Zeitschrift für Gerontologie und Geriatrie

, Volume 46, Issue 7, pp 613–622 | Cite as

Cellular senescence in normal and premature lung aging

Beiträge zum Themenschwerpunkt

Abstract

The incidence of chronic respiratory diseases (e.g., chronic obstructive pulmonary disease, COPD) and interstitial lung diseases (e.g., pneumonia and lung fibrosis) increases with age. In addition to immune senescence, the accumulation of senescent cells directly in lung tissue might play a critical role in the increased prevalence of these pulmonary diseases. In the last couple of years, detailed studies have identified the presence of senescent cells in the aging lung and in diseased lungs of patients with COPD and lung fibrosis. Cellular senescence has been shown for epithelial cells of bronchi and alveoli as well as mesenchymal and vascular cells. Known risk factors for pulmonary diseases (cigarette smoke, air pollutions, bacterial infections, etc.) were identified in experimental studies as being possible mediators in the development of cellular senescence. The present findings indicate the importance of cellular senescence in normal lung aging and in premature aging of the lung in patients with COPD, lung fibrosis, and probably other respiratory diseases.

Keywords

Cellular senescence Lung Aging Pulmonary disease Smoking 

Abbreviations

53BP1

p53-binding protein-1

ATM

ataxia telangiectasia-mutated

ATR

ATM- and Rad-3-related kinase

CDC

cell division cycle

CDK

cyclin-dependent kinase

Chk

checkpoint kinase

COPD

chronic obstructive pulmonary disease

CKI

cyclin-dependent kinase inhibitor

DDR

DNA damage response

DNA-PK

DNA-dependent protein kinase

ds

double stand

GADD45

growth arrest and DNA damage 45

HR

homologue recombination

hTERT

telomerase catalytic subunit

IPF

idiopathic pulmonary fibrosis

ICD-10

international statistical classification of diseases and related health problems, version 10

IL

interleukin

MAPK

mitogen-activated protein kinase

MCP-1

monocyte chemotactic protein-1

mTOR

mammalian target of rapamycin

NAD

nicotinamide adenine dinucleotide

NHEJ

non-homologue end-joining

NF-κB

nuclear factor κ-light-chain-enhancer of activated B-cells

P

phosphorylated

p16Ink4a

protein 16 (CKI 2A)

p19Arf

protein 19 (CKI 2A)

p21Cip1/Waf1

protein 21 (cyclin-dependent kinase inhibitor protein 1A)

p53

protein 53

pRb

retinoblastoma susceptibility protein

SA

senescence-associated

SAHF

senescence-associated heterochromatin foci

SAM

senescence accelerated mouse

SIRT

sirtuin (silent mating type information regulation)

Src

Swiss raid commando

Zelluläre Seneszenz bei normaler und verfrühter Lungenalterung

Zusammenfassung

Chronische Atemwegserkrankungen, insbesondere die chronisch obstruktive Lungenerkrankung (COPD), sowie interstitielle Lungenerkrankungen wie die Pneumonie und die Lungenfibrose nehmen mit dem Alter deutlich zu. Dabei könnte neben der Immunseneszenz auch das vermehrte Auftreten von seneszenten Zellen direkt in der Lunge eine wichtige Rolle spielen. In den letzten Jahren wiesen detaillierte Studien seneszente Zellen in der alten Lunge und in der erkrankten Lunge von Patienten mit COPD oder Lungenfibrose nach. Neben den epithelialen Zellen von Bronchien und Alveolen waren von der Seneszenz auch Bindegewebszellen und Gefäßzellen betroffen. Mithilfe experimenteller Studien wurden bekannte Risikofaktoren von Atemwegserkrankungen (Zigarettenrauch, Luftverschmutzung, bakterielle Infektionen etc.) als mögliche Auslöser der zellulären Seneszenz identifiziert. Die Erkenntnisse weisen auf die Bedeutung der zellulären Seneszenz bei der normalen Lungenalterung hin, aber auch bei der verfrühten Alterung der Lunge bei Patienten mit COPD, Lungenfibrose oder möglicherweise anderen Atemwegserkrankungen.

