Respiratory Physiology & Neurobiology 187 (2013) 199–210

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Respiratory Physiology & Neurobiology

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a
te/resphysiol

Frontiers review

The aging respiratory system—Pulmonary structure, function and neural control

∗
Peter M. Lalley
Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Medical Sciences Center, 1300 University Avenue, Madison, WI 53706, United States

a r t i c l e i n f o a b s t r a c t

Article history:
Pulmonary structure and function change significantly between young adulthood and old age. Elastic
Accepted 26 March 2013
ele- ments of the lung degenerate, parenchymal tissue is lost, alveolar ducts and bronchioles dilate,
chest wall compliance decreases, intercostal muscle mass and force are reduced and gas exchange
Keywords:
surface lessens. Disturbances of innate immunity predispose the elderly to pulmonary inflammation.
Cognition
These changes affect pulmonary function tests and gas exchange, but adaptive changes in breathing
Sleep apnea
Cough frequency and tidal volume serve to maintain adequate ventilation. Aging depresses cough reflexes
Comorbidity and ventilatory responsiveness to hypoxia and hypercapnia. Sleep-associated apnea and periodic
breathing occur more frequently in the elderly, implying that neural feed back and feed-forward
control (loop gain) are impaired. Low loop gain may contribute to sleep apnea but not to periodic
breathing. A likely cause of age related pulmonary tissue degeneration and a future therapeutic target is
defective protein folding in the endoplasmic reti- culum. Nervous system adaptations that accompany
structural and functional changes in the elderly are poorly understood.
© 2013 Elsevier B.V. All rights reserved.

