Receptor-Level Modulation of Sleep Architecture: The Role of Adenosine, Orexin, and GABAergic Systems in Aging Brains

Sleep architecture undergoes significant changes with aging, marked by reduced slow-wave sleep, increased fragmentation, and diminished sleep efficiency. These alterations are closely linked to neurochemical shifts in key receptor systems—adenosine, orexin, and GABAergic—that regulate sleep onset, maintenance, and transitions. Understanding receptor-level modulation offers a promising way for targeted interventions in age-related sleep disturbances. This review synthesizes current literature on the roles of adenosine A1/A2A, orexin OX1R/OX2R, and GABA_A receptor subtypes in sleep regulation. It examines age-related changes in receptor expression, signaling pathways, and neurophysiological interactions. Comparative analysis highlights receptor crosstalk and compensatory mechanisms in aging brains, with emphasis on translational and therapeutic implications. Aging is associated with reduced adenosine receptor sensitivity, orexinergic tone decline, and diminished GABAergic inhibition—each contributing to disrupted sleep architecture. Crosstalk among these systems reveals synergistic and antagonistic dynamics that influence sleep-wake stability. Emerging receptor-targeted therapies, including dual orexin receptor antagonists and subtype-selective GABA_A modulators, show promise in improving sleep quality in elderly populations. Non-pharmacological interventions such as neurofeedback and light therapy further support receptor plasticity and circadian alignment. Receptor-level modulation provides a mechanistic framework for understanding sleep deterioration in aging. Targeting adenosine, orexin, and GABAergic systems offers novel strategies to restore sleep architecture and mitigate cognitive and metabolic consequences of sleep disruption. Future research should prioritize personalized receptor profiling and integrative therapeutic approaches to enhance sleep health in older adults.