1. Introduction Life is a self-organizing and self-sustaining process that involves the transformation of energy, primarily regulated by the brain. A fundamental condition for these energy processes is the organism’s adaptation to its environment. To achieve this, a living organism learns about its surroundings through its senses. The sensory patterns it acquires, along with the corresponding responses to the environment, are stored in the brain’s memory structures, which shape our behavior. The processes involved and the behaviors they generate are referred to as “information metabolism” [ 1]. This term encompasses the mental processes of organizing, identifying, and interpreting sensory information to understand the environment. To facilitate this, the brain uses various neurotransmitters and neuromodulators to assign emotional and motivational values—positive or negative—to the sensory information it perceives. Information metabolism enables the exchange of information between a living organism and its environment, aiming to preserve its identity and structure. Self-awareness is considered the highest form of information metabolism and is associated with several important behavioral markers, such as arousal, attention, facial expressions, body movements, and task engagement ( Figure 1). Recent evidence links thalamic inhibition and its disruption to attentional deficits and disturbed sleep patterns observed in schizophrenia [ 5]. The thalamus integrates sensory and motor information, which helps maintain alertness and wakefulness [ 6, 7]. It is the primary subcortical structure supplying signals to the neocortex [ 8]. The thalamus transmits almost all sensory information (except for olfaction) to the cerebral cortex, regulating consciousness, sleep, attention, and motor functions. The basal dendrites of neocortical pyramidal neurons receive most of these signals [ 8]. Additionally, the thalamus receives projections from the limbic system, which supports the processing and management of emotions as well as the formation and storage of emotionally labeled memory traces. Higher-order thalamocortical projections convey information about the overall state of arousal, providing contextual cues that can flexibly modulate cortical sensory processing [ 6, 7]. An essential aspect of consciousness is the perception of one’s environment, which is recorded in the brain as an egocentric representation. These perceived egocentric representations are stored in primary sensory cortex areas [ 3], while allocentric representations, which are defined concerning the external world, are stored in the hippocampus, entorhinal cortex, and adjacent areas [ 3, 11]. The formation of these representations is a continuous process, relying on streams of sensory information from exteroceptors (vision, hearing, smell) and interoceptors that are activated during motor activities and transmitted to the cortex via the thalamus. The perceived egocentric representations are again recorded in the primary sensory cortex areas [ 3], while allocentric representations are cataloged in the hippocampus and related regions [ 3, 11]. Both spatial memory and spatial orientation experience a gradual yet noticeable decline due to neurobiological changes and a general slowdown in cognitive functions [ 12]. Both motor and cognitive functions are particularly vulnerable to deterioration with age, a symptom commonly associated with Alzheimer’s disease [ 12]. 2. Energy Metabolism, Mood, Emotions, and Motivation Energy deficiency poses a significant threat to life, acting as a major stressor for the body. In response to this deficit, the brain may exhibit symptoms such as low mood, increased anxiety, and aggressive behaviors. Meeting hunger needs and restoring energy levels activate the brain’s reward system, ultimately enhancing overall well-being. Emotional balance relies on the coordinated activity of several brain regions, particularly the prefrontal cortex and the amygdala. When these systems are disrupted by stress, illness, or metabolic issues, emotional states can become unstable or negative. Notably, energy metabolism and emotional regulation are closely linked, and disruptions in either process can lead to decreased motivation. Low or inefficient energy use can hinder mood regulation, concentration, and motivation. Motivation is significantly impaired in individuals with depression, reflecting actual changes in the brain systems responsible for drive and reward. The primary cause of a low mood may be an energy deficit and related changes in the motivational-emotional system. A key symptom of low mood is anhedonia, or the inability to experience pleasure. The key brain structure involved in mitigating fear and anxiety is the dopaminergic system of the nucleus accumbens, which plays a crucial role in the experience of reward, pleasure, and motivation. The nucleus accumbens functions as a limbic-motor interface, transforming emotional stimuli from the limbic system into behaviors executed by the motor system. Various types of social interactions engage the nucleus accumbens, and insufficient or poor social relationships are often linked to several mental disorders, including depression, schizophrenia, and anxiety disorders [ 13]. To alleviate stress, oxytocinergic neurons located in the paraventricular, supraorbital, and accessory nuclei of the hypothalamus produce the neuropeptide oxytocin [ 14]. Fear is an acquired response to aversive stimuli, while anxiety is a chronic state characterized by a low mood, indicating the body’s struggle to cope with real or imagined threats. Both fear and anxiety are mediated by different regions in the brain [ 15]. Fear responses