Cell Tissue Res (2017) 367:469–480

DOI 10.1007/s00441-016-2511-x

REVIEW

Mechanisms of lung aging

Christina Brandenberger 1,2,3 & Christian Mühlfeld 1,2,3

Received: 12 August 2016 / Accepted: 16 September 2016 / Published online: 14 October 2016
# Springer-Verlag Berlin Heidelberg 2016

Abstract Lung aging is associated with structural remodel- and in several cell types of the lung as well as of the immune
ing, a decline of respiratory function and a higher susceptibil- system. Thereby, this survey not only aims at providing a better
ity to acute and chronic lung diseases. Individual factors that understanding of the mechanisms of pulmonary aging but also to
modulate pulmonary aging include basic genetic configura- identify gaps in knowledge that warrant further investigations.
tion, environmental exposure, life-style and biography of sys-
temic diseases. However, the actual aging of the lung takes Keywords Pulmonary aging . Cellular senescence .
place in pulmonary resident cells and is closely linked to aging Immunosenescence . Pulmonary cells . Lung function .
of the immune system (immunosenescence). Therefore, this Microbiome .
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 Introduction
in depth. Hallmarks of aging include alterations at molecular,
cellular and cell–cell interaction levels. Because of the great With advancing age, the respiratory tract undergoes structural and
variety of cell types in the lung, the consequences of aging functional changes. These changes are mostly associated with a
display a broad spectrum of phenotypes. For example, aging is decrease in lung function, pulmonary remodeling, limited regen-
associated with more collagen and less elastin production by eration and an enhanced susceptibility to pulmonary diseases in
fibroblasts, thus increasing pulmonary stiffness and lowering the elderly (>65 years of age) (Sharma and Goodwin 2006).
compliance. Decreased sympathetic airway innervation may Even in healthy humans, lung function declines with in-
increase the constriction status of airway smooth muscle cells. creasing age. Breathing patterns were reported to show a
Aging of resident and systemic immune cells leads to a pro- smaller tidal volume and a higher respiratory rate (Janssens
inflammatory milieu and reduced capacity of fighting infec- et al. 1999) and the maximal aerobic capacity (VO2 max) is
tious diseases. The current review provides an overview of reduced with age (McClaran et al. 1995). As a consequence,
cellular changes occurring with advancing age in general the elderly show a lower pulmonary oxygenation and exercise
capacity. This age-dependent decline in pulmonary function is
directly linked to structural remodeling of the lung (Miller
* Christina Brandenberger 2010). For example, different studies in humans and rodents
[email protected] give evidence that the pulmonary elastic recoil capacity re-
gresses with age due to structural remodeling of the extracel-
1
Institute of Functional and Applied Anatomy, Hannover Medical
lular matrix in the lung parenchyma and lowers the pulmonary
School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany forced expiratory volume (FEV1) in the elderly (Janssens
2
Cluster of Excellence REBIRTH (From Regenerative Biology to
et al. 1999; Huang et al. 2007; Miller 2010). Other character-
Reconstructive Therapy), Hannover, Germany istics of age-related structural remodeling include a decrease
3
Biomedical Research in Endstage and Obstructive Lung Disease
in alveolar depth and an increase in acinar airway lumen, as
Hannover (BREATH), Member of the German Center for Lung measured in a recent real-time morphology study in healthy
Research (DZL), Hannover, Germany elderly (Quirk et al. 2016). These changes go along with a
470 Cell Tissue Res (2017) 367:469–480

reduction of the pulmonary gas exchange area and promote a discussed but it is often difficult to distinguish origin, cause
diminished lung function with advanced age. or effect of aging. Most likely, age-related changes originate
Pulmonary remodeling is even more pronounced in classi- from cumulative damage or stress occurring due to multiple
cal age-related pulmonary diseases, such as senescence- incidences that living beings experience over a life-time—also
related emphysema, chronic obstructive pulmonary disease called the exposome (Vrijheid 2014). The lung is in direct
(COPD) or interstitial lung disease (ILD) (Fukuchi 2009; contact with the external environment with its vast alveolar
Meyer 2012). The likelihood of developing any of these dis- surface area and faces constant challenges that promote the
eases significantly increases with age. The international com- development of a senescent phenotype. Hence, the exposome
parison study on the Burden of Obstructive Lung Disease supposably plays a crucial role in the development of pulmo-
(BOLD Study) shows that individuals with an age nary senescence and is strongly influenced by the individual
of > 70 years have a much higher chance of developing genetic background and life style (Fig. 1). Nevertheless, de-
COPD (Buist et al. 2007). Another study on ILD shows that spite individual histories of aging, the pathophysiology of
227 out of 100,000 Americans older than 75 years of age pulmonary aging shows common characteristics and within
develop ILD whereas only 4 out of 100,000 did within 18 the current review we provide an overview on the mechanisms
and 34 years of age (Raghu et al. 2006). COPD or ILD show and consequences of lung aging.
very different pathologies but are both associated with chronic
structural remodeling of the extracellular matrix and impaired
pulmonary function. Intrinsic factors or inhalation exposure to Cellular aging in the lung
noxious gases, microbes or air pollutants such as cigarette
smoke, asbestos or silica can promote the development of Age-related changes of the lung mainly include pulmonary
chronic pulmonary diseases (Kipen et al. 1987; Yoshida and stem cell exhaustion and senescence of pulmonary and in-
Tuder 2007; Cohen et al. 2008); however, the underlying flammatory cells, remodeling of the extracellular matrix, al-
mechanisms are still being investigated by large scientific terations in the composition of the pulmonary surfactant sys-
communities. tem, mucociliary clearance or the pulmonary nervous system.
Besides a predisposition to develop chronic diseases, the The implications of these different aspects in pulmonary aging
aged lung has also been shown to be more susceptible to are discussed here and summarized in Table 1.
environmental exposures and infectious agents (Green and
Pinkerton 2004). Various epidemiological studies give evi- Cellular aging and senescence
dence that the elderly are less resistant to pulmonary infectious
diseases and suffer from prolonged recovery times. For exam- A main aspect of aging is the limitation in regeneration and
ple, pneumonia and acute respiratory distress syndrome repair, associated with cell senescence. Cell senescence is rec-
(ARDS) are linked to higher morbidity and mortality rates in ognized as a state of irreversible growth cycle arrest accom-
the elderly (Suchyta et al. 1997; Meyer 2005). A survey with panied by impaired cellular function, increased production of
ARDS patients between 55 and 85 years of age showed that reactive oxygen species (ROS) and pro-inflammatory signal-
mortality in the >70 years old was twice as likely and ing and the expression of senescence-associated molecules
survivors had more difficulties in recovery than such as β-galactosidase, p16, p53 or p21 (Campisi 2013).
patients < 70 years of age (Ely et al. 2002). The elderly also Different reasons can lead to senescence-associated cell cycle
show a decreased capacity of fighting pulmonary viral infec- arrest. A well-recognized cause is telomere deficiency.
tions such as influenza or severe acute respiratory syndrome Telomeres are repetitive DNA sequences with associated pro-
(SARS) (Gross et al. 1995; Loeb 2004) and are less responsive teins, located at the chromosomal end to stabilize and protect
to vaccination (Gross et al. 1995). These findings indicate the chromosomal DNA (Blackburn et al. 2006). With each cell
a predisposition of the elderly to pulmonary infections and division, the chromosomal DNA end is shortened, since the
diseases and give evidence that the immune response is de- end of the linear DNA cannot be replicated by the DNA po-
clining with advanced age—an effect also called lymerase. Telomeres in regular somatic cells are therefore re-
immunosenescence (Weiskopf et al. 2009; Busse and duced with each replication until critical telomere shortening
Mathur 2010). is leading to cell cycle arrest (Campisi 2013). The enzyme
With increasing life expectance and demographic shifts telomerase is capable of maintaining telomere regeneration
towards aged societies, the research focus on mechanisms of but its activity is limited to embryonic and adult stem cells
aging and age-related diseases has been reinforced in the last and only a few somatic cells. The incidence of cell senescence
decade. However, despite extensive investigations, our under- is thus increasing with progressing age. Additionally, different
standing of the mechanisms of cell and tissue aging is still chronic diseases or environmental exposure to a noxious
limited. Different factors such as telomere shortening, stem agent, such as cigarette smoke, promote tissue repair and cell
cell exhaustion, oxidative stress or inflammation are being proliferation and thereby lead to telomere shortening and
Cell Tissue Res (2017) 367:469–480 471

