Aging affects circadian clock and metabolism and modulates timing of medication

Abstract

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.