are linked to activity in the central nucleus of the amygdala, whereas state anxiety is governed by the central nucleus of the bed nucleus of the stria terminalis (BNST). The BNST acts as a relay center in neural circuits, coordinating the functions of the autonomic, neuroendocrine, and somatic motor systems to achieve organized physiological responses and behaviors [ 15]. A depressed mood alters the activity of the prefrontal cortex, diminishing its ability to initiate and sustain actions that may seem impossible under conditions of energy deficit. Furthermore, excessive activity in areas like the amygdala can promote negative emotions and depression, often creating a vicious cycle: lower motivation leads to reduced activity, fewer satisfying experiences, and deeper depression. Chronically low energy balance forces the brain to switch from utilizing external energy sources to relying on internal ones, primarily through gluconeogenesis, which restores blood sugar levels to maintain essential brain function. This shift in nutrient utilization from primarily glucose to other sources is a fundamental metabolic adaptation necessary to cope with decreased blood glucose levels and a decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays a crucial role in this metabolic adaptation [ 23]. The lateral septum is a brain structure that regulates food intake by integrating homeostatic and motivational stimuli [ 24]. Anatomically, the lateral septum connects the hippocampus, which is essential for memory and spatial orientation, with various subcortical areas, particularly those in the hypothalamus that play a crucial role in motivated behaviors necessary for survival, such as eating, arousal, energy homeostasis, and reward-related actions. The septum’s projection to the lateral preoptic area is involved in regulating sleep–wake cycles, thermoregulation, and reward-seeking motor behaviors, including locomotion and food consumption. The lateral septum, which is composed almost entirely of GABAergic neurons, is activated by glucagon-like peptide-1, a gut hormone essential for regulating blood sugar levels and feelings of fullness. These neurons express somatostatin, leading to the inhibition of growth hormone, insulin, glucagon, and calcium-dependent protein secretion. The activity of the lateral septum is modulated by several neurotransmitters and neurohormones, including vasopressin, oxytocin, ghrelin, corticotropin-releasing factor (CRF), and particularly neuropeptide Y. 3. Brain Memory System Is the Major Consumer of Energy Information processing in the cerebral cortex and hippocampus is influenced by network oscillations that vary in frequency depending on brain state and behavior. In the hippocampus, theta oscillations (4–10 Hz) are present during exploratory behavior and rapid eye movement (REM) sleep. Meanwhile, short bursts of high-frequency activity (120–200 Hz), which last about 100 ms, are typical during slow-wave sleep, waking inactivity, and consummatory behavior [ 25]. The physiological functions of the brain are determined by the integration of biochemical signals from primary neurotransmitters, specifically glutamate and gamma-aminobutyric acid (GABA). Parvalbumin, a calcium-binding protein found in rapidly responding GABAergic neurons, protects these neurons from calcium-induced apoptosis by regulating calcium ion levels. Additionally, various neuromodulators, neurohormones, and ionic signaling further modulate the activity and function of the glutamatergic and GABAergic systems ( Figure 2). Glutamate-mediated synaptic transmission accounts for 80–90% of total glucose use in the cerebral cortex, particularly in areas with the highest synaptic activity [ 26]. In the human cerebral cortex, parvalbumin-positive neurons form a dense inhibitory network that strongly influences the activity of pyramidal neurons [ 27]. Thanks to parvalbumin, the GABA interneurons in pyramidal columns can generate very rapid pulse trains in response to calcium signaling. Their inhibitory function allows for the synchronization of neural networks and the generation of gamma oscillations (30–80 Hz), which are critical for cognitive functions, memory, and neuroplasticity [ 28]. This high level of activity and metabolism results in significant energy demands [ 28]. Therefore, GABA interneurons are particularly sensitive to stress and pathological factors. As individuals age, the function of PV interneurons tends to decline, which can worsen cognitive and memory deficits. This decline is often due to impaired dopamine and glutamate signaling. Inflammation and chronic stress may also affect parvalbumin expression in the prefrontal cortex, potentially leading to behavioral and cognitive deficits. Elevated cortisol levels have been shown to reduce parvalbumin expression and contribute to cognitive and emotional impairments observed in conditions such as chronic stress, post-traumatic stress disorder, and depression [ 29]. One critical factor that increases the susceptibility of cortical neurons to damage is the energy-intensive process of neural network formation, which relies on tight integration among neurons, astrocytes, and glial cells [ 30]. Synaptic pruning is a physiological mechanism essential for the proper formation and maturation of functional neural networks; it eliminates rarely used synapses while preserving frequently used connections [ 31]. Although pruning occurs throughout life, it is particularly extensive in brain regions associated with higher cognitive functions during adolescence. Importantly, in a healthy brain, apoptotic synapses undergo local biochemical changes typical of apoptosis without leading to the death of