Schlüsselwörter

Zelluläre Seneszenz Lunge Altern Lungenerkrankungen Rauchen 

Aging is a natural process characterized by a progressive functional impairment and reduced capacity of organs and tissues to respond adaptively to environmental factors. Cellular senescence, apoptotic cell death, oxidative/carbonyl stress, protein modifications, and altered gene/protein expressions have been suggested to contribute to aging and age-associated diseases. Here, I review the identification of senescent cells in lung and their potential importance in normal lung aging as well as premature lung aging as observed in chronic respiratory diseases.

Aging and respiratory diseases

In addition to age-related changes of the thoracic cage and immune system, aging of lung tissue essentially contributes to the post-maturation decline in the respiratory function [1]. Lung tissue of old individuals is characterized by an enlargement of the alveoli and an increased diameter of alveolar ducts/sacs and higher-order respiratory bronchioles (i.e., distal duct ectasia). The alveolar walls are thicker, which might result from the cumulative deposition of basement membrane material due to the lifelong cell turnover. Qualitative changes of elastin and collagen cause reduced elasticity of bronchial and alveolar walls. Moreover, the density of lung capillaries per alveolus is reduced. These structural changes of lung parenchyma and small airways are the reason for numerous physiological changes with higher age, such as increased residual and closing volume, impaired pulmonary gas exchange, and reduced lung elastic recoil.

Air flow and vital capacity of the lung are usually determined in pulmonary function tests to assess respiratory capacity, which decreases progressively after maturation. This progressive decline starts already at about 20 years of age for women and 25 years for men, and it is accelerated by chronic exposure to cigarette smoke [2]. Despite the relevance of other noxious environmental substances to pulmonary dysfunction, such as pollutants emitted from incineration plants and particulate matters, cigarette smoke is the major risk factor for the development of respiratory diseases and lung cancer [3, 4]. In Germany, more than 110,000 persons die annually from respiratory diseases, lung cancer, and diseases of the pulmonary circulation [5]. The age-dependent analysis of causes of death demonstrates that among all causes of death the death rate due to lung cancer reaches its maximum when the persons are between 60 and 70 years old, whereas the relative mortality due to pulmonary heart diseases is less affected by age (Fig. 1a). In contrast, the death rate due to respiratory diseases steadily increases with higher age (Fig. 1a) but a subgroup analysis shows that, similar to lung cancer, the death rate due to chronic respiratory diseases also reaches its maximum when the persons are around 65 years old (Fig. 1a). This analogy is well explainable by the high prevalence of lung cancer in patients suffering from chronic respiratory diseases [6]. Although the statistical data indicate that people who reach old age are less susceptible to chronic respiratory diseases, mortality due to pneumonia induced either by pathogens or fluid/solid substances increases steadily (Fig. 1b). In particular, a decline in the immune function might be a major factor for this age-dependent increase in pneumonia and, thus, pneumonia-mediated death [7]. Waning immunity with increasing age is highly associated with the senescence of immune cells, which are characterized by the shortening length of the termini of linear chromosomes, called telomeres [8]. Smoking cigarettes significantly enhances age-related shortening of telomeres in immune cells [9, 10].

Fig. 1

Age-dependent death for selected lung diseases a relative to all death causes and b relative to death due to all respiratory diseases (1998–2011 according to ICD-10). (Adapted from [5])

Markers of cellular senescence

Telomere length is an appropriate indicator for the senescence of immune cells because immune cells replicate more often than most other cell types throughout life. Since telomerase, which normally maintains the telomeres, is less active in somatic cells, telomere shortening results finally in the uncapping of telomeres and, consequently, irreversible growth arrest [11]. In addition to telomere shortening/uncapping as a specific form of DNA damage, other forms of DNA damage are characteristic for a senescent cell phenotype. This includes DNA damage following sublethal exposure to various types of radiation, oxidants/free radicals or highly reactive chemical compounds (genotoxic stress), and DNA damage following permanent growth stimulation (oncogenic stress) [12]. Genotoxic stress often damages both strands of the DNA, but it can also cause telomere shortening due to the higher susceptibility of the GC-rich telomere sequence to oxidative damage [13].

