A minimal model of peripheral clocks reveals differential circadian re-entrainment in aging

TL;DR

This study presents a minimal coupled oscillator model of mammalian circadian clocks, revealing how aging-related changes impair re-entrainment and suggesting interventions like the feed-fast cycle to improve circadian resilience.

Contribution

The paper introduces a simple mean-field oscillator model that captures aging effects on circadian re-entrainment and highlights the role of peripheral clocks in circadian regulation.

Findings

Attenuated sympathetic input impairs re-entrainment

Reduced light responsiveness hinders clock recovery

Feed-fast cycle can accelerate circadian re-entrainment

Abstract

The mammalian circadian system comprises a network of cell-autonomous oscillators, spanning from the central clock in the brain to peripheral clocks in other organs. These clocks are tightly coordinated to orchestrate rhythmic physiological and behavioral functions. Dysregulation of these rhythms is a hallmark of aging, yet it remains unclear how age-related changes lead to more easily disrupted circadian rhythms. Using a two-population model of coupled oscillators that integrates the central clock and the peripheral clocks, we derive simple mean-field equations that can capture many aspects of the rich behavior found in the mammalian circadian system. We focus on three age-associated effects which have been posited to contribute to circadian misalignment: attenuated input from the sympathetic pathway, reduced responsiveness to light, and a decline in the expression of neurotransmitters. We find that the first two factors can significantly impede re-entrainment of the clocks following a perturbation, while a weaker coupling within the central clock does not affect the recovery rate. Moreover, using our minimal model, we demonstrate the potential of using the feed-fast cycle as an effective intervention to accelerate circadian re-entrainment. These results highlight the importance of peripheral clocks in regulating the circadian rhythm and provide fresh insights into the complex interplay between aging and the resilience of the circadian system.