Reorganization of pancreas circadian transcriptome with aging

The evolutionarily conserved circadian system allows organisms to synchronize internal processes with 24-h cycling environmental timing cues, ensuring optimal adaptation. Like other organs, the pancreas function is under circadian control. Recent evidence suggests that aging by itself is associated with altered circadian homeostasis in different tissues which could affect the organ's resiliency to aging-related pathologies. Pancreas pathologies of either endocrine or exocrine components are age-related. Whether pancreas circadian transcriptome output is affected by age is still unknown. To address this, here we profiled the impact of age on the pancreatic transcriptome over a full circadian cycle and elucidated a circadian transcriptome reorganization of pancreas by aging. Our study highlights gain of rhythms in the extrinsic cellular pathways in the aged pancreas and extends a potential role to fibroblast-associated mechanisms. Here we carried out a 24-h circadian transcriptomic analysis of pancreas from male mice at young and old ages. We define a comprehensive circadian transcriptome landscape and identify biological pathways that are reflective of aging pancreas. Additionally, analysis of pancreatic microenvironment revealed novel mechanistic insights into the fibroblast mediated regulation of rhythmicity in aged pancreas. We suggest that circadian transcriptome in aging pancreas re-organizes in response to age-specific signals from the cellular microenvironment, primarily modulated by fibroblasts.进化保守的生物钟系统（circadian system）可使生物体将自身内部生理过程与24小时周期的环境时间信号同步，从而实现最佳适应性。与其他器官类似，胰腺功能亦受生物钟调控。现有研究证据表明，衰老本身会引发不同组织的生物钟稳态失衡，进而影响器官对衰老相关病理的耐受能力。胰腺内分泌与外分泌组分的病变均与衰老相关。目前尚不清楚胰腺的生物钟转录组（transcriptome）输出是否会受衰老影响。为解答这一问题，本研究通过对年轻与老年雄性小鼠的胰腺开展24小时生物钟周期转录组分析，表征了衰老对胰腺转录组的影响，并阐明了衰老诱导的胰腺生物钟转录组重编程过程。本研究发现，衰老胰腺的外在细胞通路出现节律增益现象，并提出了成纤维细胞（fibroblast）相关调控机制的潜在作用。我们构建了全面的胰腺生物钟转录组图谱，并鉴定出可反映胰腺衰老状态的生物学通路。此外，对胰腺微环境的分析揭示了成纤维细胞介导衰老胰腺节律调控的全新机制。我们提出，衰老胰腺的生物钟转录组会响应细胞微环境传递的衰老特异性信号发生重编程，且该过程主要由成纤维细胞介导。