the entire neuron. This allows microglia and astrocytes to selectively identify and eliminate weakened or redundant synapses [ 31]. In the case of overactive synapses and neurons, excessive calcium ion influx triggers the externalization of phosphatidylserine, which activates phagocytosis. In the mature human brain, neurogenesis probably involves only GABA interneurons and glial cells, with the highest intensity of these processes observed in the early stages of development [ 37]. Neurogenesis-based memory formation allows individuals to adapt their personality and behavior to environmental demands [ 36]. Each new experience is integrated into existing memory networks as patterns of sensory and motor components, associated with contextually specific positive or negative emotional signatures. During adult neurogenesis, activated progenitor cells must be incorporated into existing memory networks, facilitating their terminal differentiation and establishing presynaptic and postsynaptic interactions with existing neurons, glial cells, and the extracellular matrix. Circulation of the cerebrospinal fluid facilitates progenitor cell migration during adult neurogenesis [ 33, 38]. These processes depend on the quality and stability of cell membranes and the physiology of the intercellular space [ 39]. Particularly, the outer layer of glycans on cell membrane surfaces, known as the glycocalyx, plays a significant role in sensing and transducing biophysical signals—specifically, mechanical forces acting on cells that elicit cellular responses [ 40, 41]. Sialic acid, a monosaccharide with high polarity and a negative electrical charge, forms a thin electrostatic layer on the surfaces of cell membranes, mitochondrial membranes, endoplasmic reticulum, and microtubules. In the brain, sialic acid is found in glycoproteins, glycolipids, and interstitial fluids, making it crucial for morphogenesis, cell recognition and adhesion, immunity, and neurotransmission. Sialic acid-containing glycosphingolipids are potent bioactive signaling molecules that regulate cell growth, differentiation, apoptosis, and inflammation [ 42]. Siglecs are key microglial receptors that recognize sialic acid on healthy neurons, helping to prevent excessive inflammation and maintain tissue homeostasis while also responding to waste products. Brain-derived neurotrophic factor (BDNF) plays a vital role in the development of brain circuits, the formation and maintenance of neuronal morphology and architecture, and synaptic plasticity, ultimately regulating learning and memory processes [ 45]. BDNF is primarily released from neurons in an activity-dependent manner, particularly through NMDA receptors and increased calcium influx, which promotes vesicle fusion and release [ 45]. This release allows BDNF to act on local TrkB receptors, strengthening neural connections [ 45]. Additionally, BDNF is released from vascular endothelial cells, which contribute to the vascularization of neuronal structures. BDNF levels in preterm neonates differ from those in full-term neonates, influencing cognitive development in early postnatal life and potentially being linked to mental health issues in children, such as autism spectrum disorders. In the adult brain, imbalances in BDNF levels and downstream signaling via its cognate TrkB tyrosine kinase receptor are associated with neurodegenerative and psychiatric diseases, including Alzheimer’s disease, major depressive disorder, and schizophrenia [ 45]. Trophic factors—such as BDNF, fibroblast growth factor (FGF), epidermal growth factor (EGF), and the neurotransmitter serotonin—are involved in enhancing adult neurogenesis [ 46]. Both acute and chronic stress are known to decrease hippocampal neurogenesis. However, persistent hippocampal neurogenesis is observed in older adults, including those in their 10th decade of life, and in patients with mild cognitive impairments and Alzheimer’s disease. The hippocampus plays a vital role in learning by maintaining a neurogenic reserve, particularly when individuals encounter new and complex experiences. Young adults typically exhibit a high level of neurogenesis, which is the process of generating new neurons, due to their active adaptation to their environment. However, neurogenesis declines significantly with age, peaking around puberty [ 46]. Under conditions of glutamine deficiency, stem cells rapidly die due to ATP depletion, resulting in impaired connectivity in the memory-related neuronal networks of older adults [ 47]. Adult neurogenesis is now recognized as a form of brain plasticity that contributes to various physiological functions and impairments in this process are linked to neurological and psychiatric disorders [ 48]. Anxiety often serves as a precursor to mental health issues and is associated with reduced neurogenesis and cognitive deficiencies in humans. Newly formed neurons in the hippocampus express glucocorticoid receptors, and any dysregulation of the hippocampus-hypothalamic–pituitary–adrenal (HPA) axis can hinder memory and learning. Stress and depression have also been correlated with decreased neurogenesis. Some studies suggest that the decline in neurogenesis can be mitigated by the use of antidepressants, antipsychotics, and/or increased physical exercise [ 46]. Neurogenesis is supported by microglia, but in an aging brain, microglial activity is characterized by pro-inflammatory cytokines that inhibit neurogenesis, which in turn impairs learning and memory [ 49]. As a result, cognitive performance in older adults declines due to limited neurogenesis, and learning and memory processes are restricted to the restructuring of neural networks by changing the number and strength of synaptic connections [ 37]. The hippocampus is critical for cognitive processes, especially in the initial formation of memory traces, while the neocortex serves as the ultimate storage area for these memories. Consequently, the most energy-demanding cortical areas include the medial temporal lobe and frontal regions, particularly when maintaining sensory representations in working memory. Dysfunction in memory processes is central to conditions such as temporal lobe epilepsy and Alzheimer’s disease, with atrophy often extending beyond the hippocampus to involve surrounding structures [ 50]. 