Cellular senescence by a critical number of cell replications (replicative senescence), or by genotoxic or oncogenic stress (stress-induced premature senescence-like phenotype [SIPS]) is mediated by a cellular process called the DNA damage response (DDR) pathway [14, 15, 16]. Although this cellular pathway does not necessarily trigger irreversible cell cycle arrest but the reversible arrest allowing DNA repair, cellular senescence results from DDR activation when DNA damage cannot be repaired (Fig. 2). That means cellular senescence is a permanently maintained DDR state, mainly in the G1 cell cycle phase. Because the irreversible cell cycle arrest also triggers cell death by apoptosis, cellular senescence and apoptosis occur simultaneously (Fig. 2). The increase in both cellular senescence and apoptosis is suggested to play an essential role in lung aging and the development of age-related respiratory diseases, whereas the age-related increase in lung cancer also results from the replication of damaged cells which were incorrectly repaired (Fig. 2). However, this is not specific for the lung but rather common for all aging organs and tissues. Especially the epithelial cells in organs and tissues are more often subjected to DNA damage and subsequent DDR activation than other cell types because of their relatively high exposure to environmental factors that can cause DNA damage. This fact also explains the high prevalence of epithelial types of cancer (carcinomas) with increasing age [5].

Fig. 2

Simplified presentation of the fate of lung epithelial cells after DNA damage and its contribution to aging and cancer of the lung but also other organs rich in epithelial cells

The detection of DDR compounds is commonly used to identify senescent cells in organs and tissues because some other senescence-associated (SA) cell characteristics, such as irreversible growth arrest and SA cell morphology, are hardly detectable in situ. As presented in Fig. 3, DDR activation triggers both cell cycle arrest and induction of the DNA repair mechanism depending on the cell cycle phase in which the damage occurred [16, 17]. Both processes are mediated by activation of the ataxia telangiectasia-mutated (ATM) kinase, ATM- and Rad-3-related (ATR) kinase and DNA-dependent protein kinase (DNA-PK). Cellular senescence is mainly associated with an irreversible arrest in the G1 cell cycle phase, in which down-stream activation of ATM/ATR kinase substrates plays a central role. Among these substrates are the checkpoint kinases (Chk) 1 and 2, and the transcription factor p53. Activation of p53 stimulates the gene expression of several targets, including the cyclin-dependent kinase (CDK) inhibitor p21Cip1 and other factors blocking CDKs (e.g., GADD45, 14-3-3), but also apoptosis-inducing factors. p21Cip1 inhibits CDK4/6 and CDK2 which causes an accumulation of the retinoblastoma protein (pRb), a regulator of the transcription factor E2F, in its unphosphorylated form in which pRb activates E2F. Finally, the expression of E2F target genes mediates the cell cycle arrest. Cell cycle arrest via p53/p21Cip1 can be stabilized by another pathway via p16Ink4a, which is often induced in response to oncogenic stress [18]. Moreover, Chk1/2 activation by ATM/ATR kinases can stabilize cell cycle arrest. Among all these factors involved in DDR, the activation of ATM/ATR kinases and Chk1/2 as well as the increased expression level of p53, p21Cip1, p16Ink4a and pRb were frequently used to identify senescent cells in lung tissue (Tab. 1 and Tab. 2). Moreover, senescent lung cells are characterized by activation (phosphorylation) of the p53-binding protein 1 (53BP1), which occurs upstream of Chk1/2 activation [19, 20]. Besides the activation of compounds of the DDR pathways, compounds of other signalling pathways have been detected in senescent lung cells. This includes the activation of mitogen-activated protein kinase (MAPK) p38 [21, 22], Src kinase [23], or nuclear factor-κB(NF-κB) [24].

