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Translating Basic Research Into Clinical Practice |

COPD as a Disease of Accelerated Lung Aging FREE TO VIEW

Kazuhiro Ito, PhD*; Peter J. Barnes, MD, FCCP
Author and Funding Information

*From Airways Disease Section, National Heart and Lung Institute, Imperial College London, UK.

Correspondence to: Kazuhiro Ito, PhD, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, UK; e-mail: k.ito@imperial.ac.uk

*VCAM = vascular cell adhesion molecule; iNOS = inducible nitric oxide synthase; ICAM = intercellular adhesion molecule; VEGF = vascular endothelial growth factor; ↑ indicates increase, enhance; ↓ indicates decrease; → indicates no change; ? indicates unknown.

The authors have no financial relationship with a commercial entity that has an interest in the subject of this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


The authors have no financial relationship with a commercial entity that has an interest in the subject of this article.

The authors have no financial relationship with a commercial entity that has an interest in the subject of this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(1):173-180. doi:10.1378/chest.08-1419
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There is increasing evidence for a close relationship between aging and chronic inflammatory diseases. COPD is a chronic inflammatory disease of the lungs, which progresses very slowly and the majority of patients are therefore elderly. We here review the evidence that accelerating aging of lung in response to oxidative stress is involved in the pathogenesis and progression of COPD, particularly emphysema. Aging is defined as the progressive decline of homeostasis that occurs after the reproductive phase of life is complete, leading to an increasing risk of disease or death. This results from a failure of organs to repair DNA damage by oxidative stress (nonprogrammed aging) and from telomere shortening as a result of repeated cell division (programmed aging). During aging, pulmonary function progressively deteriorates and pulmonary inflammation increases, accompanied by structural changes, which are described as senile emphysema. Environmental gases, such as cigarette smoke or other pollutants, may accelerate the aging of lung or worsen aging-related events in lung by defective resolution of inflammation, for example, by reducing antiaging molecules, such as histone deacetylases and sirtuins, and this consequently induces accelerated progression of COPD. Recent studies of the signal transduction mechanisms, such as protein acetylation pathways involved in aging, have identified novel antiaging molecules that may provide a new therapeutic approach to COPD.

Figures in this Article

COPD is a major and increasing global health problem with enormous amount of expenditure of indirect/direct health-care costs.1 COPD now affects > 10% of the world population over the age of 40 years,1 and the burden of disease is particularly high in developing countries. There is still a fundamental lack of knowledge about the cellular, molecular, and genetic causes of COPD, and current therapies are inadequate because no treatments reduce disease progression or mortality. COPD is caused by long-term inhalation of noxious gases and particles, such as cigarette smoke, and a chronic inflammatory disease of the lower airways and lung parenchyma, which is enhanced during exacerbations.2 The pathologic characteristics of COPD are destruction of the lung parenchyma (emphysema), inflammation of peripheral and central airways, and an increase in mucus-producing cells. Airflow limitation, measured by reduced FEV1, progresses very slowly over several decades, so that most patients with symptomatic COPD are in late middle age or are elderly. Thus, the prevalence of COPD is age dependent, suggesting an intimate relationship between the pathogenesis of COPD and aging.

Senescence or aging is defined as the progressive decline of homeostasis that occurs after the reproductive phase of life is complete, leading to an increasing risk of disease or death. Kirkwood3 has advanced the concept of “disposable soma,” in which aging, rather than being programmed and determined by selected genes, results from the stochastic interaction between injury and repair, as the result of the energy devoted by an individual to maintain organ integrity and protect DNA against oxidative injury. In this model, the failure of organ/cell maintenance/repair results from the integrated action among genes, environment, and intrinsic defects of the organism. Underlying the aging process is a lifelong, bottom-up accumulation of molecular damage. Kirkwood3 also makes the point that cellular defects often cause inflammatory reactions, which can themselves exacerbate existing damage, so that inflammatory and antiinflammatory factors can play a part in shaping the outcomes of the aging process. Thus, aging-associated inflammation/structural change is the results of failure of reactive oxygen species (ROS) elimination, failure of repair of damaged DNA, and telomere shortening, as shown below.

