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首页> 外文期刊>Aging cell. >Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
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Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

机译：亚急性卡路里限制和雷帕霉素不合时宜地改变小鼠肝脏蛋白质组的体内稳态并逆转衰老作用

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SummaryCalorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR. Protein abundance and turnover were measured in vivo using 2H3–leucine heavy isotope labeling followed by LC-MS/MS, and translation was assessed by polysome profiling. We observed 35–60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways, with opposite effects in mitochondrial (mt) dysfunction and eIF2 signaling pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions.
机译：摘要热量限制（CR）和雷帕霉素（RP）延长了模型生物的寿命并改善了其健康状况。两种治疗均能抑制哺乳动物雷帕霉素靶标（mTOR）的信号传导，保守的长寿途径和蛋白质稳态的关键调节剂，但它们对蛋白质组稳态的影响相对未知。为了全面研究衰老，CR和RP对蛋白质稳态的影响，我们进行了第一次同时测量10个月龄（3个月）和年老（25个月）小鼠肝脏中mRNA的翻译，蛋白质更新和丰度的操作。周RP或40％CR。使用 2 H 3 -亮氨酸重同位素标记，然后进行LC-MS / MS，在体内测量蛋白质丰度和周转率，并通过多核糖体谱分析评估翻译。与年龄匹配的对照组相比，我们观察到CR后蛋白质半衰期增加了35–60％，RP后蛋白质半衰期增加了15％。出乎意料的是，RP和CR对蛋白质更新和丰度的影响在典型途径之间差异很大，而在线粒体（mt）功能障碍和eIF2信号传导途径中的作用相反。 CR最紧密地概括了主要途径中的年轻表型。多核糖体图谱表明，CR减少了年轻小鼠和老年小鼠的多核糖体装载量，而RP增加了年轻和老年小鼠的多核糖体装载量，表明蛋白质合成减少的独特机制。 CR和RP均减弱了蛋白质的氧化损伤。我们的发现共同表明，CR和RP可以通过减少蛋白质合成负担和损伤以及随之而来的蛋白质质量提高来延长使用寿命。然而，这些结果挑战了RP是忠实的CR模拟和两种干预措施之间突出机制差异的观点。

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