Fig. 1 Internal and external

influences on pulmonary cellular
senescence and pulmonary aging

premature cellular senescence (Tsuji et al. 2006; Chilosi et al. recognized that ROS play an important role in aging and con-
2013). tribute to a senescent phenotype. The source and action of
Cell senescence can also be stress-induced, for example, ROS, however, are manifold and often it is not clear if their
due to elevated ROS production or mitochondrial dysfunction presence is the result or the cause of senescence. For example,
(Sahin and DePinho 2010). Cellular exposure to ROS such as damaged mitochondria are a source for cellular ROS but at the
superoxide anions can lead to oxidative protein or DNA dam- same time enhanced cellular ROS itself can impair mitochon-
age and thereby accelerate cell senescence. Besides oxidative drial function. More recent theories of aging therefore suggest
DNA damage, ROS have also been suggested to promote an that the hallmarks of aging can be divided into three different
inflammatory response and thereby potentially contribute to categories: (1) cellular dysfunction including genomic insta-
the progress of inflamm-aging—an age-dependent decline of bility, epigenetic alterations, loss of proteostasis and telomere
the function of the immune system (Franceschi et al. 2000; El attrition, (2) antagonistic response to damage such as
Assar et al. 2013). The free radical theory by D. Harman was deregulated nutrient sensing, mitochondrial dysfunction and
an early established hypothesis (in 1954; Harman 2006), sug- cell senescence and (3) a changed phenotype with altered
gesting that a variety of intrinsic or extrinsic factors can con- intercellular communication and stem cell exhaustion
tribute to induced cellular ROS levels such as environmental (López-Otín et al. 2013; Meiners et al. 2015; Aunan et al.
exposure or chronic inflammatory diseases and lead to cellular 2016). The characterization of these different aspects of aging
damage and a senescent phenotype. Up until now, it has been is clearly pointing out the variety of factors involved in the

Table 1 Age-related changes in pulmonary cells and their impact on lung function variables with age

Pulmonary cell type Effect of aging Impact on lung function

Bronchoepithelial cells Number of bronchoepithelial cells ↓ Impaired mucociliary clearance

Mucociliary clearance ↓
Mucous production and composition ↓
Alveolar epithelial cells Impaired structure of lamellar bodies Alteration in surfactant composition may affect
Changes in surfactant lipid composition lung function; increased susceptibility to
SP-A and SP-C ↑ alveolar injury in disease
Oxidative stress ↑
Alveolar stem cell renewal in disease ↓
Endothelial cells Migration and proliferation ↓ Increased susceptibility to injury, impaired vascular
Oxidative stress ↑ regulation
NO-signaling ↓
Alveolar macrophages Phagocytosis ↓ Increased susceptibility to pulmonary infections
TLR signaling and cytokines
ROS ↑
Fibroblasts and ECM Fibrogenic response ↑ Reduced pulmonary elasticity, pro-fibrotic milieu
Senescence in disease ↑
Elastin and laminin ↓
Collagen ↑
472 Cell Tissue Res (2017) 367:469–480

phenomena of aging and their interactions at molecular, cel- cells in lungs of old mice, resulting in a lower number of
lular and systemic levels (Fig. 2). Furthermore, it has been epithelial cells and epithelial thinning (Ortega-Martínez et al.
suggested that a critical amount of senescent cells can create 2016). It is, however, not yet fully investigated whether
a senescent environment by further promoting senescence it- bronchoepithelial cell senescence coincides with diminished
self via paracrine mediators (Acosta et al. 2013; Tasdemir and ciliary clearance.
Lowe 2013). An accumulation of impaired or senescent cells More information is available on pulmonary epithelial cell
in the lung could thereby exacerbate pulmonary senescence of senescence of AT2 cells. These cells produce surfactant to
certain compartments or the whole lung. lower the surface tension in respiration and serve as progenitor
The occurrence of cell senescence could be tissue- or cell- cells for the air–blood barrier forming AT1 cells. An acceler-
type-specific and the impact or outcome depends on the spe- ated cell senescence in AT2 cells has been observed in COPD
cific function of the affected tissue or cells. In the human lung, (Tsuji et al. 2006) as well as in different animal models of
there are about 40 different cell types (Ochs and Weibel 2008). fibrosis (Aoshiba et al. 2003; Torres-González et al. 2012).
Coarsely, the different pulmonary cell types can be catego- Alveolar stem cell exhaustion has been discussed as a key
rized into epithelial cells (such as bronchiolar and alveolar factor in age-related pulmonary diseases (Faner et al. 2012;
epithelial cells), endothelial cells, fibroblasts or immune cells. Chilosi et al. 2013). Since AT2 cells also serve as progenitors
Cell-type-specific senescence has been associated with differ- for AT1 cells, AT2 cell senescence can lead to a critical decline
ent pulmonary diseases, like, for example, senescence of al- in alveolar epithelial stem cell renewal (Alder et al. 2015;
veolar epithelial precursor cells with idiopathic pulmonary Chen et al. 2015). Murine models to study telomerase-
fibrosis (IPF) and mesenchymal stem cell exhaustion with related senescence in stem cell regeneration include TERT
COPD (see review by Chilosi et al. 2013). Current investiga- and TERC KO mice. These mice are either lacking the telo-
tions are therefore further elaborating the impact of cell-type- mere reverse transcriptase (TERT) or the telomerase RNA
specific senescence in the lung and its impact on age-related component (TERC)—hence disabled telomerase function—
pulmonary diseases. and show many signs of premature aging, also including ele-
vated apoptosis in AT2 cells (Amsellem et al. 2011; Chen et al.
Epithelial cells, mucous and surfactant 2015). A study by Alder and colleagues specifically investi-
gated AT2 cell-targeted telomere dysfunction and the effects
Pulmonary epithelial cells form a tight barrier to protect the of AT2 cell senescence. They found an enhanced pro-
lung from external influences. Ciliated bronchoepithelial cells inflammatory response with increased numbers of macro-
and mucous producing goblet cells are the most abundant phages in the bronchoalveolar fluid (BALF) and an enhanced
epithelial cell types in the conducting airways, as are alveolar susceptibility to injury such as bleomycin-induced ARDS in
type 1 (AT1) and type 2 (AT2) epithelial cells in the lung the animals with induced AT2 cell senescence (Alder et al.
parenchyma. Little is known about particular effects of senes- 2015). This finding gives evidence that telomere shortening
cence on bronchoepithelial cells. Given their specific func- is not only a result of chronic diseases but also a potential
tions, it is reasonable that senescence of ciliated trigger.
bronchoepithelial cells would lead to an impaired perfor- Implications of aging on AT2 cell-mediated surfactant pro-
mance in mucociliary transport and senescence in goblet cells duction and compositions have also been investigated. A sur-
and to alterations in mucous composition and production. factant is crucial for lowering the alveolar surface tension and
Indeed, a few studies have shown that mucociliary clearance surfactant protein A and D (SP-A and SP-D) are part of the
decreases in healthy elderly (Svartengren et al. 2005; De complement system. The surfactant plays not only an essential
Oliveira-Maul et al. 2013) and ciliary beat frequency is re- role in regular breathing but also in pulmonary inflammation.
duced in old C57BL/6 mice (Bailey et al. 2014). Another For instance, in acute lung injury, the surfactant is qualitatively
recent study showed an increase in apoptotic bronchoepithelial and quantitatively reduced and injury of AT2 cells worsens the