In many human somatic tissues and cells such as fibroblasts, there is a decline in cellular division capacity with age or a limited division potential before undergoing so-called replicative senescence. This appears to be linked to the fact that the telomeres, which protect the ends of chromosomes, get progressively shorter as cells divide. Oxidative stress has been found to have an even bigger effect on the rate of telomere loss,4 and telomere shortening is greatly accelerated (or slowed) in cells with increased (or reduced) levels of oxidative stress.

Somatic mutations can occur in any of the cells of the body, and this somatic mutation and other forms of DNA damage have been demonstrated to be increased age dependently. Promislow5 reported a general relationship between longevity and DNA repair. Thus, the capacity for DNA repair may be an important determinant of the rate of aging at the cell and molecular level.

Harman6 suggested that ROS, formed during normal oxygen metabolism, induce damage, the accumulation of which accounts for progressive deleterious changes called aging or senescence. This hypothesis is called the free radical theory of aging and has later been extensively supported by numerous in vivo and in vitro studies710 showing that age-related changes is accelerated under the influence of oxidative stress, while various antioxidants slow aging. This oxidative stress causes DNA damage and increases risk of cancer, as documented for the role of mammary gland senescence and the increased risk of breast cancer.

Antiaging Molecules:

Recent advance in aging research is identification of antiaging molecules. Sirtuins are nicotinamide adenine dinucleotide- dependent histone/protein deacetylases and display differential specificity toward acetylated substrates, which translates into an expanding range of physiologic functions, such as gene expression, cell cycle regulation, apoptosis, metabolism, and aging.11 Seven molecules have been identified in the human sirtuin family (SIRT1–SIRT7). As well as sirtuins (type III histone deacetylase [HDAC]), HDAC-2 (a type I HDAC) is also reported to be an antiaging molecule as knock-down of HDAC-2 induces cellular senescence by enhancing p53-dependent transrepression and transactivation of a subset of target genes.12

Homozygous mutant klotho (KL−/−) mice have a short lifespan and have pulmonary emphysema as well as some other aging phenotypes, such as arteriosclerosis, osteoporosis, skin atrophy, and ectopic calcifications13 (Table 1). The secreted Klotho protein can regulate multiple growth factor signaling pathways, including insulin/insulin-like growth factor and Wnt, and the activity of multiple ion channels. Klotho protein also protects cells and tissues from oxidative stress, yet the precise mechanism underlying these activities remains to be determined. The development of emphysema in KL−/− mice is due increased expression of matrix metalloproteinase (MMP)-9.

Table Graphic Jump Location
Table 1 Aging and Emphysema in Gene-Modified Mice

Senescence marker protein-30 (SMP30), a 34-kd protein originally identified from the rat liver, is a novel molecule that decreases with age in an androgen-independent manner. SMP30 is widely expressed in vertebrates and highly conserved. The SMP30 out (SMP30Y/–) mouse has a shorter life span, and has had senile lung with age-related airspace enlargement and enhanced susceptibility to harmful stimuli14 (Table 1). Cigarette smoke exposure generates marked airspace enlargement with significant parenchymal destruction in the SMP30Y/– mice.15 Protein carbonyl, a marker of oxidative stress that increases with aging, was also significantly increased after 8 weeks of exposure to cigarette smoke. Thus, SMP30 protects mice lungs from oxidative stress associated with aging and smoking.

