---

-
- -
-
CHEST Translating Basic Research Into Clinical Practice

COPD as a Disease of Accelerated

Lung Aging*
Kazuhiro Ito, PhD; and Peter J. Barnes, MD, FCCP

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

Key words: aging; COPD; corticosteroid; emphysema; histone deacetylase; lung function; oxidative stress; sirtuin

Abbreviations: DNA-PK = DNA-dependent protein kinase; HDAC = histone deacetylase; IL = interleukin; MMP = matrix
metalloproteinase; NF-KB = nuclear factor-xb, PI3K = phospho-inositide 3 kinase; ROS = reactive oxygen species;
SMP30 = senescence marker protein-3D; TNF = tumor necrosis factor

C OPD is a major and increasing global health

problem with enormous amount of expenditure of
indirect/direct health-care costs.' COPD now affects
> 10% of the world population over the age of 40
years,I and the burden of disease is particularly high in
"From Airways Disease Section, National Heart and Lung Insti-
tute, Imperial College London, UK.
The authors have no financial relationship with a commercial
entity that has an interest in the subject of this article.
Manuscript received June 5, 200H; revision accepted August 8,
2008.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
orglmisclreprints.shtml).
Correspondence to: Kazuhiro Ito, PhD, National Heart and Lung
Institute, Imperial College School tif Medicine, Dooehouse St,
London SW3 6LY, UK; e-mail: k.ito@imperial.ac.uk
DOl: lO.1378/chest.08-1419
developing countries. There is still a fundamental lack
of knowledge about the cellular, molecular, and genetic
causes of COPD, and current therapies are inadequate
because no treatments reduce disease progression or
mortality. COPD is caused by long-term inhalation of
noxious gases and particles, such as cigarette smoke,
and a chronic inflammatory disease of the lower airways
and lung parenchyma, which is enhanced during exac-
erbations.s The pathologic characteristics of COPD are
destruction of the lung parenchyma (emphysema),
inflammation of peripheral and central airways, and an
increase in mucus-producing cells. Airflow limitation,
measured by reduced FEVl , progresses very slowly
over several decades, so that most patients with symp-
tomatic COPD are in late middle age or are elderly.
Thus, the prevalence of COPD is age dependent,

