Circadian Rhythms, NRF2 Signalling and Redox Homeostasis: A Holy Grail for a Healthy Life Course?

SIGNIFICANCE: The circadian ∼24h timing system coordinates physiological and metabolic processes to anticipate daily environmental changes, yet how molecular clock-driven signals interface with redox signalling to shape health across the life course remain incompletely understood. Redox homeostasis encompasses the adaptive maintenance of a biological steady state through the regulation of reduction-oxidation (redox) reactions. Redox reactions are vital in maintaining cellular functions, from regulating cellular proliferation and differentiation to detoxification of harmful substances and metabolic regulation. This adaptive homeostasis allows cells and tissues to transiently adapt to fluctuating levels of internal and external environmental stressors and build stress resilience to potential damaging stimuli. As we age, our baseline stress-protective systems rise, and our cells and tissues lose the ability to transiently and temporally increase their adaptive capacity further, leading to chronic redox shifts in pathophysiological direction and increased susceptibility to disease and frailty.

RECENT ADVANCES: Here we integrate circadian timing, NRF2 signalling and redox balance into a unified circadian-NRF2-redox axis as a life course framework for maintaining health from development through ageing. We propose that circadian clocks regulate NRF2 activity through rhythmic modulation of various redox-sensitive transcriptional and post-translational co-regulators, kinases and miRNAs, thereby shaping the amplitude and timing of antioxidant and metabolic responses. Conversely, NRF2-driven transcriptional programmes modulate mitochondrial function, glutathione synthesis and xenobiotic defence in a time-of-day manner, reinforcing circadian robustness in tissues with high oxidative flux.

CRITICAL ISSUES: The bidirectional interplay between circadian clocks and NRF2-driven redox adaptations generates predictable redox oscillations that gate energy metabolism, cellular repair and immune responses, influencing susceptibility to chronic diseases, from metabolic and cardiorespiratory to neurodegenerative diseases and cancer. We review evidence from in vitro and in vivo experimental models and human studies showing that circadian/NRF/redox misalignments, whether from shiftwork, light pollution, irregular sleep or chronic feeding, amplify oxidative stress and diminish adaptive responses, accelerating health decline with age.

FUTURE DIRECTIONS: We propose that lifestyle interventions that realign circadian timing (consistent sleep/wake or feeding/fasting schedules) and pharmacological strategies that enhance NRF2 activity can restore redox balance and improve disease risk profiles, highlighting a unifying target to predict health trajectories and promote lifelong health. Understanding redox-circadian interactions will help optimise person-centred chronomedicine approaches for advocating preventative health across the life course and for designing smarter therapeutic treatments for redox-based diseases, utilising time-of-day administration of drug treatments and clinical interventions.