Telomerase Knockout in Myeloid Cells Predisposes Mice to Foam Cell Formation, Dyslipidemia, Lung Fibrosis, and...

Aging-associated changes in myeloid cells are incompletely understood. One of the culprits of aging is the downregulation of the Tert gene coding for the catalytic subunit of telomerase. Studies of mouse models with Tert knockout (KO) in specific cells have revealed the importance of the telomere-independent noncanonical function of TERT in supporting mitochondrial metabolism and protection from cell senescence. To investigate the role of TERT in myeloid cells (MCs), we analyzed mice with Tert KO in the LysM+ lineage, indelibly labeled with membrane green fluorescent protein (mG). Macrophage numbers and properties in various organs were compared. Changes in the vasculature, adipose tissue (AT) depots, lungs, heart, and other tissues were assessed. MC-Tert-KO mice displayed MC depletion in the bone marrow and abnormal frequencies in other organs. Tert-KO MCs were found to express senescence markers despite having a normal telomere length. Tert-KO macrophages were found to be polarized toward the pro-inflammatory M1 phenotype, upregulate expression of genes promoting lipid uptake and retention, and be prone to conversion into foam cells. MC-Tert-KO mice fed a high-calorie diet had increased adiposity and dysfunctional glucose metabolism. On an atherogenic diet, MC-Tert-KO mice displayed abnormal lipid metabolism and chronic fever. Aged MC-Tert-KO mice developed pulmonary fibrosis and an imbalance in right/left ventricle cardiac output. Our results show that the increased conversion of Tert-KO MCs into foam cells leads to systemic organ dysfunction. We conclude that TERT plays an important noncanonical function in MCs that prevents the development of aging-associated diseases.