www.chesljournal.org CHEST/135/1/ JANUARY, 2009 ·173

suggestingan intimate relationship between the patho-
genesis of COPD and aging.
AGING PROCESS AND ITS MOLECULAR
MECHANISM
Senescence or aging is defined as the progressive
decline of homeostasis that occurs after the reproduc-
tive phase of life is complete, leading to an increasing
risk of disease or death. Kirkwood" has advanced the
concept of "disposable soma," in which aging, rather
than being programmed and determined by selected
genes, results from the stochastic interaction between
injury and repair, as the result of the energy devoted by
an individual to maintain organ integrity and protect
DNA againstoxidative injury. In this model, the failure
of organ/cell maintenance/repair results from the inte-
grated action among genes, environment, and intrinsic
defects of the organism. Underlying the aging process
is a lifelong, bottom-up accumulation of molecular
damage. Kirkwood- also makes the point that cellular
defects often cause inflammatory reactions, which can
themselves exacerbate existingdamage, so that inflam-
matory and antiinflammatoryfactors can playa part in
shaping the outcomes of the aging process. Thus,
aging-associated inflammation/structural change is the
results of failure of reactive oxygen species (ROS)
elimination, failure of repair of damaged DNA, and
telomere shortening, as shown below.
Telomere Shortening
In many human somatic tissues and cells such as
fibroblasts, there is a decline in cellular division
capacity with age or a limited division potential
before undergoing so-called replicative senescence.
This appears to be linked to the fact that the
telomeres, which protect the ends of chromosomes,
get progressively shorter as cells divide. Oxidative
stress has been found to have an even bigger effect
on the rate of telomere loss," and telomere shorten-
ing is greatly accelerated (or slowed) in cells with
increased (or reduced) levels of oxidative stress.
Oxidative Stress and DNA Damage
Somatic mutations can occur in any of the cells of
the body, and this somatic mutation and other forms
of DNA damage have been demonstrated to be
increased age dependently. Promislow" reported a
general relationship between longevity and DNA
repair. Thus, the capacity for DNA repair may be an
important determinant of the rate of aging at the cell
and molecular level.
Harman" suggested that ROS, formed during nor-
mal oxygen metabolism, induce damage, the accumu-
174
lation of which accounts for progressive deleterious
changes called aging or senescence. This hypothesis is
called the free radical theory of aging and has later
been extensively supported by numerous in vivo and
in vitro studies7- 10 showing that age-related changes
is accelerated under the influence of oxidative stress,
while various antioxidants slow aging. This oxidative
stress causes DNA damage and increases risk of
cancer, as documented for the role of mammary
gland senescence and the increased risk of breast
cancer.
Antiaging Molecules: Recent advance in aging
research is identification of antiaging molecules.
Sirtuins are nicotinamide adenine dinucleotide-
dependent histone/protein deacetylases and display
differential specificity toward acetylated substrates,
which translates into an expanding range of physio-
logic functions, such as gene expression, cell cycle
regulation, apoptosis, metabolism, and aging. II
Seven molecules have been identified in the human
sirtuin family (SIRT1-SIRT7). As well as sirtuins
(type III histone deacetylase [HDAC]), HDAC-2 (a
type I HDAC) is also reported to be an antiaging
molecule as knock-down of HDAC-2 induces cellular
senescence by enhancing p53-dependent transrepres-
sion and transactivation of a subset of target genes.12
Homozygous mutant klotho (KL -1-) mice have a
short lifespan and have pulmonary emphysema as well
as some other aging phenotypes, such as arteriosclero-
sis, osteoporosis, skin atrophy, and ectopic calcifica-
tions'" (Table 1). The secreted Klotho protein can
regulate multiple growth factor signaling pathways,
including insulin/insulin-like growth factor and Wnt,
and the activity of multiple ion channels. Klotho pro-
tein also protects cells and tissues from oxidative stress,
yet the precise mechanism underlying these activities
remains to be determined. The development of em-
physema in KL-/- mice is due increased expression
of matrix metalloproteinase (MMP)-9.
Senescence marker protein-30 (SMP30), a 34-kd
protein originallyidentified from the rat liver, is a novel
molecule that decreases with age in an androgen-
independent manner. SMP30 is widely expressed in
vertebrates and highly conserved. The SMP30 out
(SMP30Y/-) mouse has a shorter life span, and has
had senile lung with age-related airspace enlarge-
ment and enhanced susceptibility to harmful stimu-
li14 (Table 1). Cigarette smoke exposure generates
marked airspace enlargement with Significant paren-
chymal destruction in the SMP30Y/- mice.P Protein
carbonyl, a marker of oxidative stress that increases
with aging, was also Significantly increased after 8
weeks of exposure to cigarette smoke. Thus, SMP30
protects mice lungs from oxidative stress associated
with aging and smoking.
Translating Basic Research Into Clinical Practice
