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

## TL;DR

This study shows that metformin's effects on liver circadian rhythms and aging depend on the time of administration and the feeding state, suggesting optimal treatment strategies.

## Contribution

The study introduces a systems modeling approach to optimize metformin administration for anti-aging effects based on circadian timing and metabolic state.

## Key findings

- Metformin's effects on the liver circadian clock and aging markers are phase-dependent.
- Fasting enhances metformin's anti-aging effects, while a high-fat diet reduces them.
- Administering metformin during the increasing phase of CLOCK-BMAL1 concentration yields positive outcomes.

## Abstract

What are the main findings?
•Metformin exerts phase-dependent effects on liver circadian dynamics and metabolic aging markers.•Feeding state critically modulates metformin responses, with fasting enhancing and high-fat diet attenuating anti-aging effects.

Metformin exerts phase-dependent effects on liver circadian dynamics and metabolic aging markers.

Feeding state critically modulates metformin responses, with fasting enhancing and high-fat diet attenuating anti-aging effects.

What is the implication of the main finding?
•Optimizing metformin treatment according to circadian time and metabolic state may enhance anti-aging efficacy and support more flexible drug intervention strategies.

Optimizing metformin treatment according to circadian time and metabolic state may enhance anti-aging efficacy and support more flexible drug intervention strategies.

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.