1. Introduction
In most technologically advanced countries the fastest-growing
segment of the population is over 65 years old. Consequently
there are increasing social, ethical, political and economic
pressures to understand the etiology and mechanisms of aging
and find ways to positively modify the process.
In recognition of the need to better understand and modify
the consequences of aging, several hundred journals directed at
gerontology and aging are now accessible since the first journals,
Geriatrics and the Journal of Gerontology, were published in 1946.
In PubMed, the online biomedical database developed by the US
National Library of Medicine, there are more than 158,000
literature citations on aging in humans going back to 1952.
Old age brings into play a variety of disparate physiological
changes that affect memory, cognition, vital signs and the respira-
tory system. About 10–20% of elderly subjects, 65–75 years of age,
experience mild cognitive impairment and memory loss (DeCarli,
2003), in association with reductions in brain volume and gray
mat- ter, and with lesions in transcallosal fiber tracts (Freye and
Levy,
2004; Dickstein et al., 2007; Bastin et al., 2010). Deficits of
memory and cognition can be of significance for the patient’s
awareness and caretakers’ diagnosis of changes in vital signs and
well-being. Vital signs (blood pressure, heart rate, temperature
regulation) change notably in the elderly (Chester and Rudolph,
2011). Endothelial
∗ Tel.: +1 608 263 4697; fax: +1 608 265 5512.
E-mail address: pmlalley@facstaff.wisc.edu
aging increases arterial wall stiffness with higher systolic and
pulse pressures. Vascular sympathetic receptors desensitize,
resulting in increased tendency toward postural hypotension.
Maximum heart rate decreases and resting heart rate slows,
probably due to 1 - adrenoreceptor desensitization, and
compensatory modulation of heart rate in response to external
stressors decreases. Core body temperature is lower and
thermoregulatory responses are sup- pressed.
The effects of aging on the respiratory system are many,
diverse, complex and often interactive. There is considerable
variability in what might be defined as normal respiratory
function in the elderly (Zeleznik, 2003), and it can sometimes be
difficult to distinguish it from age-related comorbidity.
In this review, normative standards of respiratory function in
the young adult are used as references to highlight changes that
accompany aging within the respiratory system. For that purpose, a
description of respiratory function and respiratory control in
young adults is presented and compared to respiratory changes
that occur in the elderly. Primary attention is given in this review to
the human respiratory system, with cross-references to animal
studies.
2. Respiratory system in young adult
mammals
The respiratory system in healthy young mammals, including
airways, lungs and respiratory muscles, efficiently delivers
oxygen to alveoli for cellular uptake and mitochondrial ATP
production and expels CO2 , the end product of cellular
metabolism, into the external atmosphere. Airflow between the
lungs and atmosphere and consequently O2 –CO2 exchange is
optimized by controlled,
1569-9048/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.resp.2013.03.012
 P.M. Lalley / Respiratory Physiology & Neurobiology 187 (2013) 199–210
rhythmic contractions and relaxations of the pump muscles
(diaphragm, intercostal and accessory chest wall muscles) and
by adjustments in the tone of bronchial smooth muscle, phar-
ynx, vocal folds and nasal skeletal muscle and the position of the
tongue (Macklem, 1978). The inspiratory pump muscles contract
in a set temporal order that optimizes leverage and minimizes
work required for air inflow (De Troyer et al., 2004). The muscles of
inspi- ration contract the diaphragm downward and expand the
chest wall outward and upward so that intrapleural pressure
becomes more negative to inflate the lungs. The extremely thin
layer of intrapleural fluid as well as the smooth exterior surface of
the lungs ensure effective coupling between chest wall and lung
expansion, and alveolar surfactant release reduces elastic recoil
force so that alveoli are open during inspiration (Bachofen et al.,
1970; Boron,
2005). Subsequent expiration during quiet breathing is mainly pas-
sive. The chest wall muscles return to their resting configuration
and elastic recoil of the lungs, vocal fold abduction, pharyngeal
muscle constriction and forward movement of the tongue in the
mouth permit expiratory airflow.
3. Changes in pulmonary structure and function in
the elderly
3.1. Respiratory pump muscles, chest wall and lungs
Several morphological changes reduce the respiratory efficiency
of the chest wall and diaphragm in the elderly. The cross
sectional areas of the intercostal muscles start to decrease after
the age of 50 years, the reduction being greater in the expiratory
muscles. There appears to be no change in the thickness of the
diaphragm with age, although structural changes in the chest
wall reduce the curvature of the diaphragm and maximal
transdiaphragmatic pressure (Zaugg and Luccinetti, 2000; Sprung
et al., 2006). In addition, the width of the esophageal hiatus is
greater after the age of 70 years. Maxi- mal static inspiratory and
expiratory pressures decrease with aging, reflecting a reduction
in respiratory muscle strength (Wijesinghe and Dow, 2006).
Diaphragmatic compound action potential latency evoked by
phrenic nerve stimulation increases with age, whereas action
potential amplitude decreases (Imai et al., 2005). The changes
are assumed to represent a disproportionate degeneration of
large myelinated phrenic nerve fibers, which could be a factor in
reduced diaphragmatic contractile strength. In addition, atrophy
and loss of fast twitch diaphragmatic muscle fibers occurs. The
changes affect- ing phrenic nerve myelinated fibers and
diaphragm muscle appear to be factors in a lower maximal
inspiratory pressure in the elderly (Tolep et al., 1995; Polkey et al.,
1997; Sharma and Goodwin, 2006; Miller, 2010).
Analysis of isolated phrenic nerve-diaphragm preparations
from aged rats have identified changes in diaphragmatic
physiology that have not been possible to measure in elderly
humans. Phrenic nerve axons innervating fast (type IIx)- and very
fast (IIb)-muscle fibers that are recruited later in the contractile
process during inspira- tion are smaller than in young rats, but
nerve terminal surface areas are larger and so are end plate areas,
indicative of age-related fragmentation of the neuromuscular
junction and compensatory restructuring that attempts to
maintain maximal inspiratory con- tractile force. The impact on
resting breathing and diaphragmatic contractile strength may
be minimal, because the fibers are recruited only for
situations requiring increased power output (Prakash and Sieck,
1998). Electrophysiological and microscopic measurements
performed on phrenic nerve-diaphragm prepara- tions from
aged rats (Smith and Rosenheimer, 1984) showed that phrenic
nerve conduction velocity does not change with age. Neu-
romuscular junctional clefts were found to be larger and
junctional
1
delay increased, but the changes were considered to be minor.
Smith and colleagues in other studies identified additional aging-
related changes in diaphragm neuromuscular junction properties,
including reduced spontaneous and stimulus evoked acetylcholine
release and reductions in the number of acetylcholine receptors,
acetylcholinesterase content, number of end plate nerve
terminals, spontaneous and stimulus evoked endplate currents
and endplate potentials (Smith and Rosenheimer, 1982; Smith,
1984; Smith and Emmerling, 1988; Smith et al., 1990).
Unfortunately, studies to determine what effects these changes
have on breathing in the aged rat have not been reported.
At human intercostal neuromuscular junctions, endplate num-
bers do not change with aging, but they increase in length along
with branching and enlargement of the post-junctional area and
degeneration of junctional folds. Junctional nerve terminals are
irregular, and Schwann cell processes project into the primary
junc- tional cleft. The number of pre-terminal axons entering an
endplate increase, and the endplate is composed of a greater
number of smaller conglomerates of ACh receptors. Similar to
the changes occurring at the diaphragm neuromuscular junction of
the aged rat, these morphological alterations reflect junctional
degeneration, changes in junctional quantal content and
compromised contrac- tile function (Oda, 1984; Wokke et al.,
1990; Jang and Van Remmen,
2011).
In addition to loss of intercostal muscle mass and strength and
deterioration of neuromuscular junctions, calcification of rib cage
cartilage and vertebral articulations, narrowing of intervertebral
disk spaces and osteoporosis contribute to reduced chest wall
com- pliance (Janssens et al., 1999).
Several notable changes in lung structure occur after the age
of 50 (Krumpe et al., 1985; Verbeken et al., 1992; Janssens et al.,
1999; Meyer, 2005; Colloca et al., 2010; Miller, 2010). Elastin fibers
in the bronchioles are disrupted and lost, and cross-linking of col-
lagen and elastin is altered. Alveoli are wider and shallower with
flattened inner surfaces (Fig. 1) and alveolar ducts are dilated. Sur-
factant content and properties on the other hand are not affected
(Rebello et al., 1996).
3.2. Pulmonary blood vessels
Beyond age 30–35 years, there is a gradual increase in the
stiff- ness of the pulmonary vasculature, likely caused by an
increase in muscle content and thickness (Taylor and Johnson,
2010). In association with structural remodeling, pulmonary
arterial pres- sure and pulmonary wedge pressure increase
gradually after 45 years, becoming significantly elevated beyond
50 years. In addition, gas exchange capability of the lungs is
compromised in association with reduced pulmonary capillary
volume and number.
3.3. Upper airways
Structural changes in nasal passages with aging are few
(Edelstein, 1996). Only the nasopharynx shows significant
physical changes, and rhinomanometry demonstrates that nasal
resistance increases. Histopathological studies show that there
is an age- related decrease in cartilage cells with no alteration in
the integrity of the mucosal lining. Status of the turbinates, nasal
ciliary motility and nasal secretions are unaffected by age.
Differences in pharyngeal size and tone exist between young
and older adults. The posterior pharyngeal wall is thinner and
does not constrict to the same extent in older subjects as in young
adults (Arminpour et al., 2011). The pharyngeal dilator genioglos-
sus muscles (GGM) exhibit inspiratory phased activity, which
during wakefulness is higher in older than in younger men (Fogel
et al., 2003). The higher wakeful muscle activity might be compen-
satory. With age-related reduction in muscle mass, the pharyngeal
 Fig. 1. Lung tissue from young (A) and old (B) human subjects.
Adapted from Janssens et al. (1999).