 Table I-Aging and Emphysema in Gene-Modified Mice
Target Molecule Lifespan Emphesema
(Knockout, Mutant) Shortening Emphysema (Plus Cigarette Smoke)
SIRT6 Yes Unknown Unknown
Klotho Yes Yes Enhanced
SMP30 Yes Yes Enhanced
Ku86 (Ku80) Yes Unknown Unknown
DNA-PK Yes Unknown Unknown
Nrf2 No No Enhanced
The molecules responsible for DNA repair, such
as DNA-dependent protein kinase (DNA-PK) and
Ku86 (or Ku80), are also a sort of anti aging mole-
cules. As shown in Table 1, DNA-PK knockout mice
showed telomere shortening and intestinal atrophy,
which are seen as aging phenotypes, Ku86 knockout
mice also showed the early onset of age-specific
changes characteristic of senescence in mice.!" In
either DNA-PK knockout or Ku-86 knockout mice,
structural change in lung and lung function have not
been evaluated. FOXO transcription factor belongs
to the large Forkhead family of proteins, a family of
transcriptional regulators characterized by a con-
served DNA-binding domain termed the forkhead
boxI? They are important transcriptional factors for
DNA repair and production of antioxidants, such as
mononuclear superoxide dismutase and catalase.
FOXO factors promote longevity and reduce age-
dependent diseases in invertebrates. The role of
FOXO in lung disease has not yet been evaluated.
Defective Protein Turnover: Protein turnover is
essential to preserve cell function by removing pro-
teins that are damaged, mistranslated, or redundant.
Age-related impairment of protein turnover is indi-
cated by the accumulation over time of damaged
proteins, and there is evidence that an accumulation
of altered proteins contributes to a range of age-
related disorders, including cataract, Alzheimer dis-
ease, and Parkinson disease. Protein turnover in-
volves the functions of chaperones, which help to
sequester and, if possible, restore denatured pro-
teins, and of proteasomes, which degrade proteins
via ubiquitination. With aging, there is evidence for
functional decline in the activities of both protea-
somes and chaperones. IS
AGING AND LUNG FUNCTION/STRUCTURAL
CHANGE
The classical epidemiologic studies of Fletcher
and Peto!? demonstrated that death and disability
www.chestjoumal.org
Other Aging Phenotype
Profound lymphopenia, loss of subcutaneous fat, lordokyphosis,
severe metabolic defects
Osteopenia, atrophic skin, hepatocellular degeneration
More susceptible to TNF-Q:- and Fas-mediated apoptosis,
deposition of lipofuscin
Osteopenia, atrophic skin, hepatocellular degeneration
Telomere shortening, lymphoma, intestinal atrophy, loss of
bone density, spine convexity
Sensitive to oxidative stress
from COPD were related to an accelerated decline
in lung function with time, with a loss of 50 to 100
mL in FEV1 per year, but even in healthy volunteers
there is a loss of 20 mL per year with aging (Fig 1).
Janssens and coworkers-" demonstrated that physio-
logic aging of the lung is associated with dilatation of
alveoliwith an enlargement of airspaces and a decrease
in gas exchange surface area, together with a loss of
supporting tissue for peripheral airways ("senile em-
physema"), resulting in decreased static elastic recoil of
the lung and increased residual volume and functional
residual capacity. This age-dependent loss of elastin
fibers is similar to the loss of skin elasticity and wrin-
kling of the skin that occurs with age. However,
Verbeken and coworkers.s' proposed that the changes
in structure and functional characteristics caused by
isolated airspace enlargement that are seen in the
elderly lung be differentiated from emphysema by the
absence of alveolar wall destruction.
Functionally, vital capacity is reduced with aging,
although the total lung capacity remains quite con-
stant. 22 Respiratory muscle strength also decreases
with aging. 23 Expiratory flows decrease with a char-
acteristic alteration in the flow-volume curve sug-
gesting small airway disease. Decreased sensitivity of
respiratory centers to hypoxia or hypercapnia results
in a diminished ventilatory response in cases of
aggravated airway obstruction. Thus, aging lungs
exhibit both structural and functional alterations. IS
AGING AND INFLAMMATION
Most age-associated diseases, such as Alzheimer
disease, cataract, rheumatoid arthritis, osteoporosis,
and cardiovascular disease as well as COPD, involve
chronic inflammation, including infiltration of in-
flammatory cells and higher circulating or local
concentrations of proinflammatory cytokines. In-
creased production of oxygen-derived free radicals is
a primary driving force for aging and activate redox-
sensitive transcriptional factors, such as activator
protein-l and nuclear factor-reb (NF-KB), which
CHEST/ 135 / 1 / JANUARY, 2009 . 175
 FIGURE 1. Hypothesis of development of COPD by an accelerating lung aging. Aging is defined as the
progressive decline of homeostasis, and this is the result of failure of organ maintenance from DNA
damage, oxidative stress, and telomere. shortening. During aging, pulmonary function deteriorates
progressivelyand pulmonary inflammation is increased with structural changes in the lung parenchyma
and small airways. Environmental exposure. for example cigarette smoke, may accelerate aging-
dependent defective lung function.

