The mechanistic target of rapamycin complex 1 (mTORC1) has a major impact on aging by regulation of proteostasis. It is well established that mTORC1 signaling is hyperactivated with aging and age-related diseases. Previous studies have shown that partial inhibition of mTOR signaling by rapamycin reverses age-related deteriorations in cardiac function and structure in old mice. However, the downstream signaling pathways involved in this protection against cardiac aging have not been established. mTORC1 phosphorylates 4E-binding protein 1 (4EBP1) to promote the initiation of cap-dependent translation. The objective of this project is to examine the role of the mTORC1/4EBP1 axis in age-related cardiac dysfunction. We used a whole-body 4EBP1 KO mouse model, which mimics a hyperactive mTORC1/4EBP1/eIF4E axis, to investigate the effects of hyperactive mTORC1/4EBP1 axis in cardiac aging. Echocardiographic measurements of middle-aged 4EBP1 KO mice show impaired diastolic function and myocardial performance compared to age-matched WT mice and these parameters are at similar levels as old WT mice, suggesting that 4EBP1 KO mice experience accelerated cardiac aging. Old 4EBP1 KO mice show further decline in systolic and diastolic function compared to middle-aged counterparts and have worse systolic and diastolic function than age-matched WT mice. Gene expression levels of heart failure markers are not different between 4EBP1 KO and WT hearts. However, ribosomal biogenesis and protein ubiquitination are significantly increased in 4EBP1 KO hearts when compared to WT controls, suggesting dysregulated proteostasis in 4EBP1 KO hearts. Together, these results show that a hyperactive mTORC1/4EBP1 axis accelerates cardiac aging, potentially by dysregulating proteostasis.

雷帕霉素复合物 1 （mTORC1） 的机制靶标通过调节蛋白质稳态对衰老产生重大影响。众所周知，mTORC1 信号转导会随着衰老和年龄相关疾病而过度激活。先前的研究表明，雷帕霉素对 mTOR 信号传导的部分抑制可逆转老年小鼠心脏功能和结构与年龄相关的恶化。然而，参与这种防止心脏衰老的下游信号通路尚未确定。mTORC1 磷酸化 4E 结合蛋白 1 （4EBP1） 以促进帽依赖性翻译的启动。该项目的目的是检查 mTORC1/4EBP1 轴在年龄相关心功能障碍中的作用。我们使用模拟过度活跃的 mTORC1/4EBP1/eIF4E 轴的全身 4EBP1 KO 小鼠模型来研究过度活跃的 mTORC1/4EBP1 轴对心脏衰老的影响。中年 4EBP1 KO 小鼠的超声心动图测量显示，与年龄匹配的 WT 小鼠相比，舒张功能和心肌性能受损，并且这些参数与老年 WT 小鼠处于相似水平，表明 4EBP1 KO 小鼠经历加速心脏衰老。与中年小鼠相比，老年 4EBP1 KO 小鼠的收缩和舒张功能进一步下降，并且收缩和舒张功能比年龄匹配的 WT 小鼠差。4EBP1 KO 和 WT 心脏之间心力衰竭标志物的基因表达水平没有差异。然而，与 WT 对照相比，4EBP1 KO 心脏中的核糖体生物发生和蛋白质泛素化显着增加，表明 4EBP1 KO 心脏中的蛋白质稳态失调。总之，这些结果表明，过度活跃的 mTORC1/4EBP1 轴可能通过蛋白质稳态失调来加速心脏衰老。