airway tends to become more collapsible, leading to increased Vital capacity (VC), the volume of gas expired by maximal
air- way resistance, whereas a reflexive increase in GGM activity expira- tion just after maximal inspiration, and equal to TLC-RV,
would serve to maintain airway patency. Airway structural volume decreases with age because RV increases while TLC is unchanged.
in gen- eral increases with age, particularly in men, in Functional residual capacity (FRC), the volume of gas at the end
association with increased soft tissue (Chan et al., 2010), while of normal tidal expiration when the respiratory muscles are
upper airway size decreases (Martin et al., 1997). relaxed, increases with age, by 1–3% per decade, along with the
Structural and histochemical changes in laryngeal muscle are FRC/TLC ratio. At FRC, the elastic forces of lung and chest walls are
observable beginning at about 60 years of age. In the equal and in opposite directions. The pleural surfaces link these
thyroarytenoid musculature, there is a marked increase of two oppos- ing forces; outward elastic chest wall forces are
connective tissue along with myopathic changes in muscle fibers, balanced by inward lung tissue elastic forces. With aging, Alveoli
including evidence of mitochondrial DNA mutation (Kersing and enlarge and coalesce, resulting in losses of elasticity and surface
Jennekens, 2004). Ossi- fication of the laryngeal skeleton is area and an increase in the fixed lung volume. Along with less
evident with increasing age, which can result in incomplete efficient gas mixing and alveolar–capillary gas exchange, static
glottal closure secondary to bowing of the vocal folds, which has pressure–volume relation- ships are shifted toward reduced
the potential to compromise respira- tory and protective elastic recoil with age. The rate of decrease in lung recoil exceeds
functions of the larynx (Paulsen et al., 2000; Kahane and Kahn, that of the chest wall so that lung volume at the end of tidal
1987). expiration increases.
Expiratory reserve volume (ERV), the volume of gas expired by
3.4. Changes in lung performance, respiratory mechanics and a maximal expiration made at the end of normal tidal expiration,
ventilation is equal to FRC − RV. ERV decreases with aging because
transmu- ral pressure increases and causes dynamic compression
Respiratory performance begins to decline after year 30. of airways, which impairs expiratory airflow and prevents
The changes detected by spirometric measurements have been dependent alveoli from emptying. Although both FRC and RV
described in detail (Verbeken et al., 1992; Stocks and Quanjer, increase with aging, RV increases more. The most likely structural
1995; Janssens, 2005; Staub, 1998a,b; Meyer, 2005; Sprung et al., factor for the increase in ERV is a loss of connective tissue
2006; Stanojevic et al., 2008; Colloca et al., 2010) and summarized around small airways that normally have a stenting effect.
in this review in Table 1 and Fig. 3.
Most of the aging-associated changes in the respiratory
system evolve from a decrease in chest wall compliance, a Table 1
Lung performance in the young adult and how it is affected by aging.
reduction in
static elastic recoil of the lungs (Fig. 2), and decreasing strength of
the respiratory muscles. Measurements Values, 15–40 yrs. Change, ≥60 yrs.
The next few paragraphs briefly explain how changes in lung FRC 2.4 LM , 1.8 LF a Increase
and chest wall muscles alter tests of pulmonary function, TLC 6.0 LM , 4.2 LF Unchanged
respiratory mechanics and gas exchange. TV 0.6 LM , 0.5 LF Modest increase
IRV 3.0 L M, 1.9 L F Modest increase
Total lung capacity (TLC), the volume of gas in the lungs after a
maximal inspiratory effort, is determined by the strength of the RV 1.2 LM , 1.1 LF Increase
ERV 1.2 LM , 1.0 LF Increase
inspiratory muscles and the elastic recoil of the chest wall and
TLC 6.0 LM , 4.2 LF Unchanged
lungs. TLC does not change significantly with age because
VC 4.8 LM , 3.4 LF Decrease
decreased outward elastic recoil of the chest wall that IC 3.6 LM , 2.4 LF Increase
accompanies loss of respiratory muscle strength is offset by FVC 5.5 LM , 3.8 LF Decrease
decreased inward lung recoil associated with deterioration of FEV1 4.6 LM , 3.3 LF Decrease
elastic airway connective tissue. FEV1 /FVC 0.84M , 0.87F Decrease
Residual volume (RV), the volume of gas remaining in the lung Peak expiratory flow 600–670 L min−1M Decrease
425–465 L min−1F
after a maximal forced expiration, increases with age along with
Chest wall compliance at FRC 0.2 L cm−1 H2 O Decrease
the ratio RV/TLC. RV is determined by two factors: (1) the Lung compliance at FRC 0.2 L cm−1 H2 O Increase
strength of expiratory muscle that oppose outward chest wall Mean pleural pressure −5 cm H2 O Unchanged
recoil at low tho- racic volumes, and (2) collapse of small airways Airway resistance 2.0 L cm−1 H2 O s−1 Increase
and trapping of gas in alveoli during forced expiration. With loss Values and changes obtained from: Clouter (2005), Miller et al. (2005), Stanojevic
of expiratory muscle strength, outward chest recoil is less et al. (2008), Staub (1998a,b), and Stocks and Quanjer (1995).
opposed, thus RV increases. a F: female; M: male.
 Fig. 2. Opposite changes in lung and chest wall compliances with aging. (A) Increasing lung compliance. (B–D) Decreasing chest wall
compliance. Adapted from (A) Lai-Fook and Hyatt (2000) and (B) Estenne et al. (1985).

Dynamic lung compliance decreases with age largely because
elastic tissue is lost from alveoli and smaller airways, increasing
resistance to flow.
Dynamic chest wall compliance decreases such that elastic
recoil changes from outward to inward at much lower lung
volumes. Structural factors include loss of compliance in the
upper rib cage and lower thorax due to calcification of costal
cartilages and degenerative changes of the dorsal spine that
cause chest wall stiffening. The reduction in dynamic chest
wall compli- ance exceeds the reduction in dynamic lung
compliance, and
total respiratory system compliance is progressively reduced with
aging.
Other estimators of dynamic lung function decrease with age,
including forced vital capacity (FVC), a measure of maximal expi-
ratory flow rate, and forced expiratory flow rate over one second
(FEV1 ); both are linked to reduced chest wall compliance and
expi- ratory muscle strength and a greater tendency of smaller
airways to close during forced expiratory effort.
Closing volume (CV), the lung volume at which small airways
begin to close during forced expiration, increases. CV can exceed