Fig. 2 Molecular, cellular and

interactive hallmarks of aging.
(Figure adapted from López-Otín
et al. 2013)
Cell Tissue Res (2017) 367:469–480 473

prognosis in acute lung injury (Ingenito et al. 2001). However, and limited regeneration capacity to injury (Lu et al. 2012).
very little is still known about age-related changes in surfac- Ex-vivo experiments with pulmonary endothelial arteries of
tant composition. Early investigations on the surfactant and young and old rats have furthermore shown that pulmonary
age, including studies in rats and dogs, show varying out- arteries of old rats have impaired endothelial function with
comes (Orgeig and Daniels 2004), which might be due to higher levels of ROS and decreased catalase expression
interspecies variability and varying interpretations of the def- (Podlutsky et al. 2010). Accordingly, a review by Jane-Wit
inition Bold^. A more recent study addressed changes in the and Chun also summarized the three main features of pulmo-
ultra-structure of the pulmonary surfactant in 2- to 3-month nary endothelial senescence as the vulnerability to oxidative
and 26-month-old rats (Walski et al. 2009), showing that the stress, impaired NO signaling and deficits in repair (Jane-Wit
structures of lamellar bodies and tubular myelin in older rats and Chun 2012). These features make the elderly more sus-
resemble those of young animals that were treated with a pro- ceptible to diseases such as pulmonary sepsis or pulmonary
tein synthesis inhibitor. Another study in mice and humans hypertension.
found that levels of pro-inflammatory cytokines, SP-A and
SP-D and activity of myeloid peroxidase increase with ad-
vanced age and lipid composition of surfactant changes in Fibroblasts and ECM
the alveolar lining fluid (ALF) (Moliva et al. 2014). The au-
thors suggest a more pro-inflammatory and more oxidative Pulmonary fibroblasts are involved in tissue repair and the
milieu of the ALF with advanced age, partly due to AT2 cell construction and/or remodeling of the extracellular matrix
dysfunction, which could also be a result of AT2 cell senes- (ECM). The composition of the ECM has, particularly in the
cence. However, more research addressing the composition lung parenchyma, a direct impact on lung function and most
and secretion of the surfactant is needed to understand the senescence-related lung diseases, including COPD, ILD or
impact of senescence-related surfactant dysfunction and its lung cancer, show remodeling of the ECM (reviewed in
impact in pulmonary health and disease. Meiners et al. 2015). It is therefore not surprising that fibro-
blast senescence has been associated with pulmonary remod-
Endothelial cells eling and age-related diseases such as emphysema and COPD
or fibrosis and has been addressed in various studies (Calhoun
Senescence in vascular endothelial cells has been well studied, et al. 2015; Yanai et al. 2015; Hashimoto and Sugiura 2016).
particularly in regard to arteriosclerosis, angiogenesis or arte- Investigations on fibroblast senescence were mostly per-
rial stiffening and remodeling. A detailed report on the current formed in vitro with cell lines. In these models, cell senes-
research on vascular endothelial senescence would be beyond cence was induced by exhaustive replication or chemical
the scope of this review, hence we summarize here only the stressors and measured by specific senescence markers such
most relevant findings, in particular in regard to pulmonary as β-galactosidase or the upregulation of cell cycle proteins
vasculature and refer to other reviews on this subject for fur- p21, p53 and p16 that control and arrest cell division (Tigges
ther information (Erusalimsky 2009; El Assar et al. 2013; et al. 2014; Maciel-Barón et al. 2016). The expression of cer-
Regina et al. 2016). In brief, senescence in endothelial cells tain microRNAs has also been attributed to senescence (Lee
has a direct impact on angiogenesis by limiting vascular et al. 2014; Holly et al. 2015). Fibroblast senescence has fur-
growth (Zaccagnini et al. 2005; Falchetti et al. 2008). thermore been investigated in regard to the development of
Furthermore, endothelial vasodilatation has been shown to fibrosis. For instance, primary fibroblasts isolated from IPF
be compromised with advanced age, as senescent endothelial patients show signs of cell senescence, i.e., decreased cell
cells show less endothelial nitric oxide synthase (eNOS) ac- growth, β-galactosidase increase after induction of oxidative
tivity and NO expression (Tschudi et al. 1996; Van der Loo stress, altered cell morphology and expression of α-smooth
et al. 2000). It is suggested that this effect is mostly governed muscle actin (α-SMA) in replicative stress-induced senes-
by increased ROS levels in senescent cells that directly com- cence (Yanai et al. 2015). Studies with murine models suggest
promise NO signaling (Bhayadia et al. 2016). Besides ROS, that pulmonary fibroblasts from old mice are more resistant to
pro-atherogenic and pro-thrombogenic effects have also been bleomycin-induced apoptosis compared to fibroblasts from
reported in senescence, including an increased expression of young mice and seem to have a greater fibrotic response to
intercellular adhesion molecule 1 (ICAM-1) and plasminogen transforming growth factor β (TGF-β) (Huang et al. 2015),
activator inhibitor-1 (PAI-1) (Maier et al. 1993; Comi et al. whereas investigations in the senescence-accelerated prone or
1995). Results of investigations in pulmonary endothelial cells resistant mouse model (SAM P/R mice) with bleomycin, in-
are mostly in line with these findings. For example, a study duced lung injury show more fibrotic lesions and higher levels
with primary pulmonary microvascular endothelial cells dem- of TGF-β expression in SAMP compared to SAMR animals
onstrated that cells isolated from old rats have a decreased (Xu et al. 2009). Hence, these data support the hypothesis of
migration and proliferation ability, suggesting cell senescence senescence-related mechanisms in fibrosis.
474 Cell Tissue Res (2017) 367:469–480

Alterations in the composition of the ECM with age recognition. Studies on age-related effects of alveolar
have been associated with changes in fibroblast function and pulmonary macrophages provide evidence that the
and have received increasing attention. Proteomics and phagocytic capacity declines with age (Higashimoto
microarray analysis in young and senescent human fibro- et al. 1993; Hearps et al. 2012), hence the clearance of
blasts show that transcription and expression of ECM pathogens in infection is potentially impaired or delayed
proteins is altered in senescent cells (Yang et al. 2015). in the elderly. The capability of PAMP recognition via
The impact of altered ECM composition on the lung toll-like receptor (TLR) signaling was also investigated
parenchyma with age has mostly been investigated in in this context but the results are controversial and prob-
rodents, with particular focus on elastin and collagen. ably differ with pathogen stimulus and TLR signaling
Generally, it was shown that the percentage of elastic pathways (Murciano et al. 2008; Shaw et al. 2011; Boyd
fibers is reduced with progressing age and collagen is et al. 2012). Different experimental studies furthermore
increased, with a direct impact on lung function such give evidence that macrophages from old animals have
as reduced elasticity and tissue dampening (Huang higher ROS levels or a decline in the ROS defense sys-
et al. 2007; Calhoun et al. 2015). Changes in the ECM tem. For example, BALF macrophages from old mice or
correlated with an increase in cell senescence markers blood monocytes from the elderly show a decreased anti-
(p16 and p53) in old mice along with an activation of oxidative response via the nuclear factor (erythroid-de-
mTOR signaling, suggesting that cell senescence is re- rived 2)-like 2 (Nrf2) pathway, whereas oxidized glutathi-
sponsible for physiological changes with advanced age one and carboxylated albumin levels increase after ciga-
(Calhoun et al. 2015). A recent study with decellularized rette smoke exposure (Suzuki et al. 2008) compared to
murine lung scaffolds of various ages also confirmed those of young individuals. Similarly, the expression of
changes in ECM, showing that collagen increases and heme oxigenase-1 (HO-1) was reduced in BALF macro-
elastin and laminin decrease with age (Godin et al. phages from old compared to young mice after LPS ex-
2016). Interestingly, the authors also demonstrated that posure (Ito et al. 2009). The increased ROS levels are
the repopulation of the scaffolds with primary human likely a sign of cell senescence and also attributed to
bronchoepithelial cells and lung fibroblasts is affected pro-inflammatory signaling. However, reports on inflam-
by age-related changes of the ECM. These studies em- matory signaling and cytokine expression with advanced
phasize the role of the ECM in pulmonary senescence age in alveolar macrophages are controversial. Some stud-
and certainly more investigations will follow on this sub- ies report that cytokine expression by alveolar macro-
ject in the future. Furthermore, investigations addressing phages from old animals is enhanced after inflammatory
the three-dimensional organization of the pulmonary stimulation (Canan et al. 2014), whereas others show the
ECM would improve our understanding on ECM remod- contrary (Higashimoto et al. 1993; Lakshman et al. 2006).
eling with advancing age. It is furthermore not clear if alterations in macrophage
response with advanced age are related to cell senescence
Alveolar macrophages or to other age-related changes. In addition, non-tissue-
resident macrophages and monocytes are also recruited
Immune cells are also affected by senescence, a condition to the lung in inflammation and influence inflammatory
which is collectively termed immunosenescence. Different signaling. Macrophages show high plasticity and form
cells of the innate and adaptive immunity are present in heterogenic subpopulations, distinguished by different
the lung and their senescence has an impact on the pul- cellular markers (Misharin et al. 2013). Depending on
monary immunity. However, most of them, including non- the environment and stimulus, their phenotypic profile
tissue-resident macrophages and other leukocytes, are re- tends more to a pro-inflammatory, also called M1 profile
cruited from the circulation/bone marrow and transiently or to an M2 or alternative macrophage profile, which has
present in the lungs. The immune cell that is resident to been considered as anti-inflammatory but is also associat-
the lung is the alveolar macrophage. The alveolar macro- ed with the development of fibrosis or allergies (Johnston
phages belong to the tissue-resident macrophages. They et al. 2012; Lech and Anders 2013). It has been discussed
represent a population of specialized, long-lived resident how the macrophage plasticity changes with age and how
macrophages in different tissues that evolve during em- different sub-populations are affected by aging (Stout and
bryogenesis (Gomez Perdiguero et al. 2014). The alveolar Suttles 2005; Mahbub et al. 2012). However, no conclu-
macrophages act as the first immune defense of the lung sive answer to that question is available so far. Besides, a
by clearing airborne and microbial particles in the lung new nomenclature for macrophage activation and polari-
and activating the innate immune system via a pathogen- zation has recently been suggested (Murray et al. 2014).
associated molecular pattern (PAMP) and danger- Hence, proper characterizations of macrophage popula-
asso ciated molecu lar p attern (DAMP) mole cule tions in the aging lung are required in healthy and
Cell Tissue Res (2017) 367:469–480 475

diseased individuals to better understand the impact of The latter changes may be related to a higher susceptibility of
macrophage senescence in pulmonary aging. bronchoconstriction in the elderly.

