Elsevier

Respiratory Medicine

Volume 102, Issue 9, September 2008, Pages 1215-1230
Respiratory Medicine

Review
Aging and induced senescence as factors in the pathogenesis of lung emphysema

https://doi.org/10.1016/j.rmed.2008.04.013Get rights and content
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Summary

Classically, the development of emphysema in chronic obstructive pulmonary disease is believed to involve inflammation induced by cigarette smoke and leukocyte activation, including oxidant-antioxidant and protease-antiprotease imbalances. While there is substantial evidence for this, additional aspects have been suggested by a number of clinical and experimental observations.

Smokers exhibit signs of premature aging, particularly obvious in the skin. The link between aging and chronic disease is well-known, e.g., for the brain and musculoskeletal or cardiovascular system, as well as the clinical link between malnutrition and emphysema, and the experimental link to caloric restriction. Interestingly, this intervention also increases lifespan, in parallel with alterations in metabolism, oxidant burden and endocrine signaling.

Of special interest is the observation that, even in the absence of an inflammatory environment, lung fibroblasts from patients with emphysema show persistent alterations, possibly based on epigenetic mechanisms. The importance of these mechanisms for cellular reprogramming and response patterns, individual risk profile and therapeutic options is becoming increasingly recognized. The same applies to cellular senescence. Recent findings from patients and experimental models open novel views into the arena of gene-environment interactions, including the role of systemic alterations, cellular stress, telomeres, CDK inhibitors such as p16, p21, pRb, PI3K, mTOR, FOXO transcription factors, histone modifications, and sirtuins.

This article aims to outline this emerging picture and to stimulate the identification of challenging questions. Such insights also bear implications for the long-term course of the disease in relation to existing or future therapies and the exploration of potential lung regeneration.

Keywords

p53
HDAC
HAT
Methylation
Acetylation
SIRT1

Abbreviations

α1-AT
alpha-1-antitrypsin
Akt
serine-threonine-kinase, member of the protein kinase B (PKB) family
ALT
alternative mechanisms of telomere lengthening
Bad
Bcl-2-associated death promoter, member of the B-cell leukemia/lymphoma 2 (Bcl-2) family
Bax
member of the Bcl-2 family
CDK
cyclin-dependent kinase
COPD
chronic obstructive pulmonary disease
DHEAS
dehydroepiadrosterone sulphate
DNA
deoxyribonucleic acid
FOXO
forkhead box O
GM-CSF
granulocyte/macrophage-colony-stimulating factor
H2O2
hydrogen peroxide
HAT
histone acetyltransferase
HDAC
histone deacetylase
IL
interleukin
IGF-1
insulin-like growth factor 1
MMP
matrix metalloproteinase
PCNA
proliferating cell nuclear antigen
PI3K
phosphatidylinositol 3-kinase
pRb
retinoblastoma protein
PPAR-γ
peroxisome proliferator-activated receptor gamma
PTEN
phosphatase and tensin homolog, tyrosine and lipid phosphatase
RNA
ribonucleic acid
ROS
reactive oxygen species
SA-β-gal
senescence-associated β-galactosidase
SIPS
stress-induced proliferative senescence
Sir2
silent information regulator 2
SIRT1
homolog of Sir2 in mammals
TNF-α
tumor necrosis factor alpha
mTOR
mammalian target-of-rapamycin kinase
UV
ultraviolet

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