biostudies-literatureLipskaia LInstitut National Du Cancer (INCa)Institut National de la Santé et de la Recherche Médicale (Inserm)Ligue Contre le Cancer (French League Against Cancer)Ministerio de Ciencia e Innovación (MCIN)Canceropôle PACA (Canceropole PACA)PHENOMIN (French National Infrastructure for Mouse Phenogenomics)Fondation ARC pour la Recherche sur le Cancer (ARC)Comunidad de Madrid (Community of Madrid)1650-1684https://www.ebi.ac.uk/biostudies/studies/S-EPMC10933469biostudies-literatureUnknown25(3)Lung diseases develop when telomeres shorten beyond a critical point. We constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTert^CI), is expressed from the p21^Cdkn1a locus. Expression of either TERT or TERT^CI reduces global p21 levels in the lungs of aged mice, highlighting TERT non-canonical function. However, only TERT reduces accumulation of very short telomeres, oxidative damage, endothelial cell (ECs) senescence and senile emphysema in aged mice. Single-cell analysis of the lung reveals that p21 (and hence TERT) is expressed mainly in the capillary ECs. We report that a fraction of capillary ECs marked by CD34 and endowed with proliferative capacity declines drastically with age, and this is counteracted by TERT but not TERT^CI. Consistently, only TERT counteracts decline of capillary density. Natural aging effects are confirmed using the experimental model of emphysema induced by VEGFR2 inhibition and chronic hypoxia. We conclude that catalytically active TERT prevents exhaustion of the putative CD34 + EC progenitors with age, thus protecting against capillary vessel loss and pulmonary emphysema.EMBO reportsmTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema.PMC10933469Projet ARCEquipe LabelliséeProjet EmergentComité Paris RS21/75-24AGEMEDPID2019-110339RB-I00S2017/BMD-3875PLBIO2019ANR10-INBS-07Cayrou CJosselin ELondono-Vallejo ACurras-Alonso SLachaud CFlores IChurikov DBreau MLipskaia LFiore FGiovinazzo GGilson EAdnot SSanchez-Ferrer CGeli VBraud LFouillade CJourquin FCastellano RJacquet JBorn EBauwens SfalsemTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema.Lung diseases develop when telomeres shorten beyond a critical point. We constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTert^CI), is expressed from the p21^Cdkn1a locus. Expression of either TERT or TERT^CI reduces global p21 levels in the lungs of aged mice, highlighting TERT non-canonical function. However, only TERT reduces accumulation of very short telomeres, oxidative damage, endothelial cell (ECs) senescence and senile emphysema in aged mice. Single-cell analysis of the lung reveals that p21 (and hence TERT) is expressed mainly in the capillary ECs. We report that a fraction of capillary ECs marked by CD34 and endowed with proliferative capacity declines drastically with age, and this is counteracted by TERT but not TERT^CI. Consistently, only TERT counteracts decline of capillary density. Natural aging effects are confirmed using the experimental model of emphysema induced by VEGFR2 inhibition and chronic hypoxia. We conclude that catalytically active TERT prevents exhaustion of the putative CD34 + EC progenitors with age, thus protecting against capillary vessel loss and pulmonary emphysema.2024-01-01T00:00:00Z2024 Mar2025-04-04T12:58:39.548Z2025-04-04T12:58:39.548ZS-EPMC109334693842423010.1038/s44319-023-00041-1