The molecules responsible for DNA repair, such as DNA-dependent protein kinase (DNA-PK) and Ku86 (or Ku80), are also a sort of antiaging molecules. As shown in Table 1, DNA-PK knockout mice showed telomere shortening and intestinal atrophy, which are seen as aging phenotypes. Ku86 knockout mice also showed the early onset of age-specific changes characteristic of senescence in mice.16 In either DNA-PK knockout or Ku-86 knockout mice, structural change in lung and lung function have not been evaluated. FOXO transcription factor belongs to the large Forkhead family of proteins, a family of transcriptional regulators characterized by a conserved DNA-binding domain termed the forkhead box.17 They are important transcriptional factors for DNA repair and production of antioxidants, such as mononuclear superoxide dismutase and catalase. FOXO factors promote longevity and reduce age-dependent diseases in invertebrates. The role of FOXO in lung disease has not yet been evaluated.

Defective Protein Turnover:

Protein turnover is essential to preserve cell function by removing proteins that are damaged, mistranslated, or redundant. Age-related impairment of protein turnover is indicated by the accumulation over time of damaged proteins, and there is evidence that an accumulation of altered proteins contributes to a range of age-related disorders, including cataract, Alzheimer disease, and Parkinson disease. Protein turnover involves the functions of chaperones, which help to sequester and, if possible, restore denatured proteins, and of proteasomes, which degrade proteins via ubiquitination. With aging, there is evidence for functional decline in the activities of both proteasomes and chaperones.18

The classical epidemiologic studies of Fletcher and Peto19 demonstrated that death and disability from COPD were related to an accelerated decline in lung function with time, with a loss of 50 to 100 mL in FEV1 per year, but even in healthy volunteers there is a loss of 20 mL per year with aging (Fig 1). Janssens and coworkers20 demonstrated that physiologic aging of the lung is associated with dilatation of alveoli with an enlargement of airspaces and a decrease in gas exchange surface area, together with a loss of supporting tissue for peripheral airways (“senile emphysema”), resulting in decreased static elastic recoil of the lung and increased residual volume and functional residual capacity. This age-dependent loss of elastin fibers is similar to the loss of skin elasticity and wrinkling of the skin that occurs with age. However, Verbeken and coworkers.21 proposed that the changes in structure and functional characteristics caused by isolated airspace enlargement that are seen in the elderly lung be differentiated from emphysema by the absence of alveolar wall destruction.

Figure Jump LinkFigure 1 Hypothesis of development of COPD by an accelerating lung aging. Aging is defined as the progressive decline of homeostasis, and this is the result of failure of organ maintenance from DNA damage, oxidative stress, and telomere shortening. During aging, pulmonary function deteriorates progressively and pulmonary inflammation is increased with structural changes in the lung parenchyma and small airways. Environmental exposure, for example cigarette smoke, may accelerate aging-dependent defective lung functionGrahic Jump Location

Functionally, vital capacity is reduced with aging, although the total lung capacity remains quite constant.22 Respiratory muscle strength also decreases with aging.23 Expiratory flows decrease with a characteristic alteration in the flow-volume curve suggesting small airway disease. Decreased sensitivity of respiratory centers to hypoxia or hypercapnia results in a diminished ventilatory response in cases of aggravated airway obstruction. Thus, aging lungs exhibit both structural and functional alterations.18

Most age-associated diseases, such as Alzheimer disease, cataract, rheumatoid arthritis, osteoporosis, and cardiovascular disease as well as COPD, involve chronic inflammation, including infiltration of inflammatory cells and higher circulating or local concentrations of proinflammatory cytokines. Increased production of oxygen-derived free radicals is a primary driving force for aging and activate redox-sensitive transcriptional factors, such as activator protein-1 and nuclear factor-κB (NF-κB), which switch on multiple genes encoding proinflammatory molecules.24 The regulation of NF-κB is greatly influenced by the intracellular redox status and plays a major role in the regulation of inflammation process during aging. Increased NF-κB activity during aging is due to hyperphosphorylation of inhibitory κBα. Activation of signal transducer, signal transducer and activator of transcription-3, and signal transducer and activator of transcription-5, which are downstream of IL-6 signaling, is also reported in T-cells from elderly subjects.25 Stress kinases also play important roles in aging process. Phospho-inositide 3 kinase (PI3K) and mitogen-activated protein kinase are known as aging kinases (Fig 2).