Fig. 3. (A) Lung volumes and capacities detected by sprirometry or indirectly, for example by helium dilution, nitrogen washout or whole body plethysmography. (B)
Relative changes in lung volumes and capacities with age. TLC: total lung capacity; VC: vital capacity; IRV: inspiratory reserve volume; RV: reserve volume; ERV: expiratory
reserve volume; FRC: functional reserve capacity. (C) Flow–volume loops obtained from spirometer measurements. Positive flow is during forced expiration, negative
flow during forced inspiration. FVC: forced vital capacity, equal to TLC-RV. Older subject produces lower forced inspiratory and forced expiratory airflows, as well as
lower FVC, than younger subject.
(A) Figure adapted from Corrette-Bennett, Lung Volumes and Capacities, Science in Motion.3.1.10B (www.westminster.edu/acad/sim/pdf). (B) From Janssens et al. (1999). (C)
Adapted from Janssens (2005).
FRC, in which case airway closure is present and alveoli may be
under-ventilated in dependent areas of the lung, i.e., in the lower
regions near the base of the lung where intrapleural pressure is
less negative. The overall effect is less efficient matching of lung
ventilation and perfusion (VA /Q mismatch, or inequality).
Arterial PO2 decreases progressively with age, however alveolar
PO2 in well-ventilated regions of the lungs doses not, therefore
the alveolar–arterial oxygen difference, (A − a)DO2 , increases
progres- sively.
Alveolar dead space, regions of the lung that are ventilated but
not adequately perfused, increases in association with reduced
car- diac output.
Ventilation–perfusion (VA /Q) inhomogeneity, or mismatch
increases with age. There is a greater tendency toward airway
closure in lower lung regions, where intrapleural pressure is
higher and there is less elastic tissue in older humans to hold
small airways open and resist airway collapse. CV may
approach FRC, so that a substantial percentage of airways may
be closed and produce a low VA /Q during normal tidal breathing
(Janssens, 2005).
Pulmonary diffusing capacity (DFC), the volume of gas that
diffuses across the membranes between the alveoli and lung
capillaries, decreases with age. Factors responsible for the reduc-
tion include loss of alveolar surface area, decreased capillary
blood volume and decreased surface area for alveolar–capillary
gas dif- fusion. The reduction in DFC, along with a small
increase in physiological shunting (transfer of blood from the left
cardiac ven- tricle to systemic circulation without undergoing
pulmonary gas exchange) and increased VA /Q mismatching
contribute to falling PaO2 and increasing (A − a)DO2 .
Gas exchange. PaO2 decreases progressively with age, from about
95 mm Hg at 20 years of age to about 75 mm Hg at 70 years
(Cerveri et al., 1995). The decrease in PaO2 occurs in
association with increased VA /Q heterogeneity in lower regions
of the lung (Cardús et al., 1997), where airway compression linked
to loss of lung elastic recoil and reduced resistance to collapse
result in airway closure, significant ventilation–perfusion
impairment during quiet breath- ing and reduction in lung
diffusing capacity (Holland et al., 1968; Paoletti et al., 1985). Lung
perfusion can also be reduced with aging because of lower cardiac
output (Levitzky, 1984; Wagner, 2005). Although PaO2 declines
with aging, PaCO2 is maintained constant (Wahba, 1983; Sprung
et al., 2006). Various hypotheses have been offered to explain
unchanging PaCO2 , including decreasing basal metabolic rate
(Sprung et al., 2006) and greater diffusivity of CO2 through the
alveolar–capillary barrier (Levitzky, 1984). The most likely
explanation is that because the Hb–O2 dissociation curve lev- els
off at PaO2 values greater than 60 mmHg in lung regions with
high VA /Q ratios, there is not much of an increase in the O2 con-
tent of blood leaving these regions. In contrast, lung regions
with low VA /Q ratios have low O2 content (Martin, 1987, figs.
5–13). When blood from these different regions mixes in the
pulmonary veins, the result is a lower than normal content with
a resultant low PO2 , which will not have much impact on
breathing until PO2 drops below 60 mmHg. On the other hand for
CO2 , the relationship between PCO2 and CO2 content does not
flatten out. Thus, lung regions with high VA /Q have low CO2
content that can offset the impact of low VA /Q in regions that
have high CO2 content. Further- more, neural control of
ventilation is more sensitive to elevated PaCO2 than to reduced
PaO2 (Dubose and Berde, 1997). In situa- tions where there is a
residual increase in PCO2 in older subjects with increased VA /Q
heterogeneity, it is offset by increased minute alveolar ventilation.
3.5. Immunosenescence
Changes suggestive of immune dysfunction in the airways of
elderly subjects have been reported (Meyer et al., 1996; Sharma
and Goodwin, 2006; Busse and Mathur, 2010; Shaw et al., 2010).
There are several notable changes that affect lung tissue. For exam-
ple, natural killer (NK) and NK-T lymphocytes, immunoglobulins
and interleukin-6 concentrations are higher while microphages
are lower relative to young adults. Neutrophil numbers may or
may not change, but their chemotactic activity diminishes.
Overall, these changes are interpreted to reflect persistent low-
grade respira- tory tract inflammation (inflamm-aging) linked to
depression of innate immune function in the elderly. Changes in
epithelial cells and ciliary motility also contribute to disturbances
of innate immu- nity in the elderly, because ciliated cells
normally propel antigens and irritants trapped in mucous up the
tracheobronchial tree and nasal passages. Ciliary motility in
smaller airways is significantly decreased and mucous cell
production is reduced in subjects over
60 years of age.
4. Control of breathing and the stimulus to
breathe
Aggregates of rhythmically active neurons in respiratory
regions of the pons and medulla provide primary control over