Fig. 3

DNA damage triggers the activation of cell cycle checkpoints by transducer proteins (ATM, ATR, DNA-PK) and effector proteins (e.g., Chk2, p53), which leads to an arrest of the cell cycle at the G1/S, intra-S, or G2/M phase. DNA damage can be repaired by non-homologues end-joining (NHEJ) or homologue recombination (HR) during cell cycle arrest. Telomere shortening can be repaired by telomerase with its catalytic subunit hTERT. Cellular senescence is mainly associated with an irreversible arrest in the G1 cell cycle phase. Therefore, selected proteins of the DNA damage response are used for detecting cellular senescence (e.g., ATM, p21Cip1, pRb)

Tab. 1

Detection of senescent cells in lung

Model (species)

SA phenotype detection

Ref.

Location

DDRa

SAHFb

β-Galc

Othersd

Human

Aging

Lung tissue homogenate

x

x

x

[27]

Mouse

Aging

Lung tissue homogenate

x

x

[27]

Mouse

Aging

Alveolar tissue in situ

x

[25]

Mouse

Aging

Alveolar tissue in situ

x

[26]

Human

Allografts

Small airway epithelial cells in situ

x

[44]

Human

COPD

Isolated alveolar epithelial cells in vitro

x

[34]

Human

COPD

Pulmonary vascular endothelial cells in situ

Isolated pulmonary vascular endothelial cells in vitro

x

x

x

[36]

Human

COPD

Alveolar epithelial cells in situ

Alveolar endothelial cells in situ

x

x

x

[24]

Human

COPD

Isolated pulmonary vascular smooth muscle cells in vitro

x

x

[63]

Human

Emphysema

Isolated lung fibroblasts in vitro

x

x

[43, 50]

Human

Emphysema

Isolated lung fibroblasts in vitro

x

[33]

Human

Emphysema

Alveolar epithelial cells type II in situ

Alveolar endothelial cells in situ

x

x

[64, 65]

Human

IPF

Alveolar epithelial cells type II in situ

x

[41]

Human

IPF

Lung fibroblasts in situ

x

[51]

Human

IPF

Bronchial epithelial cells in situ

x

x

x

[37]

Human

IPF

Lung tissue in situ

x

[52]

Detection of acompounds of the DNA damage response (DDR)bsenescence-associated heterochromatin foci (SAHF)cacid β-galactosidase activity (β-Gal), ordother SA phenotypes.

Tab. 2

Experimental models indicating cellular senescence of lung cells

Mechanism

SA phenotype detection

Ref.

Location

DDRa

SAHFb

β-Galc

Othersd

Accelerated aging

SAM model

Mouse lung tissue homogenate

x

[66]

Telomerase deficiency

Mouse lung tissue in situ

x

x

[20]

Bacterial toxins

Lipopolysaccharide

Human alveolar epithelial cell line (A549) in vitro

x

x

[30]

Pseudomonas aeruginosapyocyanin

Human alveolar epithelial cell line (A549) in vitro

Human lung fibroblasts in vitro

x

x

[21, 31]

Genotoxic stress

Air pollutions

Rat alveolar type II-like cells (RLE-6TN) in vitro

x

x

[23]

Human alveolar type II-like cells (A549) in vitro

x

x

[19]

Bleomycin

Human alveolar type II-like cells (A549) in vitro

Primary rat alveolar type II-like cells in vitro

x

x

[32]

Human alveolar type II-like cells (A549) in vitro

x

x

x

[27]

Human alveolar type II-like cells (A549) in vitro

x

x

x

[54]

Mouse alveolar tissue in situ

x

[32]

Mouse alveolar type II-like cells (MLE-15) in vitro

Isolated alveolar epithelial cells from treated mice

x

x

[57]

Mouse lung tissue in situ

x

[56]

