Comprehending the underlying mechanisms and potential interventions related to cognition and brain health requires a thorough understanding of the interaction and interconnection between memory, aging, sleep, and the glymphatic system. Memory, which involves the stabilization and storage of memories, is subject to influences such as age-related alterations in the brain [1]. The process of aging is accompanied by a range of neurobiological alterations in the brain, which entail an accumulation of toxic proteins, such as beta-amyloid plaques and tau tangles, as well as a decrease in brain volume and synaptic connections. These changes have the potential to affect the functionality of cerebral areas associated with memory, such as the hippocampus and prefrontal cortex, which lead to memory loss. In addition, the process of aging is accompanied by a decline in energy production, as well as an increase in oxidative stress and mitochondrial dysfunction .This may cause injury to cellular functions and memory loss [2]. Besides this effect, another interaction of aging is the changes in sleep. Aging causes frequent modifications in sleep patterns, such as a reduction in sleep efficiency, heightened wakefulness throughout the night, and modifications in sleep architecture [3]. Changes in sleep patterns may have an impact on the process of memory consolidation and overall cognitive functioning. There is a wealth of evidence suggesting that sleep plays a significant role in this phenomenon, primarily due to the distinct neurochemical milieu and electrophysiological patterns observed during the sleeping period. Two hypothetical models, which may not be mutually exclusive, have been suggested to account for the valuable impact of sleep on memory functions. These models are referred to as the hippocampal–neocortical dialogue and the synaptic homeostasis hypothesis [4]. Both sleep patterns and aging can affect the glymphatic system’s functionality [5]. During sleep, specifically slow-wave sleep (SWS), the glymphatic system is at its most active. During SWS, the interstitial space within the brain enlarges, allowing the glymphatic system to flush out accumulated waste products [6,7]. Typically, older adults experience diminished SWS, diminished sleep efficacy, and increased sleep fragmentation [8]. The activation and process of the glymphatic system may be impacted by these age-related changes in sleep patterns. Also associated with aging are modifications to the glymphatic system itself [9]. Studies suggest that the effectiveness of glymphatic clearance declines with age, which may contribute to the accumulation of waste products in the brain [9,10]. Changes in the structural integrity of glymphatic vessel networks and the modulation of specific molecules [11], alongside age-related vascular changes such as diminished cerebral blood flow and an increased permeability of the blood–brain barrier [12], are potential factors that may contribute to the compromised glymphatic function observed in older individuals. Consequently, sleep disturbances and impaired glymphatic function can impede the efficient clearance of metabolic waste products, such as beta-amyloid [13]. This accumulation of waste products can negatively impact brain health, lead to memory loss, and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD) [14]. Combined with age-related changes in sleep patterns, the impaired glymphatic function observed with aging may contribute to the increased prevalence of neurodegenerative diseases in older individuals [13,14].

Memory is essential for cognitive ability, personal identity, and emotional well-being. It enables us to learn, adapt, and navigate the environment around us. Memory can at the same time be thought of as a behavior, a process, a brain function, or even a model of neural activity [15]. Memory is multimodal and is comprised of long-term memory (LTM), short-term memory, and working memory [16]. Long-term memory is formed and maintained by neuronal ensembles composed of excitatory and inhibitory neurons, which undergo synaptic and neuronal modifications at various stages of their formation [17,18]. Long-term potentiation is a crucial process that responds to memory-related stimuli and induces brain-activity-induced changes. Other cell types, such as astrocytes and microglia, have been found to play a role in memory regulation [19]. Long-term memory is formed and stored in the hippocampus, notably the dentate gyrus and Cornu Ammonis (CA) regions 1 and 3. Schaffer’s collaterals are critical to long-term potentiation memory storage [20]. AMPA, NMDA, and glutamate receptors enhance action potentials and calcium and sodium ion exchange to facilitate this process [21]. Although the investigation of memory is very demanding and complicated, researchers have made progress in elucidating the structures, processes, and molecular systems involved in the formation and consolidation of long-term memory. However, there is still a need for the identification of the effects of factors such as sleep and aging [22]. Long-term memory and short-term memory are interconnected through the processes of the formation and retrieval of memories. Together, they facilitate the storage and retrieval of information in the human brain [23]. Short-term memory relies on alterations in synaptic strength among pre-existing neuronal connections through the covalent modification of proteins, particularly enzymes of the kinase family [24,25]. Key enzymes involved in this process include A-protein kinase (APK), protein kinase C (PKC) [25], calcium/calmodulin-dependent protein kinase II (CaMK II) [26], and mitogen-activated protein kinase (MAPK) [27]. These proteins play important roles in modulating synaptic plasticity and the consolidation of short-term memory [25]. Working memory uses frontoparietal brain regions like the parietal cortices, prefrontal cortex, and cingulate gyrus. Working memory and protein dephosphorylation depend on the prefrontal cortex and other cortical areas [28]. Intracellular signaling pathways, particularly involving calcium- and cAMP-dependent protein kinases, can impair working memory [29]. Understanding working memory neural mechanisms and variables is crucial to comprehend cognitive processes and manage memory deficits or declines in diverse circumstances (please see Table 1).

