Induction of Telomerase in P21-Positive Cells Counteracts Capillaries Rarefaction and Preserves Lung Function of Aging Mice

IntroductionVariations in telomere state are critical for cellular senescence and the development of lung diseases that increase in frequency with age, particularly pulmonary emphysema and pulmonary fibrosis.MethodWe have generated a mouse model in which telomerase (mTert), or its catalytically inactive form (mTertCI), is expressed from the p21Cdkn1a promoter.ResultsWe found that this particular expression of Tert curbs age-related emphysema and pulmonary perivascular fibrosis in aged mice and reduces age-dependent accumulation of senescent cells, many of which are endothelial cells (EC). We further show that Tert counteracts age-related decline in capillary density and promotes maintenance of high numbers of Cd34+ cells identified as a subclass of EC with proliferative capacity. In addition, young p21+/mTert mice exposed to hypoxia and treated with the VEGF receptor inhibitor SUGEN were protected against loss of capillary density and the development of pulmonary emphysema. Importantly, expression of mTertCI did not prevent EC senescence, decreased capillary density, and development of emphysema, although mTert and mTertCI significantly reduced p21 levels in old mouse lungs.ConclusionCollectively, these results show that mTert reduces age-related lung function decline by promoting regeneration of the microvasculature and by preventing replicative senescence of EC.