switch on multiple genes encoding proinflammatory
molecules.w The regulation of NF-KB is greatly
influenced by the intracellular redox status and plays
a major role in the regulation of inflammation pro-
cess during aging. Increased NF-KB activity during
aging is due to hyperphosphorylation of inhibitory
KBa. Activation of signal transducer, signal trans-
ducer and activator of transcription-3, and signal
transducer and activator of transcription-5, which are
downstream of IL-6 Signaling, is also reported in
T-cells from elderly subjects.P Stress kinases also
play important roles in aging process. Phospho-
inositide 3 kinase (PI3K) and mitogen-activated pro-
tein kinase are known as aging kinases (Fig 2).
As the results of transcriptional factors activation
by ROS, several genes are known to be regulated
with aging process.l" Cyclooxygenase is an enzyme
responsible for prostaglandin synthesis, and cycloox-
ygenase messenger RNA level and cyclooxygenase
activation increase with aging. This prostaglandin
synthesis pathway contributes to ROC accumulation
during aging. Nitric oxide is also increased with age
by increase in inducible nitric oxide synthase expres-
sion. Nitric oxide interacts with oxygen radicals to
form peroxynitrite, which induces nitration of ty-
rosine residues of proteins. Accumulation of nitroty-
rosine deposits is found in age-related diseases such
as COPD and Alzheimer disease, and nitration alters
enzyme activity and protein stability. Increased lev-
els of interleukin (IL)-lJ3, IL-6, IL-B, IL-IB, IL-l
receptor antagonist, and tumor necrosis factor
(TNF)-a are also found in plasma and mononuclear
blood cell culture from elderly subjects as well as
serum.!" It is also reported that the immune system
is impaired with aging, and this may lead to a
reduction in the adaptive immune response. In
contrast to IL-6 and IL-B, IL-2 production is de-
creased with aging, suggesting a decrease in the
clonal expansion of T cells leading to a decrease in
the specific immune response.!" This situation cre-
ates an imbalance between the adaptive and innate
immune responses.
The number of neutrophils in the lower respira-
tory tract of healthy elderly individuals is increased.w
and there is increased release of neutrophil elastase,
which could contribute to the loss of elastic recoil
and of elastin fibers in the aging lung, which in turn
would reduce interdependence between the airways
and parenchymal structures, thus contributing to de-
terioration oflung function. Glucocorticoid sensitivity is
reduced during aging as well as in COPD. For exam-
ple, dexamethasone-induced tyrosine aminotransferase
and tryptophan oxygenase activities as the markers of
steroid-induced transactivation are decreased with
age,27 and several reports I8 ,2Il show a decline in glu-
cocorticoid receptor expression during aging.
Reactive oxygen species-induced stress kinase activa-
tion is also one of age-related process. PI3K is known as
aging kinase29 and is activated by oxidative stress. We
also found cigarette smoke to be a strong stimulant of
PI3K, and this involves in HDAC-2 inactivation seen
under oxidative stress (in preparation),