Bromodeoxyuridine

Mouse Clara cells in situ

Human Clara-like cells (NCI-H441) in vitro

x

x

x

x

[22]

Cigarette smoke extracts/condensates

Human bronchial epithelial cells in vitro

x

x

[34, 35]

Human alveolar type II-like cells (A549) in vitro

Human bronchial epithelial cells in vitro

x

x

[67, 68, 69]

Human tracheobronchial epithelial cells in vitro

Human lung fibroblasts in vitro

x

[33]

Smoking

Mouse alveolar epithelial cells in situ

x

x

x

[29]

Mouse lung tissue in situ

x

x

[20]

Others

Hyperoxia

Human fibroblasts from adult lung in vitro

x

x

[70]

Mouse lung tissue homogenate

x

[49]

TGF-β1

Human bronchial epithelial cells in vitro

x

x

x

[37]

Detection of acompounds of the DNA damage response (DDR)bsenescence-associated heterochromatin foci (SAHF)cacid β-galactosidase activity (β-Gal), ordother SA phenotypes.

Permanent DDR activation in senescent cells causes the stable formation of heterochromatin foci, which are commonly called senescence-associated heterochromatin foci (SAHF; or senescence-associated damage foci [SDF]). Classical SAHF are well detectable with DNA fluorescent dyes in senescent cells in vitro, but its precise detection in situ is rather difficult [25]. Therefore, SAHF in lung tissues or isolated lung cells are identified by detection of distinct proteins enriched in SAHF [22, 24, 25, 26, 27]. Among these marker proteins are the histone variant H2A.X phosphorylated at serine-139 (γH2AX) and the histone variant macro H2A (mH2A). The presence of active DDR compounds in SAHF (e.g., 53BP1 and Chk1/2) emphasizes the interplay of DDR activation in SAHF formation [28].

Besides telomere uncapping and SAHF formation as important SA nuclear changes, senescence of lung cells in situ or in vitro has been characterized by acid β-galactosidase activity (Tab. 1 and Tab. 2) and other cytoplasmic changes, such as lipofuscin accumulation [29], higher lysosomal content [21, 30, 31, 32], and increased proteosomal degradation of proteins [33, 34, 35]. Moreover, senescent lung cells release more inflammatory cytokines, among which are the interleukins (IL)-6, -8, and -1β and the monocyte chemotactic protein (MCP)-1 [24, 34, 35, 36, 37]. Because none of the SA cell characteristics mentioned above is absolutely specific, only the simultaneous detection of various SA markers indicates the cellular senescence precisely.

Senescence in aging lung and age-related respiratory diseases

Population studies investigating telomere length in peripheral leukocytes indicated a direct relationship between immune senescence and the extent of pulmonary dysfunction in patients with chronic respiratory disease [10, 38, 39, 40] or the risk for idiopathic pulmonary fibrosis [41, 42]. These findings emphasize the importance of the aging immune system in the development of respiratory diseases. However, they do not indicate the potential importance of the senescence of resident lung cells in the structural changes of lung parenchyma and small airways associated with normal aging and age-related lung diseases.

