The nutrition-sleep-circadian axis in age-related neurodegeneration: Cellular mechanisms, metabolic dysfunction, and neuroprotective interventions.

Advanced age is accompanied by progressive metabolic, nutritional, mitochondrial, and neuroimmune dysregulation, which may increase susceptibility to neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting the need to identify modifiable mechanisms that influence disease initiation and progression. Increasing evidence indicates that nutrition, sleep, and circadian rhythms function as an interconnected biological network regulating metabolic homeostasis, mitochondrial function, neuroinflammation, oxidative stress, proteostasis, and neuronal resilience. Disruption of this integrated axis accelerates age-related neurodegeneration through impaired glymphatic clearance, altered protein aggregation, circadian misalignment, gut-brain axis dysfunction, and metabolic imbalance. Although these factors have traditionally been investigated independently, recent studies demonstrate extensive mechanistic crosstalk linking nutritional status, sleep architecture, circadian regulation, and cellular ageing processes. This review synthesizes recent experimental, clinical, epidemiological, and translational evidence describing how dysfunction of the nutrition-sleep-circadian axis contributes to the pathogenesis of AD and PD. Particular emphasis is placed on molecular pathways involving mitochondrial dysfunction, oxidative damage, neuroimmune activation, clock-gene regulation, impaired protein clearance, and gut microbiota interactions that collectively drive neurodegenerative progression. We further evaluate emerging interventions, including chrononutrition, Mediterranean-style dietary patterns, time-restricted feeding, light-based circadian therapies, and lifestyle strategies that target multiple ageing-related mechanisms simultaneously. Finally, we discuss current knowledge gaps, methodological limitations, and future research priorities for integrating nutritional, circadian, and metabolic approaches into precision strategies for healthy brain ageing. Collectively, the available evidence supports the nutrition-sleep-circadian axis as a central regulator of biological ageing and a promising therapeutic target for delaying neurodegeneration, preserving cognitive function, and improving healthy lifespan.