Autonomous and sensory nervous system

Alterations of the immune system
The pulmonary nervous system consists in afferent and effer- and the microbiome with impact on the lung
ent nerve fibers that help maintain organ homeostasis.
Afferent fibers play important roles in sensing mechanical Immunosenescence
(e.g., inflation status) or chemical (e.g., capsaicin) stimuli
and in being involved in protective reflexes such as cough The poor prognosis and recovery in pulmonary inflammatory
reflex. The efferent fibers mainly belong to the sympathetic diseases with advanced age goes along with various age-
and parasympathetic nervous system and affect the constric- related changes in innate and adaptive immunity (Frasca and
tion status of airways and blood vessels as well as the secre- Blomberg 2015). In general, this includes decreased phagocy-
tion of mucus. In general, the innervation of the proximal totic function of macrophages and neutrophils, reduced activ-
airways is far more abundant than the innervation of the alve- ity of natural killer (NK) cells, altered serum levels of pro-
olar region (reviewed in Belvisi 2002). The functional charac- inflammatory cytokines greater numbers of airway neutro-
teristics of the autonomous innervation make it an important phils, as well as decreased T-cell stimulation by dendritic cells.
pharmaceutical target in pulmonary diseases such as asthma These changes support the development of chronic pulmonary
and COPD. Besides the innervation of the lower airways, the diseases and favor a poor prognosis in infectious and inflam-
passage from the upper to the lower airways at the larynx matory diseases in the elderly (Opal et al. 2005; Boyd and
requires a complex interplay between sensory and motor Orihuela 2011).
nerve fibers regulating the swallowing reflex. The disturbance
of this reflex may lead to aspiration of contents from the oro- Changes in innate immunity with impact on the respiratory
pharynx or the stomach and thereby cause pulmonary syn- tract
dromes of which aspiration pneumonia is most frequent
(Ebihara et al. 2012). In addition, the patency of the upper The first response to pathogens is regulated by the innate
airways relies on the function of the genioglossus muscle that immunity, including DAMP/ PAMP recognition by phagocyte
is impaired in obstructive sleep apnea. and other cells, cytokine and chemokine secretion, recruit-
As with COPD, aspiration pneumonia and obstructive ment of leukocytes such as neutrophils and macrophages to
sleep apnea become more frequent in later life (Petroianni the site of infection/injury and elimination of pathogens.
et al. 2006; Edwards et al. 2010; Meiners et al. 2015) and Several reports have shown that systemic and pulmonary
therefore it is of importance to know whether changes of the levels of pro-inflammatory cytokines interleukin (IL)-1β,
upper or lower airway innervation may contribute to them. IL-6 and tumor necrosis factor α (TNFα) are enhanced in
Currently, studies on the nervous system of the upper and lower the elderly (Meyer et al. 1996; Ogawa et al. 2008). This effect
airways during aging are scarce and far from delivering a com- is also called inflamm-aging and associated with a greater
prehensive picture. However, those studies that are available chronic pro-inflammatory milieu (Franceschi et al. 2000).
clearly indicate that the nervous system of the respiratory tract The elevated levels of pro-inflammatory cytokines are poten-
and related structures do change during aging. For example, tially the result of cell senescence, as senescent cells show
experimental evidence suggests that in male rats—in contrast increased ROS and NF-kB signaling (Salminen et al. 2008).
to female rats—serotonin decreases in the hypoglossal nucleus As a consequence, the elderly with enhanced IL-6 and TNFα
but is not compensated for by an increase in receptor density serum levels are more likely to develop pneumonia, as shown
(Seebart et al. 2007), which may be related to the higher col- in a longitudinal study over the course of 6.5 years by Yende
lapsibility of the upper airways in 30-month-old than in 6- et al. (2005). It is furthermore suggested that the pro-
month-old rats (Ray et al. 2008). Several recent studies have inflammatory response in the elderly is more severe and
indicated that aging affects the sensory side of reflexes rather prolonged in comparison to younger individuals (Inoue et al.
than the efferent part (Ebihara et al. 2011; Malandraki et al. 2014). Pathogen elimination by phagocytic cells is delayed
2011) and that stimulation of the transient receptor potential with advanced age, due to a decline in phagocytic capability
channel TRPV1 decreases the delay in the swallowing reflex by macrophages and neutrophils (Higashimoto et al. 1993;
(Ebihara et al. 2006). In the lower airways, aging is associated Fulop et al. 2012) and DAMP/PAMP signaling potentially
with a reduction of the noradrenergic innervation of the bron- impaired (Murciano et al. 2008; Boyd et al. 2012). Murine
chial tree (Ricci et al. 1997) as well as with changes in neuro- studies on acute inflammation furthermore give evidence that
peptide levels, namely a decrease in vasoactive intestinal pep- levels of pro-inflammatory cytokines are higher in old ani-
tide concentration and nerve fiber density (Geppetti et al. 1988). mals, particularly the neutrophil chemoattractant
476 Cell Tissue Res (2017) 367:469–480

keratinocyte-derived chemokine (KC, CXCL1), a murine ho- (Zhao et al. 2011), antigen processing (Chougnet et al. 2015)
mologue of IL-8 (Gomez et al. 2007; Chen et al. 2014). This or T-cell activation (Zacca et al. 2015). The pool of available
goes along with increased numbers of neutrophils as, for ex- naïve T-cells was furthermore found to degenerate with age,
ample, in pneumonia or acute lung injury of old rodents whereas the number of memory T-cells increases
(Gomez et al. 2007; Linge et al. 2015). Neutrophils secrete a (Brandenberger et al. 2014), which diminishes the efficiency
variety of enzymes and radicals in order to defeat pathogens; for T-cell activation (Haynes and Swain 2006). This effect is
however, if present in excess, they can also induce tissue in- accompanied by impaired B-cell-mediated antibody produc-
jury in the host. Although it has been reported that pathogen tion and specificity (Meyer 2010) and by a reduced IL-2 re-
elimination by neutrophils declines with age (Fortin et al. lease—a cytokine that promotes the stimulation of the adap-
2008), increasing numbers of neutrophils could still lead to tive immunity (Haynes and Swain 2006). Together, these in-
greater tissue injury (Starr et al. 2012). Particularly in acute cidences lead to an enhanced susceptibility of the elderly to
lung injury, elevated neutrophil numbers can promote the de- infections and a declined response to vaccines (Toapanta and
velopment of edema and enhance the severity of the disease Ross 2009; Meyer 2010; Stout-Delgado et al. 2012) in pul-
(Zemans et al. 2009). monary infection and disease.
Another cell type of the innate immunity that has the ability In addition, a shift in T-helper cell subpopulations has been
to recognize and eliminate virally infected and damaged cells proposed with advanced age. T-helper cells are classified into
are the NK cells. It has been described that both function and T-helper type I (Th1) cells that secrete interferon γ (IFNγ) and
phenotype of NK cells are altered with advanced age (Hayhoe IL-2 and stimulate the adaptive immune response, Th2 cells
et al. 2010; Gayoso et al. 2011; Campos et al. 2014) and that that secrete IL-5 and IL-13 and are involved in parasitic de-
NK cell senescence impairs the antiviral immune response fense or allergic reaction and Th17 cells that secrete IL-17, IL-
(Beli et al. 2011). Other functions of NK cells have been 21 and IL-23 that activate neutrophilic granulocytes and are
recognized, such as resolution of inflammation and elimina- predominantly present in chronic inflammation (Lee et al.
tion of senescent or stressed cells as well as stimulating the 2012; Hirahara and Nakayama 2016). Reports on alterations
adaptive immune response (reviewed in Hazeldine and Lord of the Th-subpopulation with age are not consistent and vary
2013). With respect to the lung, it has been shown that im- with subject age and model of investigation (Lee et al. 2012).
paired NK function is leading to greater incidence in myco- In chronic pulmonary diseases such as COPD or in allergic
bacterium tuberculosis or staphylococcus aureus infection as airway disease with advanced age, Th17 cells have been
well as the development of lung cancer (Small et al. 2008; shown to play a predominant role (Doe et al. 2010;
Hazeldine and Lord 2013; Hodge et al. 2014). Hence, NK Vanaudenaerde et al. 2011; Brandenberger et al. 2014). Th17
senescence might have further implications besides declined cells were described as developing from the same lineage as
elimination of virally infected cells, which have not yet been the anti-inflammatory regulatory T-cells (T-regs) (Diller et al.
fully explored. 2016). Hence, a bias toward Th17 response may abate the T-
In summary, it has been shown that certain aspects of the reg response and possibly support a pro-inflammatory milieu
innate immune response decline with age, such as the elimi- as reported in the elderly (Schmitt et al. 2013).
nation of pathogens and infected or damaged cells. But other Most aspects of the adaptive immune response have been
aspects of pro-inflammatory signaling remain intact or are reported to decline with advancing age, with the consequence
even chronically enhanced with advanced age and potentially that pulmonary infections are prolonged and more severe in
support the development of chronic inflammatory diseases. the elderly. If or how alterations in Th-cell subpopulations
contribute to the pro-inflammatory status in the elderly, how-
Changes in adaptive immunity with impact on lung ever, still needs further investigation.

