. At the molecular level, our findings indicated that treatment with naringin stimulated the mitochondrial biogenesis pathway through regulation of the LKB1/AMPK/PGC-1α signals and upregulated FOXO1-mediated autophagy. Furthermore, naringin exhibited antioxidant properties by activating the Nrf2/NQO1 pathway and inhibiting MDA and AGEs levels. In addition, Naringin ameliorated alveolar spaces destruction and bronchial wall thickening, as well as alleviated P53/caspase-3 apoptosis signaling. Naringin exerts protective effects against D-galactose-induced lung aging and enhances longevity by activating SIRT1. SIRT1 regulates various aging-related molecular pathways via restoring pro-oxidant/antioxidant homeostasis, activation of mitochondrial biogenesis, modulating of autophagy and inhibition of apoptosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Aging is a major driving factor in lung diseases. Age-related lung disease is associated with downregulated expression of SIRT1, an NAD+-dependent deacetylase that regulates inflammation and stress resistance. SIRT1 acts by inducing the deacetylation of various substrates and regulates several mechanisms that relate to lung aging, such as genomic instability, lung stem cell exhaustion, mitochondrial dysfunction, telomere shortening, and immune senescence. Chinese herbal medicines have many biological activities, exerting anti-inflammatory, anti-oxidation, anti-tumor, and immune regulatory effects. Recent studies have confirmed that many Chinese herbs have the effect of activating SIRT1. Therefore, we reviewed the mechanism of SIRT1 in age-related lung disease and explored the potential roles of Chinese herbs as SIRT1 activators in the treatment of age-related lung disease. [Display omitted] • Aging is a major driving factor in lung diseases. • Age-related lung disease is associated with downregulated expression of SIRT1. • Activating SIRT1 could achieve anti-aging and improve age-related lung disease. • A variety of Chinese herbal medicine can act as SIRT1 activators, having the potential in the treatment of age-related lung disease. [ABSTRACT FROM AUTHOR]

Natural lung aging is marked by molecular changes that occur during development, maturation, and late-life decline. At the cellular and whole organ level, degenerative changes that are a hallmark of natural aging (shorter telomeres, increased expression of cellular senescence markers, increased DNA damage, oxidative stress, and apoptosis, accompanied by diminished elasticity) reach pathological levels in aging humans in the form of chronic respiratory disease. Aging strongly correlates with the development and incidence of chronic respiratory diseases, including cancer and idiopathic pulmonary fibrosis, but is most strongly linked with development of chronic obstructive pulmonary disease. Lung failure due to aging can be traced to loss of lung stem cell regenerative capacity within the distinctive stem cell niches found within each compartment of the lung. Current knowledge about the identity and function of these stem cell compartments has been largely drawn from a variety of transgenic and spontaneously mutated mouse models that are characterized by rapid rates of aging or have been used to examine regeneration from injury in the context of natural or accelerated aging. While much work has focused on the failure of epithelial cell populations as a key component of the aging process, additional studies have shown that aging, as a global phenomenon in the lung, also impacts resident endothelial, mesenchymal, and immune cell populations. In this review, we examine aging as a process dependent on specific changes in molecular pathways within multiple lung cell populations. [ABSTRACT FROM AUTHOR]

Lung aging is associated with structural remodeling, a decline of respiratory function and a higher susceptibility to acute and chronic lung diseases. Individual factors that modulate pulmonary aging include basic genetic configuration, environmental exposure, life-style and biography of systemic diseases. However, the actual aging of the lung takes place in pulmonary resident cells and is closely linked to aging of the immune system (immunosenescence). Therefore, this article reviews the current knowledge about the impact of aging on pulmonary cells and the immune system, without analyzing those factors that may accelerate the aging process in depth. Hallmarks of aging include alterations at molecular, cellular and cell-cell interaction levels. Because of the great variety of cell types in the lung, the consequences of aging display a broad spectrum of phenotypes. For example, aging is associated with more collagen and less elastin production by fibroblasts, thus increasing pulmonary stiffness and lowering compliance. Decreased sympathetic airway innervation may increase the constriction status of airway smooth muscle cells. Aging of resident and systemic immune cells leads to a pro-inflammatory milieu and reduced capacity of fighting infectious diseases. The current review provides an overview of cellular changes occurring with advancing age in general and in several cell types of the lung as well as of the immune system. Thereby, this survey not only aims at providing a better understanding of the mechanisms of pulmonary aging but also to identify gaps in knowledge that warrant further investigations. [ABSTRACT FROM AUTHOR]

