Yang Guangrui, Chen Lihong, Grant Gregory R, Paschos Georgios, Song Wen-Liang, Musiek Erik S, Lee Vivian, McLoughlin Sarah C, Grosser Tilo, Cotsarelis George, FitzGerald Garret A
The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Transl Med. 2016 Feb 3;8(324):324ra16. doi: 10.1126/scitranslmed.aad3305.
The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy, which are altered in standard Bmal1 knockout mice, remained unaltered, whereas atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, whereas overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt reevaluation of the systemic consequences of disruption of the molecular clock.
核心生物钟基因Bmal1的缺失会导致小鼠昼夜节律丧失、衰老加速以及寿命缩短。为了探究昼夜节律在衰老过程中的重要性，我们构建了条件性Bmal1基因敲除小鼠，这些小鼠在成年期缺乏BMAL1蛋白，结果发现其转轮活动、心率和血压的野生型昼夜变化消失。眼部异常和脑星形胶质细胞增生不受Bmal1基因敲除时间的影响。然而，标准Bmal1基因敲除小鼠中发生改变的寿命、生育能力、体重、血糖水平和年龄相关性关节病，在条件性成年期Bmal1基因敲除小鼠中并未改变，尽管其生物钟功能丧失，但动脉粥样硬化和毛发生长却得到改善。肝脏RNA测序显示，成年期Bmal1基因敲除小鼠中振荡基因的表达受到抑制，而整体基因表达基本未变。因此，传统Bmal1基因敲除小鼠中许多迄今归因于昼夜节律紊乱的表型，反映了BMAL1独立于其在生物钟中的作用的特性丧失。这些发现促使人们重新评估分子生物钟紊乱的全身影响。
