Metformin Regulation of the Liver Circadian Clock and Metabolic Aging: A Systems Modeling Study

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.

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.

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.

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.