Background: Given the heterogeneity of predisposing factors associated with pulmonary infarction (PI) and the lack of clinically relevant outcomes among patients with acute pulmonary embolism (PE) complicated by PI, further investigation is required., Methods: Retrospective study of patients with central PE in an 11-year period. Data were stratified according to the diagnosis of PI. Multivariable logistic regression analysis was used to analyze factors associated with PI development and determine if PI was associated with severe hypoxemic respiratory failure and mechanical ventilation use., Results: Of 645 patients with central PE, 24% ( n  = 156) had PI. After adjusting for demographics, comorbidities, and clinical features on admission, only age (OR 0.98, CI 0.96-0.99; p  = 0.008) was independently associated with PI. Regarding outcomes, 35% ( n  = 55) had severe hypoxemic respiratory failure, and 19% ( n  = 29) required mechanical ventilation. After adjusting for demographics, PE severity, and right ventricular dysfunction, PI was independently associated with severe hypoxemic respiratory failure (OR 1.78; CI 1.18-2.69, p  = 0.005) and mechanical ventilation (OR 1.92; CI 1.14-3.22, p  = 0.013)., Conclusions: Aging is a protective factor against PI. In acute central PE, subjects with PI had higher odds of developing severe hypoxemic respiratory failure and requiring mechanical ventilation.

Background: The prevalence of aging-related diseases has increased significantly and this imposes a burden on both families and society. The lung is one of the few internal organs that is continuously exposed to the external environment, and lung aging is associated with a number of lung diseases. Ochratoxin A (OTA) is a toxin that is widely present in food and the environment but an effect for OTA on lung aging has not been reported., Methods: Using both cultured lung cell and in vivo model systems, we studied the effect of OTA on lung cell senescence using flow cytometry, indirect immunofluorescence, western blotting, and immunohistochemistry., Results: Results obtained showed that OTA caused significant lung cell senescence in cultured cells. Furthermore, using in vivo models, results showed that OTA caused lung aging and aging fibrosis. Mechanistic analysis showed that OTA upregulated the levels of inflammation and oxidative stress, and that this may be the molecular basis of OTA-induced lung aging., Conclusions: Taken together, these findings indicate that OTA causes significant aging damage to the lung, which lays an important foundation for the prevention and treatment of lung aging., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Background: Early natural menopause has been regarded as a biomarker of reproductive and somatic aging. Cigarette smoking is the most harmful factor for lung health and also an established risk factor for early menopause. Understanding the effect of early menopause on health outcomes in middle-aged and older female smokers is important to develop preventive strategies.Objective: This study aimed to examine the associations of early menopause with multiple lung health and aging biomarkers, lung cancer risk, and all-cause and cause-specific mortality in postmenopausal women who were moderate or heavy smokers.Study Design: This study was conducted on postmenopausal women with natural (n=1038) or surgical (n=628) menopause from the Pittsburgh Lung Screening Study. The Pittsburgh Lung Screening Study is a community-based research cohort of current and former smokers, screened with low-dose computed tomography and followed up for lung cancer. Early menopause was defined as occurring before 45 years of age. The analyses were stratified by menopause types because of the different biological and medical causes of natural and surgical menopause. Statistical methods included linear model, generalized linear model, linear mixed-effects model, and time-to-event analysis.Results: The average age of the 1666 female smokers was 59.4±6.7 years, with 1519 (91.2%) of the population as non-Hispanic Whites and 1064 (63.9%) of the population as current smokers at baseline. Overall, 646 (39%) women reported early menopause, including 198 (19.1%) women with natural menopause and 448 (71.3%) women with surgical menopause (P<.001). Demographic variables did not differ between early and nonearly menopause groups, regardless of menopause type. Significant associations were identified between early natural menopause and higher risk of wheezing (odds ratio, 1.65; P<.01), chronic bronchitis (odds ratio, 1.73; P<.01), and radiographic emphysema (odds ratio, 1.70; P<.001) and lower baseline lung spirometry in an obstructive pattern (-104.8 mL/s for forced expiratory volume in the first second with P<.01, -78.6 mL for forced vital capacity with P=.04, and -2.1% for forced expiratory volume in the first second-to-forced vital capacity ratio with P=.01). In addition, early natural menopause was associated with a more rapid decline of forced expiratory volume in the first second-to-forced vital capacity ratio (-0.16% per year; P=.01) and incident airway obstruction (odds ratio, 2.02; P=.04). Furthermore, women early natural menopause had a 40% increased risk of death (P=.023), which was mainly driven by respiratory diseases (hazard ratio, 2.32; P<.001). Mediation analyses further identified that more than 33.3% of the magnitude of the associations between early natural menopause and all-cause and respiratory mortality were explained by baseline forced expiratory volume in the first second. Additional analyses in women with natural menopause identified that the associations between continuous smoking and subsequent lung cancer risk and cancer mortality were moderated by early menopause status, and females with early natural menopause who continued smoking had the worst outcomes (hazard ratio, >4.6; P<.001). This study did not find associations reported above in female smokers with surgical menopause.Conclusion: Early natural menopause was found to be a risk factor for malignant and nonmalignant lung diseases and mortality in middle-aged and older female smokers. These findings have strong public health relevance as preventive strategies, including smoking cessation and chest computed tomography screening, should target this population (ie, female smokers with early natural menopause) to improve their postmenopausal health and well-being. [ABSTRACT FROM AUTHOR]