The adaptive or humoral immunity regulates the specific path- Microbiome

ogen defense. In brief, antigen-presenting cells, such as den-
dritic cells, collect foreign particles, process antigens, migrate Current research has focused on investigations on the com-
to lymph nodes and activate T-cells and B-cells for specific mensal human microbiome in health and disease. However,
pathogen elimination, antibody production and elimination of little is still known about the microbiome in the lung and only
infected cells. The dendritic cells act here as mediators be- lately has it been found that the lungs are not as sterile as
tween the innate and the adaptive immunity and senescence presumed (Dickson et al. 2015). Alterations in the pulmonary
of dendritic cells has a direct impact on the activation of the microbiome with advancing age have not yet been analyzed
adaptive immunity. Different investigations have shown a de- but investigations have shown that the pulmonary microbiome
cline in efficacy of dendritic cells in antigen presentation, in- is altered in patients with COPD (Pragman et al. 2012; Garcia-
cluding impaired DAMP recognition via nod-like receptor Nunez et al. 2014; Sze et al. 2015). To what extent the changes
signaling (Stout-Delgado et al. 2012), reduced migration correlate with age is still unknown. In contrast to the lung, the
Cell Tissue Res (2017) 367:469–480 477

microbiome in the gut has been well investigated and a close Acknowledgments The authors’ work is supported by DFG via the
Cluster of Excellence Rebirth, BMBF via the Deutsches Zentrum
relationship between the composition of the gut microbiome,
für Lungenforschung (DZL) and by the Hochschulinterne
diet and healthy aging has been suggested (Claesson et al. Leistungsförderung (HilF) of the Hannover Medical School.
2011, 2012; Odamaki et al. 2016). The gut microbiome not
only plays an important role in maintaining intestinal homeo-
stasis by supporting colonic energy balance but also in mod- References
ulating the intestinal immune response (Hooper et al. 2012). The
immune response influenced by the gut microbiome, howev- Acosta JC, Banito A, Wuestefeld T et al (2013) A complex secretory
er, is not restricted just to the gut. Other organs, including the program orchestrated by the inflammasome controls paracrine se-
lung, can also be affected (Chen et al. 2011). Alterations in nescence. Nat Cell Biol 15:978–90
immune function due to changes in the gut microbiome have Alder JK, Barkauskas CE, Limjunyawong N et al (2015) Telomere dys-
function causes alveolar stem cell failure. Proc Natl Acad Sci U S A
been related to a number of pulmonary diseases. For instance, 112:5099–5104
the susceptibility to pneumonia was increased by disturbance Amsellem V, Gary-Bobo G, Marcos E et al (2011) Telomere dysfunction
of the commensal gut bacterial community using antibiotics causes sustained inflammation in chronic obstructive pulmonary
(Tsay et al. 2011; Chen et al. 2011) and an enhanced suscep- disease. Am J Respir Crit Care Med 184:1358–1366
Aoshiba K, Tsuji T, Nagai A (2003) Bleomycin induces cellular senes-
tibility for the development of allergic airway disease with a
cence in alveolar epithelial cells. Eur Respir J 22:436–443
decreased immunological tolerance has been shown in germ- Aunan JR, Watson MM, Hagland HR, Søreide K (2016) Molecular and
free mice (Herbst et al. 2011; Hörmannsperger et al. 2012). A biological hallmarks of ageing. Br J Surg 103:e29–e46
correlation between the severity of allergic airway disease and Bailey KL, Bonasera SJ, Wilderdyke M et al (2014) Aging causes a
changes in gut microbiome has also been found with ad- slowing in ciliary beat frequency, mediated by PKCε. Am J
Physiol Lung Cell Mol Physiol 306:L584–9
vanced age in a house dust mite model of young and old mice,
Beli E, Clinthorne JF, Duriancik DM et al (2011) Natural killer cell func-
showing a more pronounced pathology with advanced age tion is altered during the primary response of aged mice to influenza
along with a shift in the microbial community (Vital et al. infection. Mech Ageing Dev 132:503–510. doi:10.1016/j.
2015). With respect to aging, it has been reported that the mad.2011.08.005
integrity of the gut epithelium declines and the secretions of Belvisi MG (2002) Overview of the innervation of the lung. Curr Opin
Pharmacol 2:211–215
mucus and defensins are reduced (Larbi et al. 2008; Biagi
Bhayadia R, Schmidt BMW, Melk A, Hömme M (2016) Senescence-
et al. 2013). This can facilitate the entry of pathogens and induced oxidative stress causes endothelial dysfunction. J Gerontol
generate a low-grade inflammation (Biagi et al. 2013). An A 71:161–9
enhanced level of bacterial LPS has been measured in feces Biagi E, Candela M, Turroni S et al (2013) Ageing and gut microbes:
and serum of old mice and related to greater levels of p16 and perspectives for health maintenance and longevity. Pharm Res 69:
11–20
NF-kB activation, thereby potentially accelerating inflamm-
Blackburn EH, Greider CW, Szostak JW (2006) Telomeres and telome-
aging (Kim et al. 2016). Certainly, these findings indicate that rase: the path from maize, Tetrahymena and yeast to human cancer
changes of the immune status as well as the host microbiome and aging. Nat Med 12:1133–1138
with progressing age have an impact on health and disease. Boyd AR, Orihuela CJ (2011) Dysregulated inflammation as a risk factor
However, little is still known about how individual microbial for pneumonia in the elderly. Aging Dis 2:487–500
Boyd AR, Shivshankar P, Jiang S et al (2012) Age-related defects in
species or the composition of entire communities interact with
TLR2 signaling diminish the cytokine response by alveolar macro-
and shape the immune system with impact on the lung. phages during murine pneumococcal pneumonia. Exp Gerontol 47:
507–18
Brandenberger C, Li N, Jackson-Humbles DN et al (2014) Enhanced
Concluding remarks allergic airway disease in old mice is associated with a Th17 re-
sponse. Clin Exp Allergy 44:1282–1292
Buist AS, McBurnie MA, Vollmer WM et al (2007) International varia-
The present review article aimed at providing an overview on tion in the prevalence of COPD (The BOLD Study): a population-
the changes of pulmonary resident cells and the immune sys- based prevalence study. Lancet 370:741–750
tem associated with aging. Despite a growing knowledge Busse PJ, Mathur SK (2010) Age-related changes in immune function:
about general mechanisms of cellular and molecular aging, effect on airway inflammation. J Allergy Clin Immunol 126:690–9
Calhoun C, Shivshankar P, Saker M et al (2015) Senescent cells contribute
the contribution of the different cellular systems of the lung to the physiological remodeling of aged lungs. J Gerontol A 1:1–9
to the impact of aging has been addressed to a much lesser Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev
extent. In particular, the interaction between various types of Physiol 75:685–705
cell and how this is affected by aging needs to be further Campos C, Pera A, Lopez-Fernandez I et al (2014) Proinflammatory
addressed. We are convinced that a better understanding of status influences NK cells subsets in the elderly. Immunol Lett
162:10–14. doi:10.1016/j.imlet.2014.06.015
pulmonary aging (i.e., degeneration as the physiological op- Canan CH, Gokhale NS, Carruthers B et al (2014) Characterization of
posite of regeneration) may help to develop new strategies for lung inflammation and its impact on macrophage function in aging.
modern regenerative approaches. J Leukoc Biol 96:473–80
478 Cell Tissue Res (2017) 367:469–480