176 Translating Basic Research Into Clinical Practice

 FIGURE 2. Molecular mechanisms of aging and development of COPD. Accumulation of endogenous
ROS induce DNA damage, NF-KB activation via phosphorylation of IKBa, activates oxidative stress
responsible kinases (MAPK [mitogen-activated protein kinase], PI3K), reduced sirtuin activity, and
proteasome inhibition. This result in chromatin structure instability and amplified inflammation as well
as structural change by apoptosis and hyperplasia. Cigarette smoking enhances all of these mechanisms
and also decreases HDAC expression and antioxidant/nitrosant activity, resulting in further amplifica-
tion of inflammation and accumulation of oxidatedlnitrated proteins. Lung image is from http://
www.yourlunghealth.orgllung...disease/copdlindex.cfm.

SIMILARITIES BETWEEN AGED LUNG AND
LUNG
It is not clear how the aging process is involved in
the decline of lung function and inflammation in
capo. However, there are a lot of similarities
between aged lung and capo lung (Table 2).
Especially, there have been important advances in
understanding the molecular mechanisms of ages,
and several of these pathways are relevant to accel-
erated lung aging in COPD patients.
As shown in the model in Figure 1, lung function
is declined in capo quicker than normal aged lung.
The lung function/age curve looks to be shifted
leftward in capo patients. Thus, we hypothesized
that emphysema/chronic obstruction may be one of
the phenomena underlying accelerated lung aging
process resulting from a failure of lung maintenance
and repair due to significant and sustained lung
injury by exposed cigarette smoke, air particulates,
and pollutants (Fig 1).
Functionally, vital capacity is reduced with aging
as well as in capo, although the total lung capacity
remains constant. Respiratory muscle strength also
decreases in capo as similar to aging process.
capo There are several similarities in inflammation be-
tween aging and capo, such as neutrophil accumu-
lation, NF-KB activation.P? and increase in IL-6/IL-
8/fNF-a. capo patients are also corticosteroid
insensitive as similar to healthy aged people.
At the molecular level, there is also evidence that
capo lungs have shortened telomeres as compared
with age-matched nonsmoker lungs. Telomere length
has been demonstrated to be significantly shorter in
patients with emphysema than in asymptomatic non-
smokers in alveolar type II cells and endothelial
cells,3I peripheral blood mononuclear cells,32 and
fibroblast.33
As suggested in "the free radical theory of aging"
by Harman," ROS accounts for progressive deleteri-
ous changes called aging or senescence. There is
ample evidence that oxidative stress plays a major
role in COPD,34 with increased expression of mark-
ers of oxidative stress in patients with capo system-
ically and in diseased lung. DNA damage is induced
by oxidative stress and cigarette smoke, and these are
risk factors for carcinogenesis. In fact, patients with
capo have an increased risk for lung cancer,
suggesting cellular senescence could also explain the

www.chestjoumal.org CHEST /135/ 1 / JANUARY, 2009 177

 Table 2-Comparison of Aged Lung With COPD tural change of lung, such as emphysema. Inter-
Lung* estingly COPD patients show exaggerated skin wrin-
Variables Aging COPD kling compared to normal smokers, and this has been
associated with increased MMP-9 expression by
Lung function
keratinocytes.P SIRT6 loss leads to abnormalities
Alveolar spaces r t t , with alveolar
in mice that overlap with aging-associated degen-
wall destruction
Neutrophils r rr erative processes, and SIRT6 is a nuclear, chromatin-
Basophils t Unknown associated protein that promotes resistance to DNA
IL-6 t t damage. It is unknown whether SIRT6-deficient mice
IL-B, TNF-a, t t r
IL-2 --+ have emphysema or not, but at least we preliminarily
showed that SIRT6 expression is also reduced in
VEGF t
