Programmed cell death 5 (PDCD5) is a tumor suppressor gene that regulates the cell cycle, apoptosis and immune responses. However, the physiological function of Pdcd5 in cardiac aging remains unknown. We find that Pdcd5 mRNA and protein levels were significantly increased in the heart of mice with age. Therefore, we hypothesize that Pdcd5 regulates cardiac aging. To test the hypothesis, we generated muscle-specific Pdcd5-deficient mice. Mature adult Pdcd5-deficient mice had normal cardiac morphology and function. In naturally aged mice, Pdcd5 deficiency alleviated age-related cardiac phenotypes including reduced fibrosis and suppressed cardiomyocyte hypertrophy. Moreover, muscle-specific Pdcd5 deficiency attenuated cellular senescence in the heart as demonstrated by decreased number of senescence-associated β-galactosidase-positive cells, diminished p53, p21 and p16 expression, and reduced the senescence-associated secretory phenotype. Apoptotic cell death was reduced by Pdcd5 deficiency in the heart as revealed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay, which was coincident with diminished Bcl-2-associated X protein, and enhanced B-cell lymphoma 2 and X-linked inhibitor of apoptosis protein expression. Mitochondrial quality in cardiomyocytes was improved by Pdcd5 deficiency through increased Parkin-mediated mitophagy. In addition, Pdcd5 deficiency alleviated doxorubicin-induced premature cellular senescence and cardiac aging. Furthermore, Pdcd5 protein abundance was significantly correlated with p53 protein abundance, and Pdcd5 interacted with p53 in the heart. Taken together, our results reveal that Pdcd5 deficiency attenuates cardiac aging by reducing cellular senescence and apoptosis, and increasing Parkin-mediated mitophagy, likely through p53. Pdcd5 is a novel regulator of cardiac aging and a potential therapeutic target.

程序性细胞死亡 5 (PDCD5) 是一种肿瘤抑制基因，可调节细胞周期、细胞凋亡和免疫反应。然而，Pdcd5 在心脏衰老中的生理功能仍然未知。我们发现随着年龄的增长，小鼠心脏中的Pdcd5 mRNA 和蛋白质水平显着增加。因此，我们假设 Pdcd5 调节心脏衰老。为了检验该假设，我们生成了肌肉特异性Pdcd5 缺陷小鼠。成熟的成年Pdcd5 缺陷小鼠具有正常的心脏形态和功能。在自然衰老的小鼠中，Pdcd5缺乏会减轻与年龄相关的心脏表型，包括减少纤维化和抑制心肌细胞肥大。此外，肌肉特异性Pdcd5衰老相关的 β-半乳糖苷酶阳性细胞数量减少，p53、p21 和 p16 表达减少，以及衰老相关分泌表型减少。末端脱氧核苷酸转移酶 dUTP 缺口末端标记测定表明，心脏中Pdcd5缺乏可减少凋亡细胞死亡，这与 Bcl-2 相关 X 蛋白减少、B 细胞淋巴瘤 2 和 X 连锁凋亡抑制剂增强一致蛋白质表达。Pdcd5缺乏通过增加Parkin介导的线粒体自噬改善了心肌细胞的线粒体质量。此外，Pdcd5缺乏减轻了多柔比星诱导的细胞过早衰老和心脏衰老。此外，Pdcd5 蛋白丰度与 p53 蛋白丰度显着相关，并且 Pdcd5 与心脏中的 p53 相互作用。总之，我们的研究结果表明，Pdcd5缺乏通过减少细胞衰老和凋亡以及增加 Parkin 介导的线粒体自噬（可能通过 p53）来减轻心脏衰老。Pdcd5 是一种新的心脏衰老调节剂和潜在的治疗靶点。