Abstract
INTRODUCTION: Aging affects both metabolic and circadian systems, leading to disruptions in energy homeostasis and phase shifts in the circadian clock. Metformin, a widely used antihyperglycemic drug, exerts anti-aging effects by modulating key pathways in the liver and also influences the liver circadian clock. However, the optimal medication strategy, including dosage and timing, that achieves significant anti-aging effects while minimizing negative impacts on the circadian clock remains unclear. This study aims to identify a rational metformin administration strategy considering both aspects. METHODS: An extended mathematical model of the liver circadian clock incorporating metformin regulation was developed, and numerical simulations were performed to evaluate different dosing times and feeding conditions. RESULTS: Metformin administration at different times produced distinct effects on both the circadian clock and anti-aging outcomes. Administration during the increasing phase of CLOCK-BMAL1 concentration showed positive effects on the circadian clock and effective anti-aging properties. Regarding feeding patterns, a fed-like state was not conducive to anti-aging, whereas fasting was beneficial. CONCLUSIONS: These findings highlight the importance of dosing time and feeding styles in optimizing metformin efficacy and provide insights into its potential pharmacological applications in anti-aging therapy.