StefanHadzic1, SrikanthKarnati2, DjuroKosanovic1, MichaelSeimetz1
1) Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
2) Institute for Anatomy and Cell Biology II, Division of Medical Cell Biology, Justus Liebig University, Aulweg 123, D-35385 Giessen, Germany
Chronic obstructive pulmonary disease (COPD) is described as treatable and preventable, but also incurable disease, manifested as persistent airflow limitation with alveolar wall destruction resulting in emphysema which is not fully reversible(1). It is proven to involve inflammation, for instance induced by cigarette smoke, including oxidant-antioxidant and protease-antiprotease imbalances(2, 3). COPD is an increasing global health problem, which is predicted to become the third most common cause of death by 2030. On the one hand, tobacco smoke and air pollution in industrial countries, on the other hand, in house cooking with wood in developing countries are the major causes for COPD. However, in the time of increasing life expectancy, age may contribute to the development of COPD as well (Fig. 1). This is supported by observations that incidence of COPD positively correlates with advanced age (1, 4).
Aging is without doubt an important factor in many diseases (5,6), but there is also an intensive discussion about characterization of premature aging (7) and senescence, cellular aging and its involvement in diseases (8). This article aims to discuss if aging and senescence are critical events for the development of COPD/emphysema. Based on our previous article “Pulmonary arterial hypertension and aging: Is there a connection?” (Vol. 3, Issue 2) describing an involvement of aging in the context of pulmonary hypertension (PH), we now discuss its role in the context of COPD, a disease often associated with PH.
Aging is a natural and inevitable process represented as progressive loss of physiological integrity, leading to impaired function and lower adaptive capacity to stress (5, 9). Even though aging is one of the most obvious processes, clearly visible at all levels from the cell to organism, it still remains poorly understood. Despite intensive research, there is no unique strong, well-accepted hypothesis providing comprehensive explanation for the mechanism of aging (5, 6), in particular in the context of diseases. However, there are hypotheses which survived constant scientific challenging. Somatic mutation theory is one of them, which suggests mutations to be accumulated in somatic cells resulting in senescent phenotype(10). Mitochondrial theory suggests similar mechanism, but in mitochondrial DNA causing leaky electron transport chain and increased ROS release(11). Replicative senescence is supported by telomere loss theory, placing telomere shortening as hallmark of senescence(12). Indeed, stress and in particular oxidative stress (shown to be increased in COPD patients) are proven to cause telomere shortening(13). Altered protein and accumulated waste theories have also been postulated associated with decline in activities of proteasomes(14,15) and chaperones(16), and cellular waste accumulation(17). Kirkwood´s network theory (disposable soma theory) indicates a connection of the mentioned hypotheses. He believes that they occur simultaneously, causing, or at least supporting, each other (5, 18).
Not in all cases aging is linked to the chronological age. For that reason the term premature aging and senescence are used (5,8). Major efforts are made in distinguishing senescence and premature aging from the actual, chronological, aging of an organism (7). This gives a solid ground to continue discovering triggers (e.g. ROS, cigarette smoke)(4,9,19) and markers (e.g. telomerase activity, cell cycle arrest)(12,16) of senescence.
The lung, like any other organ, ages with progressive functional impairment and reduced capacity to respond to environmental stresses and injury (20, 21). Lung function declines with increasing age and that decline is even greater in smoking individuals (3, 22). Physiologic aging of the lung is associated with dilatation of alveoli with an enlargement of airspaces, a decrease in gas exchange surface area and elasticity (24). This age-dependent loss of elastin fibers is similar to the loss of skin elasticity and wrinkling of the skin that occurs in elderly (25). Age-related changes in lung, also called ‘senile emphysema’, do not include alveolar wall destruction or bronchial inflammation, the usual pathological changes seen in COPD patients (22). Also COPD in non-smokers is not just due to accelerated aging, but aging could contribute to the development of COPD in both, smokers and nonsmokers (22, 26).
Many studies show that telomeres are shorter in COPD patients, but it is unknown whether telomere shortening is a cause or a consequence of COPD (13). Telomere shortening occurs in normal aging and in smokers and patients with COPD. It provides a biological marker for aging and has a critical role in cellular senescence (7, 13, 19). Studies suggest that telomere shortening could make individuals more susceptible to the development of emphysema and lowers the threshold for damage induced by cigarettes (13).
Aging cells accumulate damaged proteins due to decreased autophagy (degradation and removal of damaged protein and organelles in lysosomes), and exposure to cigarette smoke can lead to additional cellular damage pushing cells towards senescence (17).
As mentioned above, the most known hallmarks of senescence include telomere attrition (11), cumulative DNA damage, impaired DNA repair (5, 10), protein damage (14, 16, 29) and accumulation of waste products(17). It is believed that this hallmarks lead to terminal cell cycle arrest as an evolutionary preserved defense mechanism preventing malignant transformation (27, 28). In lung alveoli, cells replicate to replace damaged cells but eventually cannot keep up with replacement because of replicative senescence. The consequences of the lack of alveolar cell replacement, which is the case in senescent lung, can be an increase in alveoli size and a decrease of the surface area (13). In aged tissue, this repair system may become inefficient due to the impaired regenerative capacity of stem cells, leading to the accumulation of senescent cells and lowering threshold towards damage which cannot be repaired (6, 26).
COPD pathology and aging are both complex processes involving many mechanisms on cellular level as well as on the level of whole organism. Despite the obvious connection, it still remains unclear which players are really important and in which conditions. Our brief discussion is aimed to stimulate thinking about a core riddle behind the COPD pathology and senescence/aging.
The question for interactive discussion
Based on the above described facts, ideas and suggestions, additionally we would like to raise few questions: Is there a strong connection between COPD/emphysema and aging? Is COPD/emphysema a cause or consequence of aging? Senescence and aging are shown to severely impair the regenerative potential of cells and tissues. Thus, does COPD/emphysema develop due to accumulated stress or inadequate repair? Is this disease age-related, or just the lung cannot recover anymore that efficiently? Should the focus of ongoing research be directed to the mechanisms of insult or repair? These questions are directed to all the scientists, clinicians and others interested in this topic across the world to try to answer and expose their own views, perspectives and visions in the next volume/issue of the PVRI Chronicle.
1. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007; 176:532-55.
2. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 2003; 22:672-88.
3. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1:1645–1648.
4. Karrasch S, Holz O, Jorres RA. Aging and induced senescence as factors in the pathogenesis of lung emphysema. Respiratory Medicine 2008; 102, 1215-1230.
5. Kirkwood, T.B. Understanding the odd science of aging. Cell 2005; 120, 437–447.
6. Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013; 153:1194–217
7. Johnson TE. Recent results: biomarkers of aging. Exp Gerontol 2006; 41:1243-6.
8. Vidak S and Foisner R. Molecular insights into the premature aging disease progeria. Histochem Cell Biol 2016; 145:401–417.
9. Bratic A, Larsson NG. The role of mitochondria in aging. J. Clin. Investig. 2013; 123, 951–957.
10. Promislow DE. DNA repair and the evolution of longevity: a critical analysis. J. Theor. Biol. 1994; 170, 291–300.
11. Wallace DC. Mitochondrial diseases in man and mouse. Science 1999; 283, 1482–1488.
12. Kim S, Kaminker P, and Campisi J. Telomeres, aging and cancer: in search of a happy ending. Oncogene 2002; 21, 5