Cellular senescence in the aging lung was first described by Wang et al. [26] who showed positive staining for the SAHF marker γH2AX in the alveolar epithelium of old mice. Although these data have been directly or indirectly confirmed by other studies on mice (Tab. 1), in situ investigations of human lung are still lacking. Only biochemical investigations of tissue lysates indirectly indicated the existence of senescent cells in human lung tissue of old individuals (Tab. 1, [27]). In contrast, various studies have directly indicated the presence of senescent cells in human lung tissues of patients with chronic respiratory diseases (Tab. 1). The first indication for the potential importance of senescent cells in the progression of chronic respiratory diseases was made by Holz et al. [43] who identified a reduced proliferation rate of human lung fibroblasts isolated from emphysema patients. Lung emphysema typically develops from chronic obstructive bronchitis, and both conditions (i.e., emphysema and chronic bronchitis) are generally termed chronic obstructive pulmonary disease (COPD). Evidence for cellular senescence in COPD has been adduced by further studies investigating isolated lung cells or lung tissue from COPD/emphysema patients (Tab. 1). In addition to fibroblasts, a senescent phenotype was also identified for other cell types including alveolar epithelial cells (Tab. 1). Lung allografts also showed cellular senescence of small airway epithelial cells, which was higher in allografts with bronchiolitis than in stable allografts [44]. Because of the close relationship between aging and COPD as a major chronic respiratory disease as well as some structural similarities between old lungs and emphysematous COPD lungs [45], the identification of senescent host cells in the lung tissue of COPD patients has led to the idea of the premature aging lung in chronic respiratory diseases [46]. Moreover, idiopathic pulmonary fibrosis (IPF) is associated with an increased accumulation of senescent cells in the lung as shown for fibroblasts and bronchial epithelial cells (Tab. 1).This observation also suggests accelerated aging of the lung in IPF [47].

Cause of cellular senescence in lung

Long-term exposure of the lung to environmental substances causing moderate genotoxic stress (e.g., oxidants and highly reactive chemical compounds/carbonyls in cigarette smoke and air pollutants) contributes to development and progression of COPD. Experimental studies showed that these substances can also mediate cellular senescence in vitro and in vivo (Tab. 2), again indicating the involvement of cellular senescence in the development of COPD. The impaired autophagy of damaged cellular components due to their chemical reaction with oxidants/carbonyls seems to play a critical role in the senescence induction [35]. The senescence-mediating effect of cigarette smoke or air pollutants might be enhanced by higher age and bacterial infections, which often occur in COPD patients due to the increased susceptibility of the lung to infections and the waning immune system. This assumption was confirmed by means of the senescence-accelerated mouse (SAM) model and telomerase-deficient mice, which showed more pronounced damage of the lung in response to cigarette smoke than normal mice [20, 48]. Moreover, in vitro studies identified a senescence-inducing effect of bacterial toxins (Tab. 2). These findings also proposed the importance of cellular senescence in pneumonia, but in situ studies investigating cellular senescence in the pneumonic lung are still lacking.

The accumulation of senescent cells is accompanied by an increase in apoptotic cell death (Fig. 2). Therefore, it is well conceivable that both cell fates together cause the irreversible damage and, finally, loss of the alveolar walls in the emphysematous lung of COPD patients. Moreover, senescence of vascular cells in COPD could contribute to the pulmonary hypertension frequently observed in COPD patients (Tab. 1). In most studies, cellular senescence was identified by detection of DDR compounds indicating substantial DNA damage as the primary cause of the cellular senescence (Tab. 1 and Tab. 2). The contribution of DNA damage to the senescence of lung cells was also shown experimentally using mutagenic bromodeoxyuridine in vitro and in vivo (Tab. 2). Moreover, oxidative damage of DNA and other cell structures by chronic hyperoxia caused cellular senescence (Tab. 2). The fact that hyperoxia finally leads to alveolar hypoplasia [49] again emphasizes the relationship between cellular senescence and structural changes of the lung. In addition to compounds of the DDR pathway, several other characteristics of cellular senescence were detected in response to genotoxic/oxidative stress, in particular acid β-galactosidase activity (Tab. 2).

