Circadian clocks govern calorie restriction-mediated life span extension through BMAL1-and IGF-1-dependent mechanisms
Circadian clocks govern calorie restriction-mediated life span extension through BMAL1-and IGF-1-dependent mechanisms
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DOI：
10.1096/fj.15-282475
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发表时间：
2016-04-01
期刊：
影响因子：
4.8
通讯作者：
Kondratov, Roman V.
中科院分区：
文献类型：
--
作者：
Patel, Sonal A.;Chaudhari, Amol;Kondratov, Roman V.
热量限制（CR）通过未知的机制延长了许多物种的寿命。生物钟被认为是 CR 的潜在中介。生物钟核心成分转录因子 BMAL1（脑和肌肉 ARNT [芳基碳氢化合物受体核转位蛋白] 样蛋白 1）的缺乏会导致加速衰老。在这里，我们研究了 BMAL1 在 CR 机制中的作用。与随意（AL）饮食的小鼠相比，30％CR饮食使野生型（WT）小鼠的寿命延长了20％，但未能延长Bmal1（-/-）小鼠的寿命。 BMAL1 缺乏会损害 CR 介导的血浆 IGF-1 和胰岛素水平的变化。我们在每日测试的几个时间点检测到 WT 小鼠中 CR 与 AL 中的 IGF-1 统计显着降低了 50% 至 70%，而 Bmal1(-/-) 中的降低并不显着。在所有测试时间点，WT 中的胰岛素水平降低了 5% 至 9%，而 Bmal1(-/-) 则诱导胰岛素水平降低了 10% 至 35%。 CR 上调了 Bmal1 的日平均表达量（150%）及其下游靶基因 periods（Per1 上调 470%，Per2 上调 130%）。我们认为 BMAL1 是 CR 的重要介质，BMAL1 的激活可能将 CR 机制与生物钟联系起来。
Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock-transcriptional factor BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1)-results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR. The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on an ad libitum (AL) diet but failed to increase life span of Bmal1(-/-) mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CR vs. AL by 50 to 70% in WT mice at several daily time points tested, while in Bmal1(-/-) the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, while Bmal1(-/-) induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression of Bmal1 (by 150%) and its downstream target genes Periods (by 470% for Per1 and by 130% for Per2). We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.