iNOS t rr COPD lung.26 We have already shown that HDAC-2
Hemoxygenase-l t t is markedly reduced in COPD in activity and expres-
Manganese superoxide sion in peripheral lung tissue and alveolar macro-
dismutase, catalase
phages, especially in more severe disease, and that
Adhesion molecules r t this reduction is involved in enhancing inflammation
(E-selectin, P-
selectin, L-selectin, and corticosteroid insensitivity.40,41 Furthermore,
VCAM, ICAM) preliminary studies have found that Klotho and
NF -KB activation r t t SMP-30 levels are also decreased in COPD lung
Histone deacetylase 2 Slight
(unpublished data; October 26,2006).
reduction
Corticosteroid sensitivity
Reactive oxygen species r tt
Nitrated and oxidized t rr THERAPEUTIC IMPLICATIONS
proteins
*VCAM = vascular cell adhesion molecule;iNOS = inducible nitric oxide Greater understanding of the molecular mecha-
synthase; ICAM = intercellularadhesion molecule;VEGF = vascular en- nisms of aging has revealed several novel targets for
dothelial growth factor; t indicates increase, enhance; indicates
drug development, and since these processes are
decrease;--+ ?
indicates no change; indicates unknown.
involved in the pathogenesis of emphysema this may
lead to new treatments for COPD. From the oxida-
tive stress/aging theory and the fact that oxidative
significantly increased rate oflung cancers in emphy- stress is major risk factor of COPD, antioxidants are
sematous patients by DNA damage. Increased in likely to be effective antisenescence drugs or anti-
nitrotyrosine deposition is also a feature seen in COPD COPD drugs. Currently available antioxidants, such as
lung as well as aged tissue. This is the evidence of an N-acetyl cysteine, are not very potent and may not
increase in nitrativeloxidative stress, and reduction of sufficiently reduce oxidative stress in the lungs. Novel
antioxidant/nitrosant activity may contribute to this and more potent antioxidantsare needed in the future,
accumulation of nitrated and oxidizedprotein. Further- and there are several drugs in development, including
more, defect of protein degradation system in COPD new glutathione and superoxide dismutase analogues.
or aging cannot be ruled out. Nrf2 (nuclear factor-E2-related factor-2) and FOXO
Antioxidant enzyme and activity is also decreased are the transcription factors to induce endogenous
in COPD, like aging, Superoxide dismutase enzyme antioxidant molecules and potential target to increase
activity is reported to be lower in long-term healthy antioxidant activity. In fact, sulforaphane, which is
smokers and in stable COPD patients than in healthy extracted from brocolli, is reported to be a Nrf2
adults,35 although this is still controversial." COPD activator.42
patients also have reduced total antioxidant capacity. Sirtuins are antiaging molecules and control oxi-
Furthermore, ferric-reducing antioxidant power is dative stress resistance, DNA repair, and inflamma-
lower in COPD patients, and it had a positive tion. Resveratrol is a polyphenol found in red wine
correlation with the severity of airways obstruction and the skin of red fruits, which has antioxidant
(FEV 1 percentage of predicted). effects. Resveratrol is also a sirtuin activator, and this
Furthermore, expression of antiaging molecules property has been proposed to account for its anti-
are reduced in COPD. We already reported that .aging effects.v' Recently a SIRTI-specific activator
SIRTI was selectively reduced in lung tissue and that is 1,OOO-times more potent than resveratrol has
peripheral blood mononuclear cells in COPD,37 in been developed and examined possibility as therapy
agreement with a recent report." We also found for diabetics." Theophylline is also reported to inhibit
that SIRTI is a major inhibitory regulator of nicotinamide adenine dinucleotide consumption by
MMP-9, and reduction in SIRTI may cause struc- poly (adenosine diphosphate ribose)-polymerase-l ac-

