Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways.
Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways.
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膳食补充雷帕霉素可逆转与年龄相关的血管功能障碍和氧化应激，同时调节营养感应、细胞周期和衰老途径。
DOI：
10.1111/acel.12524
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发表时间：
2017-02
期刊：
影响因子：
7.8
通讯作者：
Donato AJ
中科院分区：
文献类型：
--
作者：
Lesniewski LA;Seals DR;Walker AE;Henson GD;Blimline MW;Trott DW;Bosshardt GC;LaRocca TJ;Lawson BR;Zigler MC;Donato AJ
抑制哺乳动物雷帕霉素靶标 mTOR 可延长寿命并减少与年龄相关的疾病。目前尚不清楚 mTOR 在动脉老化表型中发挥什么作用，也不知道饮食雷帕霉素抑制 mTOR 是否可以改善与年龄相关的动脉功能障碍。为了探索这一点，年轻（3.8 ± 0.6 个月）和年老（30.3 ± 0.2 个月）雄性 B6D2F1 小鼠被喂食雷帕霉素补充剂或对照饮食 6-8 周。尽管雷帕霉素治疗后动物特征几乎没有其他显着变化，但我们发现补充雷帕霉素后，老年小鼠的葡萄糖耐量有所改善，但年轻小鼠的葡萄糖耐量受损（均 P < 0.05）。衰老增加了动脉中 mTOR 的激活，表现为 S6K 磷酸化升高 (P < 0.01)，而在老年小鼠中进行雷帕霉素治疗后，这种情况出现逆转 (P < 0.05)。衰老还与颈动脉内皮依赖性扩张 (EDD) 受损有关 (P < 0.05)。雷帕霉素改善了老年小鼠的 EDD（P < 0.05）。与年轻小鼠相比，老年小鼠动脉中的超氧化物产生和 NADPH 氧化酶表达更高 (P < 0.05)，雷帕霉素使这些水平正常化 (P < 0.05)，与年轻小鼠没有差异。清除超氧化物可以改善未经治疗的老年小鼠的颈动脉 EDD（P < 0.05），但不能改善雷帕霉素治疗的老年小鼠。虽然衰老导致大动脉僵硬度增加，表现为主动脉脉搏波速度 (PWV) 增加 (P < 0.01)，但雷帕霉素治疗降低了老年小鼠的主动脉 PWV (P < 0.05) 和胶原蛋白含量 (P < 0.05)。雷帕霉素治疗老年小鼠后，主动脉单磷酸腺苷激活蛋白激酶 (AMPK) 磷酸化以及细胞周期相关蛋白 PTEN 和 p27kip 的表达增加（所有 P < 0.05）。最后，衰老导致动脉衰老标志物 p19 增加（P < 0.05），雷帕霉素治疗可以改善这种情况（P < 0.05）。这些结果证明了雷帕霉素治疗对老年小鼠动脉功能的有益影响，并表明这些改善与氧化应激减少、AMPK 激活和参与细胞周期控制的蛋白质表达增加有关。
Inhibition of mammalian target of rapamycin, mTOR, extends lifespan and reduces age‐related disease. It is not known what role mTOR plays in the arterial aging phenotype or if mTOR inhibition by dietary rapamycin ameliorates age‐related arterial dysfunction. To explore this, young (3.8 ± 0.6 months) and old (30.3 ± 0.2 months) male B6D2F1 mice were fed a rapamycin supplemented or control diet for 6–8 weeks. Although there were few other notable changes in animal characteristics after rapamycin treatment, we found that glucose tolerance improved in old mice, but was impaired in young mice, after rapamycin supplementation (both P < 0.05). Aging increased mTOR activation in arteries evidenced by elevated S6K phosphorylation (P < 0.01), and this was reversed after rapamycin treatment in old mice (P < 0.05). Aging was also associated with impaired endothelium‐dependent dilation (EDD) in the carotid artery (P < 0.05). Rapamycin improved EDD in old mice (P < 0.05). Superoxide production and NADPH oxidase expression were higher in arteries from old compared to young mice (P < 0.05), and rapamycin normalized these (P < 0.05) to levels not different from young mice. Scavenging superoxide improved carotid artery EDD in untreated (P < 0.05), but not rapamycin‐treated, old mice. While aging increased large artery stiffness evidenced by increased aortic pulse‐wave velocity (PWV) (P < 0.01), rapamycin treatment reduced aortic PWV (P < 0.05) and collagen content (P < 0.05) in old mice. Aortic adenosine monophosphate‐activated protein kinase (AMPK) phosphorylation and expression of the cell cycle‐related proteins PTEN and p27kip were increased with rapamycin treatment in old mice (all P < 0.05). Lastly, aging resulted in augmentation of the arterial senescence marker, p19 (P < 0.05), and this was ameliorated by rapamycin treatment (P < 0.05). These results demonstrate beneficial effects of rapamycin treatment on arterial function in old mice and suggest these improvements are associated with reduced oxidative stress, AMPK activation and increased expression of proteins involved in the control of the cell cycle.