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.

Hhip haploinsufficiency sensitizes mice to age-related emphysema

“…During aging, reactive oxygen species (ROS) production and oxidant burden increase in lungs, contributing to parenchymal lung destruction and emphysema (17,18). Pulmonary emphysema may result from accelerated and premature aging of the lungs because of cellular senescence (19), consistent with the observation that most COPD patients develop disease at advanced ages.…”

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…Emphysema accompanies cellular senescence, and the incidence of this disease increases with age (Karrasch, Holz, & Jörres, 2008; Tsuji et al, 2006). Recent studies on the genetic and pharmacological ablation of senescent cells have demonstrated that these cells underlie several diseases (He & Sharpless, 2017).…”

Genetic and Environmental Effects on Telomere Length and Lung Function: A Twin Study

“…Of the potential unique environmental factors, tobacco smoke is known to promote aging processes and cellular senescence (38) and telomere shortening (8) in addition to its known damaging effects on lung function (39). We found that current smoking, but not previous smoking was significantly associated with lung function variables FEV 1 , PEF and the FEV 1 /FVC ratio, but not FVC or LTL, and that smoking had a minor influence on the genetic and environmental components of the lung function variables, as observed previously (12).…”