motor out- put to the diaphragm, intercostal muscles, upper
airways and accessory muscles of respiration. Synaptic
interactions among bulbar respiratory neurons maintain a
constitutive rhythm and pattern of breathing for effective gas
exchange between lungs and atmosphere under normal resting
conditions. Bulbar respi- ratory network interactions with
cortical, cardiovascular, visceral autonomic and skeletal muscle
neural networks allow respiratory activity to adjust to changes in
posture, transitions between sleep and wakefulness and activities
such as physical exercise, phona- tion, swallowing, coughing
and defecation (Richter, 1982, 1996; Feldman, 1986; Long and
Duffin, 1986; Ezure, 1990; Turner, 1991; Bianchi et al., 1995; Horn
and Waldrop, 1998; Schäfer, 1998; Rybak et al., 2004).
Two sources of tonic excitatory synaptic drive on bulbar
respira- tory neurons adjust network respiratory drive to
maintain arterial and tissue PCO2 , pH and PO2 levels within the
physiological range. One is supplied by the brainstem reticular
activating system, which is most active in the conscious state
(Plum et al., 1962; Skatrud and Dempsey, 1983; Shea, 1996). The
other comes from O2 , CO2 and pHa sensitive cells in the carotid
bodies and brainstem. (Bainton and Mitchell, 1966;
Severinghaus et al., 1998; Nattie, 1999; Feldman et al., 2003;
Guyenet et al., 2010; Putnam, 2010). In addition to the
brainstem, chemosensitive cells have been identified in several
forebrain sites. Of these, the strongest link to breathing has been
made for orexin neurons in the lateral hypothalamus–perifornical
region (Guyenet et al., 2010, Nattie and Li, 2010). According to
one
report (Dahan et al., 2007), CNS chemoreceptor neurons provide
60–80% of the ventilatory response to CO2 /pH while the remain-
der is attributed to carotid body chemoreceptors. However, the
relative contribution of central and peripheral chemoreceptors is
still debated. There is evidence that at lower levels of hypercap-
nia, carotid body chemoreceptors have the greater influence,
while intracranial chemoreceptors are more dominant at higher
levels (Forster et al., 2008). Experiments on conscious, freely
breathing dogs have shown that carotid body and intracranial
chemorecep- tors are interdependent in regulating pHa and PaCO2
(Smith et al.,
2010), and that carotid body chemoreceptors contribute more than
50% of the total eupnoeic drive to breathe (Blain et al., 2009).
The carotid bodies are the initial and perhaps the most influ-
ential responders to hypoxia. As well as being also responsive
to hypercapnia and acidosis, they are sensitive to hypoglycemia,
hyperthermia, hyperosmolarity and hyperkalemia (Nurse, 2009;
Kumar, 2009). These stimuli depolarize type-1 glomus cells of
the carotid body, causing release of excitatory neurotransmit-
ters that increase sinus nerve afferent discharge intensity and
subsequent excitatory synaptic activation of bulbar respiratory
and cardiovascular neurons (Lahiri et al., 2006; Powell, 2007). The Increased breathing frequency that maintains VA and PaCO2
usual reflex responses to carotid body stimulation are at the same approximate level as in young adults is most likely
hyperventila- tion, bradycardia and peripheral vasoconstriction, as
a consequence of increased discharge activity in phrenic and
intercostal nerves and altered activity in sympathetic and
parasympathetic efferents (Kumar, 2009).
The CO2 /pH chemoreflex maintains respiratory homeostasis by
matching ventilation to metabolic CO2 production generated by
all types of cells within and outside of the CNS. In engineering
terms, the reflex is essentially a dynamic feedback control
system (Khoo, 2000) with two elements (Fig. 4A): a “controller”
network of CO2 /pH-sensitive chemoreceptors, and a “plant”
consisting of body tissues (the source of metabolic CO2
production) and the lungs (the CO2 exchanger). The sensitivity or
“gain” of the controller is typi- cally expressed as a change in
minute ventilation (VE ; the output) produced by a change in
PaCO2 (the input). The plant is basically an expression of tissue
metabolic rate, functional residual capacity and pulmonary dead
space volume, and its gain is expressed as the change in PaCO2
(output) produced by a change in VE (input).
The PaCO2 signal from the plant reaches the controller after a
circulatory delay determined by cardiac output and cerebral
blood flow. A change in the PaCO2 signal received by the controller
evokes a change in output that increases excitatory synaptic drive
on respi- ratory neurons and motor output, and a proportional
change in VE . Controller performance is usually measured during
CO2 adminis- tration or by rebreathing oxygen-enriched expired
gas, while plant performance is measured by voluntary hypo- and
hyperventilation (Ogoh et al., 2008). Since controller and plant
gains share common variables (VE and PaCO2 ) under closed loop
conditions, plotting the controller and plant functions together
as VE vs. PaCO2 (Fig. 4B) gives an estimate of the operating
point, or steady state where the two curves intersect. Such
curves are often superimposed to compare controller and plant
properties under control and test situations (Kiwull-Schöne et
al., 2008; Ogoh et al., 2008). Respi- ratory loop gain has also
been measured with a technique called proportional-assist
ventilation (Wellman et al., 2003).
Under conditions where plant and controller gains and circu-
latory delay are optimal, closed loop negative feedback cancels
or severely minimizes respiratory disturbances triggered by
extrane- ous sources. This type of engineering analysis has proven
useful in examining effects of exercise, chronic heart failure,
drugs (Khoo,
2000; Miyamoto et al., 2004; White, 2005; Wellman et al., 2007;
Kiwull-Schöne et al., 2008; Ogoh et al., 2008) and sleep state
(Sec- tion 7) on plant gain, controller gain and breathing.

