The Dynamic Relationship between the Glymphatic System, Aging, Memory, and Sleep

Abstract

The process of memory entails the activation of numerous neural networks and biochemical pathways throughout the brain. The phenomenon of memory decline in relation to aging has been the subject of extensive research for several decades. The correlation between the process of aging and memory is intricate and has various aspects to consider. Throughout the aging process, there are various alterations that take place within the brain and, as expected, affect other functions that have already been linked to memory and its function such as involving microcirculation and sleep. Recent studies provide an understanding of how these mechanisms may be interconnected through the relatively new concept of the glymphatic system. The glymphatic system is strongly correlated to sleep processes. Sleep helps the glymphatic system remove brain waste solutes. Astrocytes expand and contract to form channels for cerebrospinal fluid (CSF) to wash through the brain and eliminate waste. However, the details have not been totally elusive, but the discovery of what we call the glymphatic system enables us to connect many pieces of physiology to understand how such factors are interconnected and the interplay between them. Thus, the purpose of this review is to discuss how the glymphatic system, sleep, memory, and aging are interconnected through a network of complex mechanisms and dynamic interactions.

Keywords: aging; glymphatic system; memory; molecular system; neuroinflammation.

Figure 1

A simplified overview of the glymphatic system. Numbered steps (1–4) represent the main physiological processes. Alphabetically numbered text boxes represent pathological processes that disrupt the glymphatic mechanism. 1. The paravascular space conduction of cerebrospinal fluid along penetrating arterioles. 2. AQP4 channels situated at the astrocytic end feet lining the perivascular space facilitate the transport of fluid towards the extracellular space. 3. A net flow of ISF carries extracellular solutes in an advective current towards the postulated draining sites. 4. The draining of ISF to the perivenular fluid and from there to dural and cervical lymphatics and/or venous reabsorption sites. A. Aging and other concomitant factors of vascular injury disrupt normal arterial pulsatility. B. The loss of the AQP4 concentration around the periarterial space as a result of cerebrovascular accidents and neuro-autoimmune processes. C. Sleep disorders inhibit ISF flow augmentation that occurs in normal sleep. D. Accumulation of harmful waste and pro-inflammatory mediator molecules as a result of glymphatic dysfunction. The interconnectedness of pathological processes, noted with red arrows, results in positive feedback loops of damage amplification. This figure expands on a diagrammatic illustration by Illiff et al., 2012 [52].