Aging is associated with an increase in oxidative stress and inflammation. The aging lung is particularly affected since it is continuously exposed to environmental oxidants while antioxidant machinery weakens with age. Melatonin, a free radical scavenger, counteracts inflammation and apoptosis in healthy cells from several tissues. Its effects on the aging lung are, however, not yet fully understood. This study aimed to investigate the effect of chronic administration of melatonin on the expression of inflammation markers (TNF-α, IL-1β, NFκB2, HO-1) and apoptosis parameters (BAD, BAX, AIF) in the lung tissue of male senescence-accelerated prone mice (SAMP8). In addition, RNA oxidative damage, as the formation of 8-hydroxyguanosine (8-OHG), was also evaluated. Young and old animals, aged 2 and 10 months respectively, were divided into 4 groups: untreated young, untreated old, old mice treated with 1 mg/kg/day melatonin, and old animals treated with 10 mg/kg/day melatonin. Untreated young and old male senescence accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed. Lungs were collected and immediately frozen in liquid nitrogen. mRNA and protein expressions were measured by RT-PCR and Western blotting, respectively. Levels of 8-OHG were quantified by ELISA. Mean values were analyzed using ANOVA. Old nontreated SAMP8 animals showed increased (p < 0.05) mRNA and protein levels of TNF-α, IL-1β, NFκB2, and HO-1 compared to young mice and SAMR1 mice. Melatonin treatment with either dose reversed the aging-derived inflammation (p < 0.05). BAD, BAX and AIF expressions also rose with aging, the effect being counteracted with melatonin (p < 0.05). Aging also caused a significant elevation (p < 0.05) in SAMP8 8-OHG values. This increase was not observed in animals treated with melatonin (p < 0.05). In conclusion, melatonin treatment was able to modulate the inflammatory and apoptosis status of the aging lungs, exerting a protective effect on age-induced damage. [ABSTRACT FROM AUTHOR]