4.1. Breathing control in the elderly

Several changes in the ways elderly subjects breathe compen-

sate for alterations in compliance, airway closing pressure and
gas exchange at rest and during exercise: (1) elderly subjects
main- tain VA at the same approximate level as young adults by
breathing more rapidly at lower tidal volume. (2) During
exercise, the ven- tilatory response to CO2 is greater than in
young adults, although isocapnia is maintained. (3) During
hypercapnia, the CO2 threshold for increased inspiratory effort is
reduced. (4) Elderly subjects have a lessened perception of added
resistive loading. The adaptations in breathing seem linked to
altered neural integration, but the mech- anisms are poorly
understood (Peterson et al., 1981; Rubin et al.,
1982; Tack et al., 1981, 1983; Brischetto et al., 1984; Janssens et
al.,
1999; Sprung et al., 2006; García-Río et al.,
2007).

4.2. Adaptations in breathing frequency and tidal volume

an adaptation to counteract the reduction in VT (Staub, 1998b).
Changes in the reactivity and function of central chemoreceptors
and peripheral mechanoreceptors have been proposed but not
sub- stantiated (Sprung et al., 2006). Cortically mediated
readjustments in breathing frequency that maintain VE in
proportion to PaCO2 might be involved, because cortical input–
output connections that influence respiration have been
identified by functional NMRI in young adults (Davenport and
Reep, 1995; Evans et al., 1999). In addition, studies that
examined cortical control over breath- ing showed that when
spontaneous breathing was replaced by a volitionally paced
respiratory rhythm, VT decreased as breathing frequency was
increased, so that VE was maintained in accor- dance with the
background level of CO2 , dead space ventilation and metabolic
rate. (Haouzi et al., 2007; Haouzi and Bell, 2009). Assum- ing that
the cortex is a controller that adjusts breathing frequency, the
next question is how the neural circuitry is arranged. Human
studies shed no light, but anatomical experiments on cats
revealed corticospinal projections to phrenic and intercostal
motoneurons (Rikard-Bell et al., 1985). Since a direct
corticospinal projection would bypass brainstem rhythm and
pattern generating circuits, it seems likely that the pathway
influences tidal volume and not breathing frequency. Other
animal studies show that there are several parallel pathways to
and through the brainstem and respi- ratory network that
influence rhythmic motor output and have connections with the
cerebral cortex (Lois et al., 2008; Long and Duffin, 1986; Bianchi
et al., 1995; Richter, 1996; Rybak et al., 2004). This is not to infer
an obligatory role of the cortex in regulation of breathing rate,
and it is not the sole site where breathing fre- quency is
influenced. Activation of neurons of the paraventricular
hypothalamus in the rat and deep cerebellar nuclei in cats
increases phrenic nerve discharge frequency as well as intensity
(Mack et al.,
2002; Xu and Frazier, 2002).

4.3. Ventilatory response to exercise

Increased ventilatory responsiveness to exercise in the elderly

is isocapnic and compensates for greater dead space. According to
Brischetto et al. (1984), ETCO2 during exercise is lower than in
young adults when measured at a common workload, however
the ventilatory response to exercise estimated from VE / VCO2
is greater. Their study eliminated O2 desaturation and lactacidosis
as factors, and concluded that exercise hypernea is produced by
unidentified neural mechanisms unrelated to peripheral or central
chemoreceptors. In young adults, dynamic loop analysis (Fig. 4)
also shows that altered chemoreceptor gain is not a factor in the
venti- latory response to exercise (Ogoh et al., 2008), whereas
plant gain is notably reduced, as is total respiratory loop gain.
Cerebrovascu- lar CO2 reactivity increases during exercise, which
might help to maintain CO2 homeostasis. So far, no reports of
central controller and peripheral plant gains during exercise in
elderly humans are available.

4.4. Lower CO2 threshold for increased inspiratory effort

There are no known neuronal mechanisms that explain why

the CO2 threshold for increased inspiratory effort is lower in the
elderly. García-Río et al. (2007) think that it might be a
compensatory response to offset an increase in PCO2 in the CNS.
They suggest that compensation may be triggered by lowered
cerebral blood flow that produces a higher PCO2 in the region of
CNS chemoreceptors for a given level of PaCO2 .

4.5. Altered perception of added resistive loading

There is general agreement that decreased perception of

increased resistive loading during inspiration occurs within
the
Fig. 4. Dynamic chemical feedback loop. (A) Disturbances in ventilation (for example transient extraneous drive during voluntary hyperventilation, or a change in lung
volume, inspired gas or altered cardiac output) will change PACO2 in proportion to the plant gain. The resulting change in PACO2 is given by the hyperbolic function
PaCO2 = A/VE + C, where A = 863˛, C = 863ˇ, ˛ is a proportionality constant and ˇ is a constant representing work-related CO2 production (Miyamoto et al., 2004; Harms
and Dempsey, 1999). The change in PACO2 is delayed as a function of cardiac output and blood flow. Mixing with blood sets the level of arterial oxygen pressure (PaCO2 )
that reaches the CO2 /pH-sensitive chemoreceptors and evokes a change in ventilation (VE ). The change in VE opposes the original disturbance in proportion to the
controller gain (CG, given by the linear relationship VE = S[PaCO2 − B], where S = slope and B is the slope intercept). (B) Controller and plant gains share common variables
(VE and PaCO2 ). Plotting their respective functions on a common graph gives an estimate of the steady state operating point for a given ventilatory response. CCG-1 and
CCG-2 are central controller gains. (C) Oscillations in VE evoked by CCG-1 and CCG-2. Small perturbations in ventilation occur in a stable system and return quickly to a
steady state (CCG-1). Large oscillations in VE associated with a large controller gain (CCG-2) characterize an unstable state such as occurs in periodic breathing.
Adapted from (A) Khoo (2000), (B) Miyamoto et al. (2006) and (C) Manisty et al. (2006).

CNS, without consequence on ventilatory patterns (Tack et al., cortical association regions than in cortical sensory areas (Raz and
1981, Rodrigues, 2006).
1983). Two factors might account for the change in perception.
First, in older subjects, cues related to respiratory muscle force 5. Cough reflexes
seem to be most important for the sensation of lung volume
change, but muscle force development diminishes with age. On
Two or more distinctive human cough reflexes exist that
the other hand in young adults, the sensation of lung volume
depend on the evoking stimulus and its location within the
change is dependent more on lung volume displacement (Tack et
respiratory tract (Brooks, 2011). One is an involuntary reflex,
al., 1983). Second, and this is entirely speculative, decreases in
also occur- ring in nonhuman primates and guinea pigs, that is
regional cortical brain vol- ume and degeneration of white
initiated by
matter with aging are greater in
mechanosensory A fibers and is relatively insensitive to most develops (Dahan et al., 2007). Hypercapnic ventilatory drive is
chemical stimuli, but activated by aspirated gastric contents, light immediately reduced after carotid body removal, reaching a
punctate mechanical stimulation and rapid changes in pH. A nadir 3–6 months
second type of involuntary cough reflex is set up via vagal sensory
c-fibers by tissue injury, inflammation and chemicals such as
bradykinin, capsaicin, citric acid and SO2 . The motor pathways
involved in the cough reflex have been worked out in animal
studies (Brooks, 2011; Poliacek et al., 2008). They suggest that
different reflex responses utilize overlapping medullary neuron
circuit components, includ- ing the commissural subnucleus of
the nucleus tractus solitarius, the nucleus ambiguus, pre-
Bötzinger complex, the more rostral Bötzinger region and the
pool of expiratory bulbospinal neurons in the caudal
ventrolateral medulla. Signals are also transmitted by other
afferent connections to the thalamus and to cerebral cor- tical
regions involved in sensation and perception. Pontine and
medullary respiratory neurons of the medulla are activated to
gen- erate motor output to the diaphragm, vocal cords, glottis,
chest wall and abdominal muscles. The motor components of the
cough reflex involve: (1) contraction of the diaphragm and
external inter- costal muscles to expand the lungs. (2) Contraction
of the adductor vocal folds to close the glottis. (3) Relaxation of
the diaphragm and contraction of the expiratory chest wall and
abdominal muscles, increasing lung air pressure. (4) Relaxation of
vocal fold adductors and contraction of abductors, opening the
glottis to expel air from the lungs. (5) Collapse of bronchi and
non-cartilaginous portions of the trachea to form narrow
openings through which the air is forced to clear irritants from
the respiratory lining (Widdicombe,
1998; Fontana and Lavorini, 2006; Canning, 2009a,b; Magni et al.,
2011).