Aging has significant effects on memory, starting at the molecular level. These effects of aging are interconnected and thus influence one another [30]. Cellular senescence, which increases with age as the name implies, affects neuronal function and contributes to chronic inflammation [31]. Mitochondrial dysfunction impacts the energy required for cellular processes, leading to neuronal injury and memory loss associated with aging. Aging also induces synaptic changes, including a decline in synaptic density and a shift in excitatory–inhibitory neurotransmission [32]. Inflammation interferes with synapse function as well as memory development and retrieval [33]. Protein aggregation is linked to aging and cognitive impairment, and it is hypothesized to be important in the etiology of several neurodegenerative diseases [34,35]. Memory loss and the dysfunctions inherent in aging are critical and correlate with the way the brain processes biomolecules or removes likely toxic metabolites, produced through neuronal activity and interaction [36]. The clearance of these molecules is obviously vital, particularly in the case of the amyloid beta (Aβ) peptide, a byproduct mostly of membrane maintenance, which negatively affects neurons by coalescing into amyloid plaques, a key factor in the pathogenesis of AD and neurodegeneration in general [37,38]. The interplay between synaptic activity, mitochondrial function, and sleep is crucial in maintaining a healthy brain [39]. Sleep abnormalities can disrupt the typical energy metabolism of cells, including those located within the brain. Sufficient rest is essential for mitochondria to effectively synthesize adenosine triphosphate (ATP), which serves as the primary energy unit for cellular processes [40,41]. Sleep deprivation may affect the capacity of mitochondria to produce ATP, resulting in decreased cellular energy availability [42].

Sleep is one of the most important elements in human homeostasis. The interlinkage of sleep and brain functionality is provided through circuits that are interacting parts of a wider system generated by sleep’s multiple properties and interactions, including changes in memory, rhythmic brain dynamics, regulated respiratory and circulatory physiology, and clearance [43]. Studies in memory and sleep correlation have recorded individual brain areas and cell types, showing sleep-regulating areas in the hypothalamus, brainstem, basal forebrain, and other subcortical nuclei [44]. As mentioned above, sleep deprivation can lead to compromised mitochondrial function, resulting in a decrease in ATP production, which may have a detrimental impact on memory-related processes. An inadequate amount of sleep can impede the appropriate execution of mitophagy, resulting in the buildup of impaired mitochondria. The accumulation of such substances has the potential to compromise the overall functionality of mitochondria and intensify any pre-existing mitochondrial impairments [45]. Dysfunctional mitophagy has been implicated in the pathogenesis of several age-related diseases due to sleep deprivation or abnormalities, including neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease [45,46]. The discovery that sleep helps remove waste from the brain at far higher rates than during wakefulness is vastly significant due to it furthering our understanding of interstitial fluid dynamics. Sleep thus becomes a part of the removal mechanism of potentially damaging metabolic waste from neurons [47]. As individuals age, they often experience changes in their sleep patterns, with elderly people experiencing more awakenings at night and less efficient sleep. It is also possible to develop the advanced sleep phase syndrome due to changes in bedtime hours. As a consequence, sleep architecture variations due to aging affect memory and brain function.

Therefore, the relationship between aging and sleep is bidirectional. Age-related changes in brain structures, such as the suprachiasmatic nucleus (SCN) responsible for regulating the sleep–wake cycle, can disrupt the circadian rhythm. Additionally, molecular and cellular changes associated with aging, such as inflammation and hormonal alterations, can influence sleep patterns [48]. Poor sleep correlates with a cortical Aβ burden and CSF A and phosphorylated tau levels in elderly people with AD [49]. Patients with mild cognitive impairment (MCI) and AD have significantly less posterior NREM sleep than healthy older adults, with the degree of reduction predicting the severity of memory impairment [50]. Adverse post-mortem investigations have shown that neurofibrillary tangles in the preoptic region of the hypothalamus correlate with the severity of prior decreased sleep. Tau deposition is also observed in cognitively normal older adults in the locus coeruleus and basal forebrain, leading to the currently untested hypothesis that tau within these regions may induce sleep abnormalities years before the onset of degenerative disease and serve as an early diagnostic biomarker [49,50].