178 Translating Basic Research Into Clinical Practice

tivation and may therefore restore SIRTl activity re-
duced under oxidative stress. Theophylline is also a
class I HDAC activator and activates HDAC-2, an
antiaging HDAC in pulmonary cells.45 SIRT6 acti-
vator will be another option to inhibit accelerated
aging in lung.
CONCLUSION AND FUTURE DIRECTIONS
The link between aging and the pathogenesis of
COPD is strongly supported by numerous stud-
ies. Senescence is a complex outcome of both
intrinsic and environmental factors, especially oxida-
tive stress, and therefore the role of cigarette smoke/
noxious gas is a key factor linking aging lung to
COPD. However, the molecular mechanisms are not
yet been fully explored. Recently, a number of
antiaging molecules have been identified, and eval-
uation of these molecules in patients with COPD
might identify several new molecular targets for the
treatment of COPD.
ACKNOWLEDGMENT: We regret that owing to space con-
straints we were not able to cite all the important original
publications and apologies to those authors whose work we have
not cited.
REFERENCES
1 Buist AS, McBumie MA, Vollmer WM, et al. International
variation in the prevalence of COPD (the BOLD Study): a
population-based prevalence study. Lancet 2007; 370:741-750
2 Barnes PJ. Chronic obstructive pulmonary disease * 12: new
treatments for COPD. Thorax 2003; 58(9):803-808
3 Kirkwood TB. Understanding the odd science of aging. Cell
2005; 120:437-447
4 von Zglinicki T. Oxidative stress shortens telomeres. Trends
Biochem Sci 2002; 27:339-344
5 Promislow DE. DNA repair and the evolution of longevity: a
critical analysis. J Theor BioI 1994; 170:291-300
6 Harman D. Free radical theory of aging: an update: increas-
ing the functional life span. Ann N Y Acad Sci 2006;
1067:10-21
7 Reeve AK, Krishnan KJ, Turnbull DM. Age related mito-
chondrial degenerative disorders in humans. Biotechnol J
2008; 3:750-756
8 Galaris D, Mantzaris M, Amorgianiotis G Oxidative stress
and aging: the potential role of iron. Hormones (Athens)
2008; 7:114-122
9 Percy C], Power D, Gobe GG Renal ageing: changes in the
cellular mechanism of enerb'Y metabolism and oxidant han-
(Iling. Nephrology (Carlton) 2008; 13:147-152
10 Head E, Rofina J, Zicker S. Oxidative stress, aging, and
central nervous system disease in the canine model of human
brain aging. Vet Clin North Am Small Anim Pract 2008;
38:167-178
11 Grubisha 0, Smith BC, Denu JM. Small molecule regulation
of Sir2 protein deacetylases. FEBS J 2005; 272:4607-4616
12 Harms KL, Chen X. Histone deacetylase 2 modulates p53
transcriptional activities through regulation of p53-DNA
binding activity. Cancer Res 2007; 67:3145-3152
www.chestjournal.org
13 Suga T, Kurabayashi M, Sando Y, et al. Disruption of the
klotho gene causes pulmonary emphysema in mice: defect in
maintenance of pulmonary integrity during postnatal life.
Am J Respir Cell Mol BioI 2000; 22:26-33
14 Maruyama N, Ishigami A, Kuramoto M, et al. Senescence
marker protein-30 knockout mouse as an aging model. Ann N
Y Acad Sci 2004; 1019:383-387
15 Sato T, Seyama K, Sato Y, et al. Senescence marker protein-3D
protects mice lungs from oxidative stress, aging, and smoking.
Am J Respir Crit Care Moo 2006; 174:530-537
16 Vogel H, Lim DS, Karsenty G, et al. Deletion of Ku86 causes
early onset of senescence in mice. Proc Nat! Acad Sci USA
1999; 96:10770-10775
17 Kaestner KH, Knochel W, Martinez DE. Unified nomencla-
ture for the winged helixlforkhead transcription factors.
Genes Dev 2000; 14:142-146
18 Ito K. Does lung aging have an impact on chronic obstructive
pulmonary disease? J Organ Dysfunction 2007; 3:204-220
19 Fletcher C, Peto R. The natural history of chronic airflow
obstruction. BMJ 1977; 1:1645-1648
20 Janssens JP, Pache JC, Nicod LP. Physiological changes in
respiratory function associated with ageing. Eur Respir J
1999; 13:197-205
21 Verbeken EK, Cauberghs M, Mertens I, et al. The senile
lung: comparison with normal and emphysematous lungs: 1.
structural aspects. Chest 1992; 101:793-799
22 Chan ED, Welsh CH. Geriatric respiratory medicine. Chest
1998; 114:1704-1733
23 Tolep K, Kelsen SG. Effect of aging on respiratory skeletal
muscles. Clin Chest Med 1993: 14:363-378
24 Rahman I, Adcock 1M. Oxidative stress and redox regulation of
