Loss of protein homeostasis is a hallmark of the aging process. We and others have previously shown that maintenance of proteostasis is a shared characteristic of slowed-aging models. Rapamycin (Rap) exerts sex-specific effects on murine lifespan, but the combination of Rap with the anti-hyperglycemic drug metformin (Rap + Met) equally increases male and female mouse median lifespan. In the current investigation, we compare the effects of short-term (8 weeks) Rap and Rap + Met treatments on bulk and individual protein synthesis in two key metabolic organs (the liver and skeletal muscle) of young genetically heterogeneous mice using deuterium oxide. We report for the first time distinct effects of Rap and Rap + Met treatments on bulk and individual protein synthesis in young mice. Although there were decreases in protein synthesis as assessed by bulk measurements, individual protein synthesis analyses demonstrate there were nearly as many proteins that increased synthesis as decreased synthesis rates. While we observed the established sex- and tissue-specific effects of Rap on protein synthesis, adding Met yielded more uniform effects between tissue and sex. These data offer mechanistic insight as to how Rap + Met may extend lifespan in both sexes while Rap does not.

蛋白质稳态的丧失是衰老过程的标志。我们和其他人之前已经表明，维持蛋白质稳态是延缓衰老模型的共同特征。雷帕霉素 (Rap) 对小鼠寿命具有性别特异性影响，但 Rap 与抗高血糖药物二甲双胍 (Rap + Met) 的组合同样可以延长雄性和雌性小鼠的中位寿命。在当前的研究中，我们使用氧化氘比较了短期（8周）Rap和Rap + Met治疗对年轻遗传异质小鼠的两个关键代谢器官（肝脏和骨骼肌）中整体和个体蛋白质合成的影响。我们首次报告了 Rap 和 Rap + Met 治疗对年轻小鼠整体和个体蛋白质合成的明显影响。尽管通过批量测量评估蛋白质合成有所减少，但单个蛋白质合成分析表明，增加合成的蛋白质几乎与合成速率下降的蛋白质一样多。虽然我们观察到 Rap 对蛋白质合成的性别和组织特异性影响，但添加 Met 在组织和性别之间产生了更一致的影响。这些数据提供了关于 Rap + Met 如何延长两性寿命而 Rap 却不能的机制见解。