Abstract 353: Nucleolar Enlargement and Perturbed Ribosome Biogenesis Are Cellular Hallmarks of Cardiac Aging

Abstract

Introduction: Cardiac Aging manifests as structural and functional impairment of the heart and is associated with several changes in the cellular architecture. Of the many alterations in organelle structure and function that occur during aging, changes in the nucleolus and ribosome remain least studied in the cardiac context. The nucleolus functions as a stress sensor and is critical for ribosome biogenesis. Hypothesis: This study hypothesizes that perturbations in nucleolar architecture and ribosome biogenesis result in accumulation of free ribosomal proteins that stabilize p53 and trigger cardiac aging. Methods and Results: Using animal models of chronological (CA) and biological aging (BA), we observed that nucleolar size is dramatically increased in senescent myocardial cells (1.75 fold) as well as in aged hypertrophied hearts. Nucleolar enlargement is accompanied by significant increase in pre-ribosomal RNA levels (2 fold, p<0.01 in CA hearts; 9 fold in BA hearts) indicating increased ribosome biogenesis. Synthesis of ribosomal proteins (RP) in equimolar amounts to ribosomal RNA that occurs under normal conditions is disrupted in the aged heart, resulting in increased expression of RPL11 (50% in BA heart, 33% in CA heart) that is a component of the 60S large ribosomal subunit. Accumulation of RPL11 coincides with increased p53 expression (2 fold, p<0.05 in BA heart; 5.4 fold in CA heart) suggesting a role for RPL11 in mediating p53 stability in the aged heart. Conclusion: Collectively our data demonstrate nucleolar enlargement as a cellular hallmark of cardiac aging and uncover a molecular mechanism involving perturbed ribosome biogenesis and accumulation of free RPs that contribute to age-associated afflictions in the heart.