Chen L-W, Chen P-H, Hsu C-M (2011) Commensal microflora contrib- Fortin CF, McDonald PP, Lesur O, Fülöp T (2008) Aging and neutro-
ute to host defense against Escherichia coli pneumonia through Toll- phils: there is still much to do. Rejuvenation Res 11:873–882
like receptors. Shock 36:67–75 Franceschi C, Bonafè M, Valensin S et al (2000) Inflamm-aging. An
Chen MM, Palmer JL, Plackett TP et al (2014) Age-related differences in evolutionary perspective on immunosenescence. Ann N Y Acad
the neutrophil response to pulmonary pseudomonas infection. Exp Sci 908:244–254
Gerontol 54:42–46 Frasca D, Blomberg BB (2015) Inflammaging decreases adaptive and
Chen R, Zhang K, Chen H et al (2015) Telomerase deficiency causes innate immune responses in mice and humans. Biogerontology.
alveolar stem cell senescence-associated low-grade inflammation doi:10.1007/s10522-015-9578-8
in lungs. J Biol Chem 290:30813–30829 Fukuchi Y (2009) The aging lung and chronic obstructive pulmonary
Chilosi M, Carloni A, Rossi A, Poletti V (2013) Premature lung aging and disease: similarity and difference. Proc Am Thorac Soc 6:570–572
cellular senescence in the pathogenesis of idiopathic pulmonary fi- Fulop T, Fortin C, Lesur O (2012) The innate immune system and ageing:
brosis and COPD/emphysema. Transl Res 162:156–173 what is the contribution to immunosenescence. Bentham Open 6:
Chougnet CA, Thacker RI, Shehata HM et al (2015) Loss of phagocytic 121–131. doi:10.2174/1876326X01206010121
and antigen cross-presenting capacity in aging dendritic cells is as- Garcia-Nunez M, Millares L, Pomares X et al (2014) Severity-related
sociated with mitochondrial dysfunction. J Immunol 195:2624–32 changes of bronchial microbiome in chronic obstructive pulmonary
Claesson MJ, Cusack S, O’Sullivan O et al (2011) Composition, variabil- disease. J Clin Microbiol 52:4217–4223
ity, and temporal stability of the intestinal microbiota of the elderly. Gayoso I, Sanchez-Correa B, Campos C et al (2011) Immunosenescence
Proc Natl Acad Sci U S A 108:4586–91 of human natural killer cells. J Innate Immun 3:337–343
Claesson MJ, Jeffery IB, Conde S et al (2012) Gut microbiota composi- Geppetti P, De Rossi M, Mione MC et al (1988) Age-related changes in
tion correlates with diet and health in the elderly. Nature 488:178–84 vasoactive intestinal polypeptide levels and distribution in the rat. J
Cohen RAC, Patel A, Green FHY (2008) Lung disease caused by expo- Neural Transm 74:1–10
sure to coal mine and silica dust. Semin Respir Crit Care Med 29: Godin LM, Sandri BJ, Wagner DE et al (2016) Decreased laminin ex-
651–661 pression by human lung epithelial cells and fibroblasts cultured in
Comi P, Chiaramonte R, Maier JAM (1995) Senescence-dependent reg- acellular lung scaffolds from aged mice. PLoS ONE. doi:10.1371
ulation of type 1 plasminogen activator inhibitor in human vascular /journal.pone.0150966
endothelial cells. Exp Cell Res 219:304–308 Gomez Perdiguero E, Klapproth K, Schulz C et al (2014) Tissue-resident
De Oliveira-Maul JP, De Carvalho HB, Goto DM et al (2013) Aging, macrophages originate from yolk-sac-derived erythro-myeloid pro-
genitors. Nature 518:547–551
diabetes, and hypertension are associated with decreased nasal
mucociliary clearance. Chest 143:1091–1097 Gomez CR, Hirano S, Cutro BT et al (2007) Advanced age exacerbates
the pulmonary inflammatory response after lipopolysaccharide ex-
Dickson RP, Erb-Downward JR, Huffnagle GB (2015) Homeostasis and
posure. Crit Care Med 35:246–51
its Disruption in the Lung Microbiome. Am J Physiol Lung Cell
Green FHY, Pinkerton KE (2004) Environmental determinants of lung
Mol Physiol 309:L1047–55
aging. In: Harding R, Pinkerton KE, Plopper CG (eds) The lung:
Diller ML, Kudchadkar RR, Delman KA et al (2016) Balancing inflam-
development, aging and the environment. Elsevier, San Diego, pp
mation: The link between Th17 and regulatory T cells. Mediat
377–395
Inflamm. doi:10.1017/CBO9781107415324.004
Gross P, Hermogenes A, Sacks H et al (1995) The efficacy of influenza
Doe C, Bafadhel M, Siddiqui S et al (2010) Expression of the T helper 17-
vaccine in elderly persons. A meta-analysis and review of the liter-
associated cytokines IL-17A and IL-17F in asthma and COPD.
ature. Ann Intern Med 123:518–527
Chest 138:1140–1147
Harman D (2006) Free radical theory of aging: An update - Increasing the
Ebihara T, Ebihara S, Watando A et al (2006) Effects of menthol on the functional life span. Ann N Y Acad Sci 1067:10–21
triggering of the swallowing reflex in elderly patients with dyspha- Hashimoto Y, Sugiura H (2016) 27-Hydroxycholesterol Accelerates
gia. Br J Clin Pharmacol 62:369–371 Cellular Senescence in Human Lung Resident Cells. Am J Physiol
Ebihara S, Ebihara T, Kanezaki M et al (2011) Aging deteriorated per- Lung Cell Mol Physiol 310:L1028–1041
ception of urge-to-cough without changing cough reflex threshold to Hayhoe RPG, Henson SM, Akbar AN, Palmer DB (2010) Variation of
citric acid in female never-smokers. Cough. doi:10.1186/1745- human natural killer cell phenotypes with age: Identification of a
9974-7-3 unique KLRG1-negative subset. Hum Immunol 71:676–681
Ebihara S, Ebihara T, Kohzuki M (2012) Effect of aging on cough and Haynes L, Swain SL (2006) Why aging T cells fail: implications for
swallowing reflexes: Implications for preventing aspiration pneu- vaccination. Immunity 24:663–6
monia. Lung 190:29–33 Hazeldine J, Lord JM (2013) The impact of ageing on natural killer cell
Edwards BA, O’Driscoll DM, Ali A et al (2010) Aging and sleep: phys- function and potential consequences for health in older adults.
iology and pathophysiology. Semin Respir Crit Care Med 31: Ageing Res Rev 12:1069–1078
618–633 Hearps AC, Martin GE, Angelovich TA et al (2012) Aging is associated
El Assar M, Angulo J, Rodriguez-Manas L (2013) Oxidative stress and with chronic innate immune activation and dysregulation of mono-
vascular inflammation in aging. Free Radic Biol Med 65:380–401. cyte phenotype and function. Aging Cell 11:867–875
doi:10.1016/j.freeradbiomed.2013.07.003 Herbst T, Sichelstiel A, Schär C et al (2011) Dysregulation of allergic
Ely EW, Wheeler AP, Thompson BT et al (2002) Recovery rate and airway inflammation in the absence of microbial colonization. Am J
prognosis in older persons who develop acute lung injury and the Respir Crit Care Med 184:198–205
acute respiratory distress syndrome. Ann Intern Med 136:25–36 Higashimoto Y, Fukuchi Y, Shimada Y et al (1993) The effects of aging
Erusalimsky JD (2009) Vascular endothelial senescence: from mecha- on the function of alveolar macrophages in mice. Mech Ageing Dev
nisms to pathophysiology. J Appl Physiol 106:326–32 69:207–217
Falchetti ML, Mongiardi MP, Fiorenzo P et al (2008) Inhibition of telo- Hirahara K, Nakayama T (2016) CD4+ T-cell subsets in inflammatory
merase in the endothelial cells disrupts tumor angiogenesis in glio- diseases: Beyond the Th1/Th2 paradigm. Int Immunol 28:163–171
blastoma xenografts. Int J Cancer 122:1236–1242 Hodge G, Barnawi J, Jurisevic C et al (2014) Lung cancer is associated
Faner R, Rojas M, Macnee W, Agustí A (2012) Abnormal lung aging in with decreased expression of perforin, granzyme B and interferon
chronic obstructive pulmonary disease and idiopathic pulmonary (IFN)-γ by infiltrating lung tissue T cells, natural killer (NK) T-like
fibrosis. Am J Respir Crit Care Med 186:306–13 and NK cells. Clin Exp Immunol 178:79–85
Cell Tissue Res (2017) 367:469–480 479