Fibroblasts play an important role in the maintenance of the alveolar structure in the lung because of their essential contribution to the matrix generation. Thus, senescence of fibroblasts might play a role in the pathogenesis of COPD [33, 43, 50]. However, a senescent phenotype has also been detected in IPF [51, 52], which is characterized by an excess of alveolar matrix generation by fibroblasts. The cause of lung fibrosis is not clear in IPF, but viral infections and other injuries to the lung are believed to cause fibrosis [53]. Epithelial cell injury and apoptosis are recognized as early features in IPF and experimentally induced fibrosis in mice, and experimental lung fibrosis with the anti-cancer drug bleomycin causes an increased accumulation of senescent cells in lung (Tab. 2). The senescence-mediating effect of bleomycin was confirmed by numerous experimental studies (Tab. 2), which also revealed the increased expression of caveolin-1 as a mediator of the bleomycin-mediated cellular senescence [54, 55, 56]. Chronic growth stimulus (oncogenic stress) by TGF-β1 in clinical and experimental lung fibrosis could be an important accelerator of cellular senescence [37]. Although these findings indicate a potential role of cellular senescence in IPF pathology, the findings of other studies suggest that a delay of the senescence process is necessary for the early remodelling of the tissue in lung fibrosis [51, 57]. This suggestion was also supported by Liu et al. [58] who showed significantly reduced lung fibrosis in telomerase-deficient mice following bleomycin treatment. Therefore, these findings emphasize the beneficial effect of cellular senescence, namely the inactivation of damaged and misdirected cells in the body. The beneficial effect of cellular senescence is well known in the context of tumor suppression [59].

Despite this beneficial effect, cellular senescence might have notably adverse effects as suggested by the accumulation of senescent cells in aging lung and diseased lung (Tab. 1). Because it is less clear to what extent senescent cells directly contribute to structural changes associated with lung aging and age-related lung pathologies, cellular senescence might also adversely contribute to these changes in an indirect manner. In this regard, senescent cells influence their microenvironment in lung tissue by release of inflammatory cytokines, such as IL-6, IL-8 and MCP-1 [27, 34, 35, 36, 37], soluble matrix metalloproteases [60], and induction of moderate oxidative stress in neighboring cells [61]. Unfortunately, the indirect effect of senescent cells on the lung microenvironment is still insufficiently studied.

Summary

In recent years, studies on cellular senescence in pulmonary research has gained increasing interest. The findings of these studies indicate the potential relevance of cellular senescence in structural and, therefore, functional changes of the aging lung. The findings also indicate an acceleration of this process in lung diseases, particularly COPD, in which the senescence-mediating effect of cigarette smoke or other noxious substances seem to play a central role. In contrast to COPD, the importance of cellular senescence in IPF is controversial. Probably both, i.e. cellular senescence of intact cells and delay of the cellular senescence of misdirected cells, contribute to structural changes associated with IPF.

The accelerated aging process in COPD has led to the idea of the development of therapeutic agents, which interact in aging signalling pathways [62]. Especially activation of the insulin/insulin-like growth factor I signalling pathway is well described to contribute to longevity and higher stress resistance. Since compounds of this pathway are also directly involved in the stress response of cells, such as activation of the serine/threonine protein kinase mTORor inhibition of the NAD+-dependent histone deacetylases SIRT 1 and 6, therapeutic reversal of their activity could delay the aging process in COPD [62]. However, blocking cellular senescence also increases the probability of damaged and misdirected cells to survive and proliferate again, thereby increasing the risk for lung cancer and probably lung fibrosis. Therefore, future research should be directed towards the development of agents that notably affect the course of COPD without increasing the risk for cancer.

Practical conclusion

  • Senescence of lung cells occurs in aging lung of human and mouse.

  • Senescence of lung cells also occurs in age-related respiratory diseases, particularly COPD and lung fibrosis, thereby suggesting premature lung aging in both diseases.

  • Epithelial, vascular, and mesenchymal cells undergo cellular senescence in lung.

  • Increased genotoxic stress by smoking and other environmental compounds as well as bacterial infections are risk factors of cellular senescence in lung.

  • Intervention in senescence-associated signalling pathways provides a future therapeutic approach in the treatment of premature lung aging in COPD and eventually lung fibrosis.

Notes

Compliance with ethical guidelines

Conflict of interest. B. Bartling states that there are no conflicts of interests.

The accompanying manuscript does not include studies on humans or animals.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Klinik und Poliklinik für Herz- und ThoraxchirurgieUniversitätsklinikum Halle (Saale) AöRHalle (Saale)Germany

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