5.1. Cough reflexes in the elderly

Cough reflexes are less forceful and productive in the elderly.

One reason is that cough sensation is suppressed (Chang and
Widdicombe, 2007). Reduced sensitivity to irritants seems to
involve several factors, including reduced bronchial smooth mus-
cle tone, elevated thresholds in slow- and rapidly-adapting vagal
laryngeal afferents and impaired cortical perception (Newnham
and Hamilton, 1997). Since strength of the respiratory muscles
normally decreases with age, the motor component of the cough
reflex that is essential for airway clearance may also be less effec-
tive (Sharma and Goodwin, 2006). Weakening of the cough reflex
could be a factor in the higher incidence of aspiration pneumonia
in older subjects.

6. Hypercapnic and hypoxic ventilatory

drive

Standard methods for evaluating hypercapnic and hypoxic

ven- tilatory drive in humans include measuring breathing
patterns by spirometry or plethysmography or by mouth
occlusion pressure
0.1 s after the onset of inspiration (P0.1), while manipulating alve-
olar carbon dioxide (PACO2 ) and/or oxygen (PAO2 ).

6.1. Hypercapnic ventilatory drive in young adults

Respiratory responses to hypercapnia have been studied

exten- sively in nonhuman in vivo and in vitro preparations
(Sapru, 1996; Guyenet et al., 2010; Feldman et al., 2003;
Putnam, 2010). The usual response to hypercapnia is an
increase in minute venti- lation produced by elevated tidal
volume (Clark and von Euler,
1972; Cunningham and Gardner, 1977). In adult humans
subjected to carotid body resection, a functional reconfiguration
of central nervous related respiratory responsiveness to pCO2 /pH
postoperatively, followed by a slow return to preoperative values
within 2 years.

6.2. Hypoxic drive in young adults

The hypoxic ventilatory response pattern depends on the rel-

ative degree of hypoxia and the way it is presented. Exposure of
young adults to transient moderate hypoxia increases the
duration of inspiration and tidal volume, whereas expiratory
duration does not change significantly (Jennett et al., 1981).
In young male adults subjected to moderate intermittent iso-
capnic hypoxia over several days, tidal volume increases to a
plateau within 1–4 days without changing breathing frequency
significantly (Brugnlaux et al., 2011). When a single episode of
moderate isocapnic hypoxia is maintained for 20–30 min, minute
ventilation increases to a peak for several minutes, then declines
more gradually over the next 20 min to about 50% of the peak
increase (Teppema and Dahan, 2010). Repeated episodes (3–5
min) of moderate hypoxia interrupted by normoxia evokes a
progres- sive increase in respiratory motor output during
normoxic periods, referred to as long-term facilitation (LTF:
Mateika and Narwani,
2009). LTF persists for over an hour after hypoxic episodes,
evidenced by increased breathing frequency but not tidal volume
(Wadhwa et al., 2008).
Severe hypoxia maintained over several minutes evokes a
biphasic respiratory response in humans as well as other mam-
malian species. When partial pressure of tissue oxygen falls to
7.5 Torr and lower, initial augmentation of ventilatory drive related
to carotid body effects is followed by apnea and gasping that
is mediated within the CNS. Peripheral chemoreceptor denerva-
tion selectively eliminates the initial augmentation (Martin-Body
et al., 1985; Richter et al., 1991). The CNS mechanisms responsible
for respiratory depression during severe acute hypoxia are many
and complex. Neuronal depression is associated with decreasing
intracellular ATP and increased cell membrane K-conductance
and hyperpolarization, ostensibly for the purpose of energy
conserva- tion and restoration of pump mediated ionic
equilibrium in order to fend off cell death (Neubauer et al., 1990;
Ballanyi, 2004; Yamada and Inagaki, 2005). In respiratory regions
of the cat medulla, gluta- mate and GABA levels increase during
the initial augmentation of respiratory motor output, then
decline during apnea, while sero- tonin and adenosine levels
gradually increase with the onset of depression (Richter et al.,
1999).

6.3. Hypercapnic and hypoxic ventilatory drives in the elderly

Of 16 studies evaluated in this review, 14 reported significant

reductions of hypercapnic (HCVD) and/or hypoxic (HVD) ventila-
tory drive in elderly subjects. These studies can be highlighted as
follows: (1) when HVCR was measured there was no significant
difference between elderly and young subjects. However under
concomitant hypoxic conditions, HVCR increased in young adults
but not in the elderly (Nishimura et al., 1992). (2) Elderly subjects
had lower P0.1 responses to hypoxia and hypercapnia, while
there was a progressive age-related decrease in PACO2 threshold
(García- Río et al., 2007). (3) Compared to younger subjects, P0.1
responses to isocapnic hypoxia were reduced by about 50%, and to
hyperoxic hypercapnia by about 60% (Janssens et al., 1999). (4)
Ventilatory responses to hyperoxic hypercapnia and isocapnic
hypoxia using rebreathing methods were lower in aged subjects
in association with reduced neuromuscular inspiratory output
(Peterson et al.,
1981). It seems likely that blunting of hypercapnic and hypoxic
ventilatory drive in elderly humans involves both disturbances of
chemosensory function and structural changes in lung and chest
wall that reduce motor performance.
 Hypoxic LTF has apparently not been evaluated in elderly whereas Browne et al. (2003) showed that the gain of the central
humans, but in rats it declines with age when evaluated by mea-
suring phrenic and hypoglossal nerve discharges. The aging-related
decline in hypoglossal nerve LTF is greater than the decline in
phrenic nerve LTF (Zabka et al., 2001; Mateika and Narwani,
2009).