Holly AC, Grellscheid S, van de Walle P et al (2015) Comparison of Malandraki GA, Perlman AL, Karampinos DC, Sutton BP (2011)
senescence-associated miRNAs in primary skin and lung fibro- Reduced somatosensory activations in swallowing with age. Hum
blasts. Biogerontology 16:423–434 Brain Mapp 32:730–743
Hooper LV, Littman DR, Macpherson AJ (2012) Interactions between the McClaran SR, Babcock MA, Pegelow DF et al (1995) Longitudinal ef-
microbiota and the immune system. Science 336:1268–73 fects of aging on lung function at rest and exercise in healthy active
Hörmannsperger G, Clavel T, Haller D (2012) Gut matters: microbe-host fit elderly adults. J Appl Physiol 78:1957–1968
interactions in allergic diseases. J Allergy Clin Immunol 129:1452–9 Meiners S, Eickelberg O, Königshoff M (2015) Hallmarks of the ageing
Huang K, Rabold R, Schofield B et al (2007) Age-dependent changes of lung. Eur Respir J 45:807–827
airway and lung parenchyma in C57BL/6J mice. J Appl Physiol Meyer KC (2005) Aging. Proc Natl Acad Sci U S A 2:433–9
102:200–206 Meyer K (2010) The role of immunity and inflammation in lung senes-
Huang WT, Akhter H, Jiang C et al (2015) Plasminogen activator inhib- cence and susceptibility to infection in the elderly. Sem Respir Crit
itor 1, fibroblast apoptosis resistance, and aging-related susceptibil- Care Med 31:561–574
ity to lung fibrosis. Exp Gerontol 61:62–75 Meyer KC (2012) Management of interstitial lung disease in elderly pa-
Ingenito EP, Mora R, Cullivan M et al (2001) Decreased surfactant tients. Curr Opin Pulm Med 18:483–92
protein-B expression and surfactant dysfunction in a murine model Meyer KC, Ershler W, Rosenthal NS et al (1996) Immune dysregulation
of acute lung injury. Am J Respir Cell Mol Biol 25:35–44 in the aging human lung. Am J Respir Crit Care Med 153:
Inoue S, Suzuki K, Komori Y et al (2014) Persistent inflammation and T 1072–1079
cell exhaustion in severe sepsis in the elderly. Crit Care. doi:10.1186 Miller MR (2010) Structural and physiological age-associated changes in
/cc13941 aging lungs. Semin Respir Crit Care Med 31:521–527
Ito Y, Betsuyaku T, Moriyama C et al (2009) Aging affects Misharin AV, Morales-Nebreda L, Mutlu GM et al (2013) Flow cytomet-
lipopolysaccharide-induced upregulation of heme oxygenase-1 in ric analysis of macrophages and dendritic cell subsets in the mouse
the lungs and alveolar macrophages. Biogerontology 10:173–80 lung. Am J Respir Cell Mol Biol 49:503–10
Jane-Wit D, Chun HJ (2012) Mechanisms of dysfunction in senescent Moliva JI, Rajaram MVS, Sidiki S et al (2014) Molecular composition of
pulmonary endothelium. J Gerontol A 67:236–241 the alveolar lining fluid in the aging lung. Age 36:1187–1199
Janssens JP, Pache JC, Nicod LP (1999) Physiological changes in respi- Murciano C, Yáñez A, O’Connor JE et al (2008) Influence of aging on
ratory function associated with ageing. Eur Respir J 13:197–205 murine neutrophil and macrophage function against Candida
Johnston LK, Rims CR, Gill SE et al (2012) Pulmonary macrophage albicans. FEMS Immunol Med Microbiol 53:214–221
subpopulations in the induction and resolution of acute lung injury. Murray PJ, Allen JE, Biswas SK et al (2014) Macrophage activation and
Am J Respir Cell Mol Biol 47:417–426 polarization: Nomenclature and experimental guidelines. Immunity
Kim K-A, Jeong J-J, Yoo S-Y, Kim D-H (2016) Gut microbiota lipopoly- 41:14–20
saccharide accelerates inflamm-aging in mice. BMC Microbiol. Ochs M, Weibel ER (2008) Functional design of the human lung for gas
doi:10.1186/s12866-016-0625-7 exchange. In: Fishman AP (ed) Fishman’s Pulmonary Disease and
Kipen HM, Lilis R, Suzuki Y et al (1987) Pulmonary fibrosis in asbestos Disorders, 4th edn. McGraw Hill, New York, pp 23–70
insulation workers with lung cancer: a radiological and histopatho- Odamaki T, Kato K, Sugahara H et al (2016) Age-related changes in gut
logical evaluation. Br J Ind Med 44:96–100 microbiota composition from newborn to centenarian: a cross-
Lakshman CR, Liu Y, Popa D et al (2006) Molecular basis of age- sectional study. BMC Microbiol. doi:10.1186/s12866-016-0708-5
associated cytokine dysregulation in LPS-stimulated macrophages. Ogawa K, Suzuki K, Okutsu M et al (2008) The association of elevated
J Leucoc Biol 79:1314–1327 reactive oxygen species levels from neutrophils with low-grade inflam-
Larbi A, Franceschi C, Mazzatti D et al (2008) Aging of the immune mation in the elderly. Immun Ageing. doi:10.1186/1742-4933-5-13
system as a prognostic factor for human longevity. Physiology 23: Opal SM, Girard TD, Ely EW (2005) The immunopathogenesis of sepsis
64–74 in elderly patients. Clin Infect Dis 41:S504–12
Lech M, Anders HJ (2013) Macrophages and fibrosis: How resident and Orgeig S, Daniels CB (2004) Effects of aging, disease and the environ-
infiltrating mononuclear phagocytes orchestrate all phases of tissue ment on the surfactant system. In: Harding R, Pinkerton KE, Plopper
injury and repair. Biochim Biophys Acta Mol Basis Dis 1832:989–997 CG (eds) The lung: development, aging and the environment.
Lee N, Shin MS, Kang I (2012) T-cell biology in aging, with a focus on Elsevier, San Diego, pp 363–375
lung disease. J Gerontol A 67:254–63 Ortega-Martínez M, Rodríguez-Flores LE, Ancer-Arellano A et al (2016)
Lee Y, Kim SY, Bae Y (2014) Upregulation of miR-760 and miR-186 is Analysis of cell turnover in the bronchiolar epithelium through the
associated with replicative senescence in human lung fibroblast normal aging process. Lung. doi:10.1007/s00408-016-9890-3
cells. Mol Cells 37:620–627 Petroianni A, Ceccarelli D, Conti V, Terzano C (2006) Aspiration pneu-
Linge HM, Ochani K, Lin K et al (2015) Age-dependent alterations in the monia Pathophysiological aspects, prevention and management: A
inflammatory response to pulmonary challenge. Immunol Res 63: review. Panminerva Med 48:231–239
209–215 Podlutsky A, Ballabh P, Csiszar A (2010) Oxidative stress and endothelial
Loeb M (2004) Pneumonia in the elderly. Curr Opin Infect Dis 17:127–130 dysfunction in pulmonary arteries of aged rats. AJP Heart Circ
López-Otín C, Blasco MA, Partridge L et al (2013) The hallmarks of Physiol 298:H346–51
aging. Cell 153:1194–217 Pragman AA, Kim HB, Reilly CS et al (2012) The lung microbiome in
Lu H, Yuan H, Chen S et al (2012) Senescent endothelial dysfunction is moderate and severe chronic obstructive pulmonary disease. PLoS
attributed to the up-regulation of sphingosine-1-phosphate receptor- ONE. doi:10.1371/journal.pone.0047305
2 in aged rats. Mol Cell Biochem 363:217–224 Quirk JD, Sukstanskii AL, Woods JC et al (2016) Experimental evidence
Maciel-Barón LA, Morales-Rosales SL, Aquino-Cruz AA et al (2016) of age-related adaptive changes in human acinar airways. J Appl
Senescence associated secretory phenotype profile from primary Physiol 120:159–165
lung mice fibroblasts depends on the senescence induction stimuli. Raghu G, Weycker D, Edelsberg J et al (2006) Incidence and prevalence
Age. doi:10.1007/s11357-016-9886-1 of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 174:
Mahbub S, Deburghgraeve CR, Kovacs EJ (2012) Advanced age impairs 810–816
macrophage polarization. J Interf Cytokine Res 32:18–26 Ray AD, Ogasa T, Magalang UJ et al (2008) Aging increases upper
Maier JA, Statuto M, Ragnotti G (1993) Senescence stimulates U937- airway collapsibility in Fischer 344 rats. J Appl Physiol 105:
endothelial cell interactions. Exp Cell Res 208:270–274 1471–1476
480 Cell Tissue Res (2017) 367:469–480