Figure Jump LinkFigure 2 Molecular mechanisms of aging and development of COPD. Accumulation of endogenous ROS induce DNA damage, NF-κB activation via phosphorylation of IκBα, activates oxidative stress responsible kinases (MAPK [mitogen-activated protein kinase], PI3K), reduced sirtuin activity, and proteasome inhibition. This result in chromatin structure instability and amplified inflammation as well as structural change by apoptosis and hyperplasia. Cigarette smoking enhances all of these mechanisms and also decreases HDAC expression and antioxidant/nitrosant activity, resulting in further amplification of inflammation and accumulation of oxidated/nitrated proteins. Lung image is from http://www.yourlunghealth.org/lung_disease/copd/index.cfmGrahic Jump Location

As the results of transcriptional factors activation by ROS, several genes are known to be regulated with aging process.18 Cyclooxygenase is an enzyme responsible for prostaglandin synthesis, and cyclooxygenase messenger RNA level and cyclooxygenase activation increase with aging. This prostaglandin synthesis pathway contributes to ROC accumulation during aging. Nitric oxide is also increased with age by increase in inducible nitric oxide synthase expression. Nitric oxide interacts with oxygen radicals to form peroxynitrite, which induces nitration of tyrosine residues of proteins. Accumulation of nitrotyrosine deposits is found in age-related diseases such as COPD and Alzheimer disease, and nitration alters enzyme activity and protein stability. Increased levels of interleukin (IL)-1β, IL-6, IL-8, IL-18, IL-1 receptor antagonist, and tumor necrosis factor (TNF)-α are also found in plasma and mononuclear blood cell culture from elderly subjects as well as serum.18 It is also reported that the immune system is impaired with aging, and this may lead to a reduction in the adaptive immune response. In contrast to IL-6 and IL-8, IL-2 production is decreased with aging, suggesting a decrease in the clonal expansion of T cells leading to a decrease in the specific immune response.18 This situation creates an imbalance between the adaptive and innate immune responses.

The number of neutrophils in the lower respiratory tract of healthy elderly individuals is increased,26 and there is increased release of neutrophil elastase, which could contribute to the loss of elastic recoil and of elastin fibers in the aging lung, which in turn would reduce interdependence between the airways and parenchymal structures, thus contributing to deterioration of lung function. Glucocorticoid sensitivity is reduced during aging as well as in COPD. For example, dexamethasone-induced tyrosine aminotransferase and tryptophan oxygenase activities as the markers of steroid-induced transactivation are decreased with age,27 and several reports18,28 show a decline in glucocorticoid receptor expression during aging.

Reactive oxygen species-induced stress kinase activation is also one of age-related process. PI3K is known as aging kinase29 and is activated by oxidative stress. We also found cigarette smoke to be a strong stimulant of PI3K, and this involves in HDAC-2 inactivation seen under oxidative stress (in preparation).

It is not clear how the aging process is involved in the decline of lung function and inflammation in COPD. However, there are a lot of similarities between aged lung and COPD lung (Table 2). Especially, there have been important advances in understanding the molecular mechanisms of ages, and several of these pathways are relevant to accelerated lung aging in COPD patients.

Table Graphic Jump Location
Table 2 Comparison of Aged Lung With COPD Lung*

*VCAM = vascular cell adhesion molecule; iNOS = inducible nitric oxide synthase; ICAM = intercellular adhesion molecule; VEGF = vascular endothelial growth factor; ↑ indicates increase, enhance; ↓ indicates decrease; → indicates no change; ? indicates unknown.

As shown in the model in Figure 1, lung function is declined in COPD quicker than normal aged lung. The lung function/age curve looks to be shifted leftward in COPD patients. Thus, we hypothesized that emphysema/chronic obstruction may be one of the phenomena underlying accelerated lung aging process resulting from a failure of lung maintenance and repair due to significant and sustained lung injury by exposed cigarette smoke, air particulates, and pollutants (Fig 1).