lung inflammation in COPD. Eur Respir J 2006; 28:219-242
25 Fulop T, Larbi A, Douziech N, et al. Cytokine receptor
signalling and aging. Mech Ageing Dev 2006; 127:526-537
26 Meyer KC, Rosenthal NS, Soergel P, et al. Neutrophils and
low-grade inflammation in the seemingly normal aging hu-
man lung. Mech Ageing Dev 1998; 104:169-181
27 Ribarac-Stepic N, Vulovic M, Koricanac G, et al. Basal and
glucocorticoid induced changes of hepatic glucocorticoid
receptor during aging: relation to activities of tyrosine amino-
transferase and tryptophan oxygenase. Biogerontology 2005;
6:113-131
28 Grimble RF. Inflammatory response in the elderly. CUIT
Opin Clin Nutr Metab Care 2003; 6:21-29
29 Ayyadevara S, Alla R, Thaden Il- et al. Remarkable longevity
and stress resistance of nematode PI3K-null mutants. Aging
Cell 2008; 7:13-22
30 Barnes PJ. Transcription factors in airway diseases. Lab
Invest 2006; 86:867-872
31 Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence in
patients with pulmonary emphysema. Am J Respir Crit Care
Med 2006; 174:886-893
32 MorIaM, Busquets X, Pons J, et al.Telomere shortening in smokers
with and without COPD. Eur Respir J 2006; 27:525-528
33 Muller KC, Welker L, Paasch K, et aI. Lung fibroblasts from
patients with emphysema show markers of senescence in
vitro. Respir Res 2006; 7:32
34 MacNee W. Oxidants/antioxidants and chronic obstructive
pulmonary disease: pathogenesis to therapy. Novartis Found
Symp 2001; 234:169-185
35 Kirkil G, Hamdi MM, Seckin D, et al, Antioxidant effect of
zinc picolinate in patients with chronic obstructive pulmonary
disease. Respir Med 2008; 102:840-844
36 Nadeem A, Raj HG, Chhabra SI(, Increased oxidative stress
and altered levels of antioxidants in chronic obstructive
pulmonary disease. Inflammation 2005; 29:23-32
37 Vuppusetty C, Ito M, Elliot M, et al. Expression of SIRTl, an
CHEST/135/1/ JANUARY,2009 179
 anti-aging molecule, decreases with an increasing severity of
COPD [abstract]. Am J Respir Crit Care Med 2007; A553
38 Rajendrasozhan S, Yang SR, Kinnula VL, et aI. SIRTl, an
antiinflammatory and antiaging protein, is decreased in lungs
of patients with chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2008; 177:861-870
39 Patel BD, Loa WJ, Tasker AD, et aI. Smoking related COPD
and facial wrinkling: is there a common susceptibility? Thorax
2006; 61:568-671
40 Ito K, Ito M, Elliott WM, et aI. Decreased histone deacety-
lase activityin chronic obstructive pulmonary disease. N Engl
J Med 2005; 352:1967-1976
41 Ito K, Yamamura S, Essilfie-Quaye S, et aI. Histone deacety-
lase 2-mediated deacetylation of the glucocorticoid receptor
enables NF-KB suppression. J Exp Med 2006; 203:7-13
42 Mukherjee S, Gangopadhyay H, Das DK. Broccoli: a unique
vegetable that protects mammalian hearts through the redox
cycling of the thioredoxin superfamily. J Agric Food Chern
2008; 56:609-617
43 Wood JG, Rogina B, Lavu S, et aI. Sirtuin activators mimic
caloric restriction and delay ageing in metazoans. Nature
2004; 430:686-689
44 Milne JC, Lambert PD, Schenk S, et aI. Small molecule
180
activators of SIRTI as therapeutics for the treatment of type
2 diabetes. Nature 2007; 450:712-716
45 Ito K, Lim S, Caramori G, et aI. A molecular mechanism of
action of theophylline: induction of histone deacetylase activ-
ity to decrease inflammatory gene expression. Proc Nat) Acad
Sci USA 2002; 99:8921-8926
46 Tuder RM, YoshidaT, Arap W, et aI. State of the art: cellular
and molecular mechanisms of alveolar destruction in emphy-
sema; and evolutionary perspective. Proc Am Thorac Soc
2006; 3:503-510
47 Buchman AS, Boyle PA, Wilson RS, et aI. Pulmonary func-
tion, muscle strength and mortality in old age. Mech Ageing
Dev 2008, August 6 [Epub ahead of print]
48 Karrasch S, Holz 0, Jorres RA. Aging and induced senes-
cence as factors in the pathogenesis of lung emphysema.
Respir Med 2008; 102:1215-1230
49 Vogelmeier C, Bals R. Chronic obstructive pulmonary disease
and premature aging. Am J Respir Crit Care Med 2007;
175:1217-1218
50 Kojima S, Sakakibara H, Motani S, et aI. Incidence of chronic
obstructive pulmonary disease, and the relationship between
age and smoking in a Japanese population. J EpidemioI2007;
17:54-60
Translating Basic Research Into Clinical Practice