Regina C, Panatta E, Candi E et al (2016) Vascular ageing and endothelial Tsay T-B, Yang M-C, Chen P-H et al (2011) Gut flora enhance bacterial
cell senescence: Molecular mechanisms of physiology and diseases. clearance in lung through toll-like receptors 4. J Biomed Sci.
Mech Ageing Dev. doi:10.1016/j.mad.2016.05.003 doi:10.1186/1423-0127-18-68
Ricci A, Mariotta S, Greco S et al (1997) Age-related changes of the Tschudi MR, Barton M, Bersinger NA et al (1996) Effect of age on
noradrenergic innervation of rat tracheo-bronchial tree and pulmo- kinetics of nitric oxide release in rat aorta and pulmonary artery. J
nary vasculature. Mech Ageing Dev 99:245–255 Clin Invest 98:899–905
Sahin E, DePinho RA (2010) Linking functional decline of telomeres, Tsuji T, Aoshiba K, Nagai A (2006) Alveolar cell senescence in patients with
mitochondria and stem cells during ageing. Nature 464:520–8 pulmonary emphysema. Am J Respir Crit Care Med 174:886–893
Salminen A, Huuskonen J, Ojala J et al (2008) Activation of innate Van der Loo B, Labugger R, Skepper JN et al (2000) Enhanced
immunity system during aging: NF-kB signaling is the molecular peroxynitrite formation is associated with vascular aging. J Exp
culprit of inflamm-aging. Ageing Res Rev 7:83–105 Med 192:1731–44
Schmitt V, Rink L, Uciechowski P (2013) The Th17/Treg balance is Vanaudenaerde BM, Verleden SE, Vos R et al (2011) Innate and adaptive
disturbed during aging. Exp Gerontol 48:1379–1386 interleukin-17-producing lymphocytes in chronic inflammatory
Seebart BR, Stoffel RT, Behan M (2007) Age-related changes in the lung disorders. Am J Respir Crit Care Med 183:977–86
serotonin 2A receptor in the hypoglossal nucleus of male and female
Vital M, Harkema JR, Rizzo M et al (2015) Alterations of the Murine Gut
rats. Respir Physiol Neurobiol 158:14–21
Microbiome with Age and Allergic Airway Disease. J Immunol Res.
Sharma G, Goodwin J (2006) Effect of aging on respiratory system phys-
doi:10.1155/2015/892568
iology and immunology. Clin Interv Aging 1:253–260
Shaw AC, Panda A, Joshi SR et al (2011) Dysregulation of human Toll- Vrijheid M (2014) The exposome: a new paradigm to study the impact of
like receptor function in aging. Ageing Res Rev 10:346–53 environment on health. Thorax 69:876–8
Small C-L, Mccormick S, Gill N et al (2008) NK cells play a critical Walski M, Pokorski M, Antosiewicz J et al (2009) Pulmonary surfactant:
protective role in host defense against acute extracellular. J ultrastructural features and putative mechanisms of aging. J Physiol
Immunol 180:5558–68 Pharmacol 60:121–125
Starr ME, Ueda J, Yamamoto S et al (2012) The effects of aging on pulmo- Weiskopf D, Weinberger B, Grubeck-Loebenstein B (2009) The aging of
nary oxidative damage, protein nitration and extracellular dismutase the immune system. Transpl Int 22:1041–50
down-regulation during systemic inflammation. Free Radic Biol Med Xu J, Gonzalez ET, Iyer SS et al (2009) Use of senescence-accelerated
50:371–380. doi:10.1016/j.freeradbiomed.2010.11.013.The mouse model in bleomycin-induced lung injury suggests that bone
Stout RD, Suttles J (2005) Immunosenescence and macrophage function- marrow-derived cells can alter the outcome of lung injury in aged
al plasticity: dysregulation of macrophage function by age- mice. J Gerontol A 64:731–739
associated microenvironmental changes. Immunol Rev 205:60–71 Yanai H, Shteinberg A, Porat Z et al (2015) Cellular senescence-like
Stout-Delgado HW, Vaughan SE, Shirali AC et al (2012) Impaired features of lung fibroblasts derived from idiopathic pulmonary fi-
NLRP3 inflammasome function in elderly mice during influenza brosis patients. Aging (iIpact) 7:664–672
infection is rescued by treatment with nigericin. J Immunol 188: Yang S-R, Park J-R, Kang K-S (2015) Reactive oxygen species in mes-
2815–24 enchymal stem cell aging: implication to lung diseases. Oxidative
Suchyta MR, Clemmer TP, Elliott CG et al (1997) Increased mortality of Med Cell Longev. doi:10.1155/2015/486263
older patients with acute respiratory distress syndrome. Chest 111: Yende S, Tuomanen EI, Wunderink R et al (2005) Preinfection systemic
1334–1339 inflammatory markers and risk of hospitalization due to pneumonia.
Suzuki M, Betsuyaku T, Ito Yet al (2008) Down-regulated NF-E2-related Am J Respir Crit Care Med 172:1440–6
factor 2 in pulmonary macrophages of aged smokers and patients Yoshida T, Tuder R (2007) Pathobiology of cigarette smoke-induced
with chronic obstructive pulmonary disease. Am J Respir Cell Mol chronic obstructive pulmonary disease. Physiol Rev 87:1047–1082
Biol 39:673–82 Zacca ER, Crespo MI, Acland RP et al (2015) Aging Impairs the ability
Svartengren M, Falk R, Philipson K (2005) Long-term clearance from of conventional dendritic cells to cross-prime CD8+ T cells upon
small airways decreases with age. Eur Respir J 26:609–615 stimulation with a TLR7 Ligand. PLoS ONE. doi:10.1371/journal.
Sze MA, Dimitriu PA, Suzuki M et al (2015) The host response to the pone.0140672
lung microbiome in chronic obstructive pulmonary disease. Am J
Zaccagnini G, Gaetano C, Della Pietra L et al (2005) Telomerase
Respir Crit Care Med 192:438–445
mediates vascular endothelial growth factor-dependent respon-
Tasdemir N, Lowe SW (2013) Senescent cells spread the word: non-cell
siveness in a rat model of hind limb ischemia. J Biol Chem
autonomous propagation of cellular senescence. EMBO J 32:1975–6
280:14790–14798
Tigges J, Krutmann J, Fritsche E et al (2014) The hallmarks of fibroblast
ageing. Mech Ageing Dev 138:26–44 Zemans RL, Colgan SP, Downey GP (2009) Transepithelial migration of
Toapanta FR, Ross TM (2009) Impaired immune responses in the lungs neutrophils: Mechanisms and implications for acute lung injury. Am
of aged mice following influenza infection. Respir Res. doi:10.1186 J Respir Cell Mol Biol 40:519–535
/1465-9921-10-112 Zhao J, Zhao J, Legge K, Perlman S (2011) Age-related increases in
Torres-González E, Bueno M, Tanaka A et al (2012) Role of endoplasmic PGD2 expression impair respiratory DC migration, resulting in di-
reticulum stress in age-related susceptibility to lung fibrosis. Am J minished T cell responses upon respiratory virus infection in mice. J
Respir Cell Mol Biol 46:748–56 Clin Invest 121:4921–30