Functionally, vital capacity is reduced with aging as well as in COPD, although the total lung capacity remains constant. Respiratory muscle strength also decreases in COPD as similar to aging process. There are several similarities in inflammation between aging and COPD, such as neutrophil accumulation, NF-κB activation,30 and increase in IL-6/IL-8/TNF-α. COPD patients are also corticosteroid insensitive as similar to healthy aged people.

At the molecular level, there is also evidence that COPD lungs have shortened telomeres as compared with age-matched nonsmoker lungs. Telomere length has been demonstrated to be significantly shorter in patients with emphysema than in asymptomatic nonsmokers in alveolar type II cells and endothelial cells,31 peripheral blood mononuclear cells,32 and fibroblast.33

As suggested in “the free radical theory of aging” by Harman,6 ROS accounts for progressive deleterious changes called aging or senescence. There is ample evidence that oxidative stress plays a major role in COPD,34 with increased expression of markers of oxidative stress in patients with COPD systemically and in diseased lung. DNA damage is induced by oxidative stress and cigarette smoke, and these are risk factors for carcinogenesis. In fact, patients with COPD have an increased risk for lung cancer, suggesting cellular senescence could also explain the significantly increased rate of lung cancers in emphysematous patients by DNA damage. Increased in nitrotyrosine deposition is also a feature seen in COPD lung as well as aged tissue. This is the evidence of an increase in nitrative/oxidative stress, and reduction of antioxidant/nitrosant activity may contribute to this accumulation of nitrated and oxidized protein. Furthermore, defect of protein degradation system in COPD or aging cannot be ruled out.

Antioxidant enzyme and activity is also decreased in COPD, like aging. Superoxide dismutase enzyme activity is reported to be lower in long-term healthy smokers and in stable COPD patients than in healthy adults,35 although this is still controversial.36 COPD patients also have reduced total antioxidant capacity. Furthermore, ferric-reducing antioxidant power is lower in COPD patients, and it had a positive correlation with the severity of airways obstruction (FEV1 percentage of predicted).

Furthermore, expression of antiaging molecules are reduced in COPD. We already reported that SIRT1 was selectively reduced in lung tissue and peripheral blood mononuclear cells in COPD,37 in agreement with a recent report.38 We also found that SIRT1 is a major inhibitory regulator of MMP-9, and reduction in SIRT1 may cause structural change of lung, such as emphysema. Interestingly COPD patients show exaggerated skin wrinkling compared to normal smokers, and this has been associated with increased MMP-9 expression by keratinocytes.39 SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes, and SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage. It is unknown whether SIRT6-deficient mice have emphysema or not, but at least we preliminarily showed that SIRT6 expression is also reduced in COPD lung.26 We have already shown that HDAC-2 is markedly reduced in COPD in activity and expression in peripheral lung tissue and alveolar macrophages, especially in more severe disease, and that this reduction is involved in enhancing inflammation and corticosteroid insensitivity.40,41 Furthermore, preliminary studies have found that Klotho and SMP-30 levels are also decreased in COPD lung (unpublished data; October 26, 2006).

Greater understanding of the molecular mechanisms of aging has revealed several novel targets for drug development, and since these processes are involved in the pathogenesis of emphysema this may lead to new treatments for COPD. From the oxidative stress/aging theory and the fact that oxidative stress is major risk factor of COPD, antioxidants are likely to be effective antisenescence drugs or anti-COPD drugs. Currently available antioxidants, such as N-acetyl cysteine, are not very potent and may not sufficiently reduce oxidative stress in the lungs. Novel and more potent antioxidants are needed in the future, and there are several drugs in development, including new glutathione and superoxide dismutase analogues. Nrf2 (nuclear factor-E2–related factor-2) and FOXO are the transcription factors to induce endogenous antioxidant molecules and potential target to increase antioxidant activity. In fact, sulforaphane, which is extracted from brocolli, is reported to be a Nrf2 activator.42

