Maad Rayan Publishing Company Biomedical Research Bulletin 2980-9924 3 2 2025 06 30 Sleep, Glymphatic Flow, and Proteostasis: Linking Sleep Physiology to Neurodegenerative Risk 72 76 10.34172/biomedrb.9069 EN Leila Hosseini https://orcid.org/0000-0002-4203-4618 Ali Reza Shafiee-Kandjani Mojtaba Ziaee Vida Mafikandi Nasrin Abolhasanpour REVIEW 10.34172/biomedrb.9069 2025 05 30 2025 06 15 Sleep is essential for maintaining brain health, cognitive performance, and neurological function. Accordingly, increasing scientific attention has recently been directed toward understanding the physiological mechanisms through which sleep exerts its restorative effects. The discovery of the glymphatic system (GS) provides a new conceptual framework for understanding how the brain eliminates metabolic waste and neurotoxic aggregates. During sleep, GS facilitates the convective exchange of cerebrospinal and interstitial fluids in order to remove harmful byproducts. These processes are linked to proteostasis, the regulation of protein synthesis, folding, and degradation, ensuring cellular homeostasis and preventing the accumulation of misfolded proteins. The dysfunction of glymphatic flow or proteostasis significantly contributes to the onset and progression of neurodegenerative diseases. According to research findings, poor sleep quality and short sleep duration produce decreased glymphatic clearance of debris, contributing to protein aggregation and cellular die-off and injury. Conversely, restorative sleep impairs waste flushing while protecting neural function. The present review provides findings related to recent research about the interplay of sleep physiology, glymphatic flow, and proteostasis to simultaneously provide an understanding of these three interrelated processes in the context of risk of neurodegenerative disease. Moreover, it presents emerging treatment approaches, such as sleep optimization, pharmacological modulation of glymphatic flow, and enhancement of proteostasis pathways that may avoid age-related cognitive decline that ultimately plays a role in brain health across the lifespan.