Defining the age-dependent and tissue-specific circadian transcriptome in male mice

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis. Emerging evidence supports age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profiled the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in 3 age groups. We found age-dependent and tissue-specific clock output changes. Aging reduced the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. Many genes gained rhythmicity in old tissues, reflecting an adaptive response. REGs were enriched for the hallmarks of aging, adding a new dimension to understanding aging. Differential gene expression analysis found that there were temporally distinct clusters of genes in tissue-specific manner. This novel analysis extends the landscape of the understanding of aging. Increased daily gene expression variability is a common feature of aged tissues. Our data highlight the impact of aging on circadian function and temporal changes in gene expression. Hypothalamus, lung, kidney, skeletal muscle, heart, and adrenal gland tissues from Young (6mo), Aged (18mo), and Old (27mo) male mice were collected every 4h for 48h to characterize the circadian transcriptome changes with age. Two samples per age were collected and pooled for RNAseq analysis.

细胞昼夜节律时钟（cellular circadian clock）调控着维持机体稳态的每日转录程序。日益增多的研究证据表明，昼夜节律功能会随年龄增长发生改变。为在系统层面明确年龄依赖的节律变化，我们对三个年龄组小鼠的下丘脑、肺、心脏、肾脏、骨骼肌与肾上腺的昼夜节律转录组开展了表征分析。研究发现了年龄依赖且具有组织特异性的生物钟输出节律变化。衰老会使节律表达基因（rhythmically expressed genes, REGs）的数量显著减少，提示昼夜节律调控能力出现衰退。老年组织中诸多基因新获得了节律性表达特征，这反映了机体的适应性应答反应。节律表达基因显著富集于衰老标志物相关通路，为衰老研究拓展了全新维度。差异基因表达分析显示，不同组织中存在具有时间特异性的基因表达簇。这项创新性分析进一步拓展了我们对衰老机制的认知边界。每日基因表达变异程度升高是衰老组织的共性特征。本研究数据凸显了衰老对昼夜节律功能以及基因表达时序变化的影响。我们每隔4小时采集年轻（6月龄）、老龄（18月龄）与老年（27月龄）雄性小鼠的下丘脑、肺、肾脏、骨骼肌、心脏及肾上腺组织，持续采集48小时，以表征随年龄变化的昼夜节律转录组特征。每个年龄组采集两份样本并混合，用于RNAseq分析。