Abstract 18815: Genetic Deletion of Telomerase Promotes Premature Cardiac Aging

Abstract

Telomere length shortens with age and predicts the onset of cellular senescence and organ aging with progressive deterioration of function. It remains, however, to be documented whether loss of telomeric DNA in cardiac stem cells (CSCs) and myocytes is causally involved in the manifestations of the aging cardiomyopathy. To test this possibility, the third generation of mice carrying a deletion of the RNA component of telomerase (Terc -/- mice) was studied early in life at 3-12 months of age. Wild type (WT) senescent mice at 30 months of age were included in the analysis to establish whether accelerated aging in Terc -/- mice recapitulates physiological aging. Initial studies indicated that Terc -/- mice, at 4 months of age, displayed attenuated left ventricular (LV) function with respect to age-matched WT by echocardiography and hemodynamics. In contrast, severe alterations in cardiac performance were apparent at 12 months. Telomere length in Terc -/- mouse CSCs and myocytes was ~50-70% shorter than in age-matched WT cells at 4-6 months of age but was comparable to that found in 30 month-old WT cells. CSC number was 60% lower in Terc -/- than age-matched WT mice, and the fraction of BrdU-positive CSCs decreased 1.4-fold. The absence of Terc led to a 50% reduction in myocyte turnover, which was coupled with myocyte loss. BrdU and Ki67 labeling were decreased, respectively, 65% and 60% in Terc -/- myocytes. Old CSCs formed a senescent progeny composed of myocytes, which carried markedly shortened telomeres, were more prone to apoptosis, and showed a severe depression in cell shortening and re-lengthening. By mRNA screening performed in Terc -/- myocytes at 12 months, multiple apoptosis-related genes, including protein kinase A (PKA), PI3KR1, Caspase 1, and BAG3 were found to be modified. Moreover, the renewal of endothelial cells was 75% lower in Terc -/- mice mimicking the rarefaction in capillary typically seen in the old myocardium. Our findings document that loss of telomerase is a critical determinant of cardiac aging with reduced cardiomyogenesis and vasculogenesis. Understanding basic mechanisms of telomere biology in CSCs and cardiomyocytes holds the potential to advance the clinical paradigm of the senescent myopathy.