Treatment with the mechanistic target of rapamycin (mTOR) inhibitor, rapamycin (RAP), alone and in combination with the antidiabetic drug, metformin (RAP+MET), extends lifespan in mice. The mechanisms underlying lifespan extension are unclear. One possibility is improved capacity for proteostatic maintenance. We have previously characterized peripheral protein synthesis rates following treatment with RAP. However, it is unknown if RAP+MET elicits similar changes, or if either treatment affects protein synthesis in the brain. We hypothesized that 8 weeks of treatment with RAP and RAP+MET would alter brain protein synthesis rates to reflect proteostatic processes. Using the stable isotopic tracer, deuterium oxide (D2O), we demonstrate in UM-HET3 mice that protein synthesis rates measured in whole brain were unaffected by treatment in young male mice, whereas RAP+MET decreased mitochondrial protein synthesis in young females. Conversely, RAP increased mitochondrial protein synthesis rates in older females. Activity through the AMPK/mTOR pathway was affected in a sex-specific manner in young mice, and minimal changes were observed in the older cohort. Thus, we establish D2O for measurements of biogenesis in the brain. These results provide initial insights into the effects of RAP and RAP+MET on brain protein synthesis. Additionally, these data emphasize that responses to slowed aging treatments vary with sex and age.

中文翻译：

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雷帕霉素或雷帕霉素二甲双胍治疗后UM-HET3小鼠的脑蛋白合成速率。

单独使用雷帕霉素（mTOR）抑制剂，雷帕霉素（RAP）的机械靶进行治疗，并与抗糖尿病药物二甲双胍（RAP + MET）结合使用，可延长小鼠的寿命。寿命延长的机制尚不清楚。一种可能性是提高蛋白水解性维护的能力。我们先前已经表征了用RAP治疗后的外周蛋白合成速率。但是，尚不清楚RA​​P + MET是否引起类似的变化，或者两种治疗方法均会影响大脑中的蛋白质合成。我们假设用RAP和RAP + MET治疗8周会改变脑蛋白的合成速率，以反映蛋白的稳定过程。使用稳定的同位素示踪剂氘化氢（D2O），我们在UM-HET3小鼠中证明了在幼年雄性小鼠中，全脑测量的蛋白质合成率不受治疗的影响，而RAP + MET会降低年轻女性的线粒体蛋白质合成。相反，RAP增加了老年女性的线粒体蛋白质合成率。在幼年小鼠中，通过AMPK / mTOR途径进行的活动以性别特异性方式受到影响，而在较老的组群中观察到的变化很小。因此，我们建立了D2O，用于测量大脑中的生物发生。这些结果为RAP和RAP + MET对脑蛋白合成的影响提供了初步见识。此外，这些数据强调，对延缓衰老治疗的反应会随性别和年龄而变化。在较老的队列中观察到的变化很小。因此，我们建立了D2O，用于测量大脑中的生物发生。这些结果为RAP和RAP + MET对脑蛋白合成的影响提供了初步见识。此外，这些数据强调，对延缓衰老治疗的反应会随性别和年龄而变化。在较老的队列中观察到的变化很小。因此，我们建立了D2O，用于测量大脑中的生物发生。这些结果为RAP和RAP + MET对脑蛋白合成的影响提供了初步见识。此外，这些数据强调，对延缓衰老治疗的反应会随性别和年龄而变化。