title: Aging and induced senescence as factors in the pathogenesis of lung emphysema.
abstract: 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.
authors.affiliation: Institute for Inhalation Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg/Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Karrasch
authors.forename: Olaf
authors.initials: O
authors.lastname: Holz
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Jörres
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology*; D031204:Caloric Restriction; D018797:Cell Cycle Proteins / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology; D044127:Epigenesis, Genetic; D006801:Humans; D018384:Oxidative Stress; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012907:Smoking / Q000009:adverse effects; D016615:Telomere / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins