Sadria Mehrshad, Layton Anita T
Department of Applied Mathematics, University of Waterloo, Waterloo, ON, Canada.
Department of Biology, Cheriton School of Computer Science, and School of Pharmacy, University of Waterloo, Waterloo, ON, Canada.
iScience. 2021 Mar 1;24(4):102245. doi: 10.1016/j.isci.2021.102245. eCollection 2021 Apr 23.
Aging is associated with impairments in the circadian rhythms, and with energy deregulation that affects multiple metabolic pathways. The goal of this study is to unravel the complex interactions among aging, metabolism, and the circadian clock. We seek to identify key factors that inform the liver circadian clock of cellular energy status and to reveal the mechanisms by which variations in food intake may disrupt the clock. To address these questions, we develop a comprehensive mathematical model that represents the circadian pathway in the mouse liver, together with the insulin/IGF-1 pathway, mTORC1, AMPK, NAD+, and the NAD+ -consuming factor SIRT1. The model is age-specific and can simulate the liver of a young mouse or an aged mouse. Simulation results suggest that the reduced NAD+ and SIRT1 bioavailability may explain the shortened circadian period in aged rodents. Importantly, the model identifies the dosing schedules for maximizing the efficacy of anti-aging medications.
衰老与昼夜节律受损以及影响多种代谢途径的能量调节异常有关。本研究的目的是揭示衰老、代谢和生物钟之间的复杂相互作用。我们试图确定能够向肝脏生物钟告知细胞能量状态的关键因素，并揭示食物摄入量变化可能扰乱生物钟的机制。为了解决这些问题，我们开发了一个综合数学模型，该模型代表了小鼠肝脏中的昼夜节律途径，以及胰岛素/IGF-1途径、mTORC1、AMPK、NAD+和消耗NAD+的因子SIRT1。该模型是针对特定年龄的，能够模拟年轻小鼠或老年小鼠的肝脏。模拟结果表明，NAD+和SIRT1生物利用度的降低可能解释了老年啮齿动物昼夜节律周期的缩短。重要的是，该模型确定了使抗衰老药物疗效最大化的给药方案。