Sirtuins are antiaging molecules and control oxidative stress resistance, DNA repair, and inflammation. Resveratrol is a polyphenol found in red wine and the skin of red fruits, which has antioxidant effects. Resveratrol is also a sirtuin activator, and this property has been proposed to account for its antiaging effects.43 Recently a SIRT1-specific activator that is 1,000-times more potent than resveratrol has been developed and examined possibility as therapy for diabetics.44 Theophylline is also reported to inhibit nicotinamide adenine dinucleotide consumption by poly (adenosine diphosphate ribose)–polymerase-1 activation and may therefore restore SIRT1 activity reduced under oxidative stress. Theophylline is also a class I HDAC activator and activates HDAC-2, an antiaging HDAC in pulmonary cells.45 SIRT6 activator will be another option to inhibit accelerated aging in lung.

The link between aging and the pathogenesis of COPD is strongly supported by numerous studies.4650 Senescence is a complex outcome of both intrinsic and environmental factors, especially oxidative stress, and therefore the role of cigarette smoke/noxious gas is a key factor linking aging lung to COPD. However, the molecular mechanisms are not yet been fully explored. Recently, a number of antiaging molecules have been identified, and evaluation of these molecules in patients with COPD might identify several new molecular targets for the treatment of COPD.

DNA-PK

DNA-dependent protein kinase

HDAC

histone deacetylase

IL

interleukin

MMP

matrix metalloproteinase

NF-κB

nuclear factor-κ B

PI3K

phospho-inositide 3 kinase

ROS

reactive oxygen species

SMP30

senescence marker protein-30

TNF

tumor necrosis factor

We regret that owing to space constraints we were not able to cite all the important original publications and apologies to those authors whose work we have not cited.

We regret that owing to space constraints we were not able to cite all the important original publications and apologies to those authors whose work we have not cited.

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Kojima S, Sakakibara H, Motani S, et al. Incidence of chronic obstructive pulmonary disease, and the relationship between age and smoking in a Japanese population. J Epidemiol. 2007;17:54-60. [PubMed] [CrossRef]
 

Figures

Figure Jump LinkFigure 1 Hypothesis of development of COPD by an accelerating lung aging. Aging is defined as the progressive decline of homeostasis, and this is the result of failure of organ maintenance from DNA damage, oxidative stress, and telomere shortening. During aging, pulmonary function deteriorates progressively and pulmonary inflammation is increased with structural changes in the lung parenchyma and small airways. Environmental exposure, for example cigarette smoke, may accelerate aging-dependent defective lung functionGrahic Jump Location
Figure Jump LinkFigure 2 Molecular mechanisms of aging and development of COPD. Accumulation of endogenous ROS induce DNA damage, NF-κB activation via phosphorylation of IκBα, activates oxidative stress responsible kinases (MAPK [mitogen-activated protein kinase], PI3K), reduced sirtuin activity, and proteasome inhibition. This result in chromatin structure instability and amplified inflammation as well as structural change by apoptosis and hyperplasia. Cigarette smoking enhances all of these mechanisms and also decreases HDAC expression and antioxidant/nitrosant activity, resulting in further amplification of inflammation and accumulation of oxidated/nitrated proteins. Lung image is from http://www.yourlunghealth.org/lung_disease/copd/index.cfmGrahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Aging and Emphysema in Gene-Modified Mice
Table Graphic Jump Location
Table 2 Comparison of Aged Lung With COPD Lung*

*VCAM = vascular cell adhesion molecule; iNOS = inducible nitric oxide synthase; ICAM = intercellular adhesion molecule; VEGF = vascular endothelial growth factor; ↑ indicates increase, enhance; ↓ indicates decrease; → indicates no change; ? indicates unknown.

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