Telomere dysfunction and senescence in the ageing lung and age-related lung disease

Abstract

Cellular senescence, the irreversible loss of replicati ve capacity of somatic cells, bas been associated w ith diseases of accelerated lung ageing, including Chroni c Obstructive Pulmonaty Disease (COPD). However, the mechanisms und erl ying senescence of a irway epithelial cell s, parti cula rl y the role of telomere dysfunction in this process, are poorly understood . The aim of this work was to investigate senescence and telomere dysfunction in airway epithelial cells from pati ents with COPD and bronchiectasis, in the ageing murine lung and in the context of cigarette smoke exposure. DNA dam age foci (yH2A.X) and foci associated with telomeres (telomere-associated foci (TA F)), a long with other senescence-associated m arkers, were increased in small airway epith elial cells from patients with COPD, wi thout significant telomere shottening. With age, TAF increased in large and sm all aitway epithelial cells of the murine lung and predicted age-dependent lung emphysema, independen tly oftelomere length . M oreover, fomth generation telomerase-null mi ce showed early-onset emphysema. Exposure to cigarette smoke was found to increase TAF in large and small ai1way epithelial cells of the murine lung and in epith elial cells and fibrobla sts in vitro. Cigarette smoke m ay accelerate telomere dysfunction via reactive oxygen species (ROS) and contribute to Ataxia telangiectasia mutated (ATM)-dependent secretion of pro-inflammatory cytokines interleukin (lL)-6 and IL-8. Inhibition of mechan istic target of rapa myc in complex I (mTORC I ) by rapa mycin alleviated age-assoc iated increases i n TAF in vivo and supressed cigarette smoke-i nduced increases in TAF and in flammatory cytokine release in vitro. Cigarette smoke increases mitochondrial-derived ROS, which is supressed by culturing cell s at low oxygen pressure and by treating cell s w ith rapam ycin. These results suggest that activation of a DN A damage response at telomeres may be induced by oxidative stress from altered mTOR signalling ancl/or dysfu nctional mitochondri a. Telomere dys function could conttibut e to inflamm atory processes and the functional decline that occurs in the ageing lung and in the context of cigarette smoke­ induced accelerated lung ageing.