7. Sleep-associated changes in breathing

During non-rapid eye movement sleep, amplitude and fre-

quency of breathing are regular. Minute ventilation decreases
by 13–15%; mean inspiratory flow decreases and tidal volume
decreases. Rib cage displacement decreases, abdominal
contractil- ity increases slightly and diaphragmatic contractility is
unchanged. During rapid eye movement (REM), airflow and tidal
volume are highly variable. Fluctuations in RAS modulation
during REM sleep cause irregular breathing amplitude and
frequency and inter- mittent central apneas. Rib cage and
intercostal muscle activity displacement decrease, whereas
diaphragmatic activity increases. The decreased rib cage
activity results in hypoventilation and hypoxemia. Upper
airway resistance increases because of pharyn- geal dilator
muscle hypotonia and partial airway collapse.
In elderly as well as young adults, ventilatory responsiveness
to hypercapnia is blunted during sleep. In either age group, there
is a stepwise increase in end-tidal PCO2 in the progression from
wakefulness to sleep and then to REM sleep. The total increase in
PCO2 may be as much as 5 Torr during REM sleep as a consequence
of decreased alveolar ventilation. Central CO2 /pH chemosensitiv-
ity decreases; activity of accessory chest wall and neck muscles
decreases and upper airway muscle activity is depressed
(Krimsky and Leiter, 2005). The immediate consequences of sleep
apnea are negative with respect to mood, temperament, alertness
and motor performance. In addition, sleep apnea-induced
hypoxia promotes angiogenesis that can lead to tumor growth
and higher incidence of cancer mortality (Nieto et al., 2012).

7.1. Sleep disordered breathing in the elderly

The percentage of time spent in REM sleep is less in elderly

sub- jects than in young adults, while light sleep (stages 1 and 2)
and slow wave sleep stages are more frequent. In addition,
circadian rhythms are weaker, more desynchronized and less
prominent. Factors proposed to account for the changes in sleep
architecture include reduced secretion of melatonin, a key
factor in circa- dian rhythm regulation, and aging-associated
neural degeneration (Neikrug and Ancoli-Israel, 2010; Prinz et al.,
1990).
Obstructive sleep apnea (OSA), central sleep apnea (CSA) and
periodic breathing resembling Cheyne-Stokes respiration (CSR)
occur more frequently in the elderly than in young adults. CSR is
dis- tinguished by episodes of waxing and waning breathing and
results in insufficient ventilation and gas exchange. Neither
cause-effect relationships nor the neural mechanisms are
adequately under- stood, but defective chemical feedback control
has been suggested as a contributing factor (Webb, 1974; Shore et
al., 1985; Pack et al.,
1988; Hudgel et al., 1993; Hudgel and Hamilton, 1994; Wellman
et al., 2007). Fig. 4B and C depict a simulation from Manisty et al.
(2006) and show how elevated controller gain, in this case asso-
ciated with chronic heart failure, might lead to large sustained
oscillations of ventilation during sleep. See White (2005) and
Topor et al. (2007) for further theoretical discussions of how
altered loop gains can contribute to sleep disordered breathing.
Two clinical studies have examined loop gain effects on chem-
ical feedback and periodic breathing during sleep. Wellman et al.
(2007) found that elderly subjects actually have low loop gains,
even lower than young adults with stable breathing patterns,
controller in the ventilatory feedback loop is depressed to similar
degrees in young and elderly subjects during sleep. The Wellman
report (2007) suggests that low loop gain might contribute to
sleep apnea and decrease ventilatory drive to the pharyngeal
muscles, leading to airway narrowing.

8. Sensitivity to respiratory depression by opioids and

sedative-hypnotics

Elderly subjects are notably more sensitive to respiratory

depression by opioids and sedative-hypnotics due to pharma-
cokinetic and pharmacodynamic changes. Serum drug levels
are elevated because volume of distribution decreases in
associa- tion with reductions of lean muscle mass, total
body water and renal drug elimination. Decreased glomerular
filtration and reduced total and functional hepatic blood flow
reduce the capac- ity to excrete hydrophilic opioids, sedative-
hypnotics and their metabolites. Pharmacodynamic changes
related to drug-receptor interactions and intracellular second
messenger efficacy increase GABA receptor-related sedative-
hypnotic sensitivity and the intrin- sic activities of opioids such
as fentanyl and its congeners, and promote longer duration of
drug effect (Mann et al., 2003; Freye and Levy, 2004; Dowling et
al., 2008).

9. Concluding remarks and hypotheses

9.1. Structural changes lead to breathing changes set up within

the CNS

The effects of aging on ventilation and breathing are progres-

sive and gradual. The major changes in respiratory performance
emanate from degenerative structural changes, particularly as they
affect the lungs, respiratory chest wall and glottis. Breathing pat-
terns accommodate to structural deterioration through
adaptations presumably set up within the CNS respiratory
controller to main- tain effective pulmonary gas exchange even
as VA /Q mismatch progresses. Whereas structure–function
relationships that directly involve the airways and pump muscles
during aging are well known and readily explained,
readjustments within the brainstem and higher neuronal
networks remain a mystery.

9.2. The endoplasmic reticulum: potential source of degenerative

structural changes and target for future therapeutics

The ER plays critical roles in lipid biosynthesis, calcium

storage and release and in protein folding. In normal aging,
aging-related dementia, Alzheimer’s, Parkinson’s and brain-
wasting diseases, a common factor is the occurrence of the
unfolded protein response (UPR) in the ER, in which the
effectiveness of folding proteins (chap- erones), other enzymes
that facilitate protein folding (foldases) and folding sensors are
reduced. The resulting accumulation of insoluble, misfolded
proteins as fibrils or plaques triggers an ER stress response that
can ultimately lead to cellular apoptosis in all types of tissue
(Brown and Naidoo, 2012). With the rapidly accumulating
knowledge of how UPR and ER stress lead to cell malfunction
and death in the aged, therapeutic approaches that detect early
evidence of protein misfolding and promote correct folding of
ER proteins are foreseeable (Brown and Naidoo, 2012) and offer
hope that they can forestall the degenerative changes in lung
parenchyma, intercostal muscles and upper airways.

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