4. Brain Energy Metabolism The organism constantly absorbs energy from its surroundings to maintain its structure and homeostasis, facilitate self-repair, and engage in motor behaviors. The hypothalamus plays a crucial role in maintaining physiological, behavioral, and energy homeostasis [ 51]. It serves as the primary regulatory center for body temperature, hunger, thirst, sleep–wake cycles, circadian rhythms, behavior, and hormone secretion [ 52]. These regulations are closely linked to mood control, motivation, and stress response. Impaired glucose metabolism in the aging body can lead to dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, the hypothalamic–pituitary–thyroid (HPT) axis, and the hypothalamic–pituitary–gonadal (HPG) axis. Astrocytes form a metabolic network connecting neurons and blood vessels, thereby supplying neurons with nutrients, removing metabolic waste, regulating blood flow to the central nervous system, and maintaining the integrity of the blood–brain barrier. This barrier helps stabilize the composition of cerebral blood circulation, making it less susceptible to systemic fluctuations. The mechanisms of neurovascular coupling are multifaceted, involving mediators released from different cells that activate distinct signaling pathways across the entire cerebrovascular network in a highly coordinated manner [ 56]. Various brain structures, such as the subfornical organ and vascular organ of the lamina terminalis, as well as the periventricular sensory organs in the forebrain and posterior hindbrain regions, play roles in regulating systemic homeostasis [ 57]. However, these structures lack a tight blood–brain barrier, which exposes their neurons to toxins, pathogens, and elevated concentrations of signaling ions, particularly calcium and phosphate from the blood. This vulnerability makes them more susceptible to aging, neurodegeneration, and cell death (apoptosis). In the aged, reduced cerebral blood flow and abnormal cerebrovascular reactivity significantly impair brain function. This leads to the accumulation of waste products in neurons and the interstitial space, disrupting homeostasis and the kinetics of biochemical reactions. Calcium ions, distributed by blood flow, play a crucial role in regulating major physiological processes in the brain, controlling neurotransmitter release, synaptic plasticity, and growth cone motility. The blood–brain barrier is permeable to gases (such as oxygen and carbon dioxide), glucose, and ions essential for maintaining the resting and functional potentials of nerve cells. Thus, the blood–brain barrier is vital for sustaining homeostasis and physiological processes in the central nervous system. In neurons, calcium influx through NMDA receptors and voltage-dependent calcium channels mediates several physiological processes; however, impaired calcium signaling contributes to neuronal degeneration and death in neurodegenerative conditions [ 58]. The brain, which serves as the controller of life, requires a constant supply of glucose and oxygen from the blood [ 59]. Under normal physiological conditions, glucose and, to a limited extent, fatty acids are the primary energy sources [ 60, 61]. Glucose metabolism in the brain is closely tied to all life processes, including the regulation of neuroenergetics, neurotransmission, biosynthesis, and antioxidant defense [ 59]. The primary pathways for energy production in neurons are glycolysis and oxidative metabolism, which occur via the tricarboxylic acid cycle and the electron transport chain. The entry of neuroactive compounds essential for protein synthesis and energy production, such as glutamate, aspartate, glycine, and D-serine, into the brain is strongly restricted by the blood–brain barrier; therefore, these compounds are synthesized from glucose within the brain [ 62]. During energy metabolism, these neuromodulators and neurotransmitters are produced from substrates derived from glycolytic pathways. Additionally, the enzymatic process of glycosylation is closely linked to neuronal glucose metabolism. In this post-translational modification, sugar chains (glycans) are covalently attached to proteins or lipids, which is essential for protein stability, folding, trafficking, and cell longevity. Neuronal activity and repair processes are interdependent on glucose-based energy metabolism. The intensity of glucose metabolism varies significantly across different regions of the brain, influencing their susceptibility to functional disorders and damage. Notably, cortical processes associated with neural networks—such as neurotransmission, synaptogenesis, synaptic pruning, and axonal myelination—are particularly energy-intensive [ 65]. Nerve cells consist of unstable biomaterials, which leads to gradual wear and tear, resulting in progressive degeneration and age-related loss of function. Maintaining neuronal functionality and metabolic efficiency relies on the continuous remodeling of cellular and subcellular membrane structures, including mitochondria [ 61]. The kynurenine pathway plays an essential role in modulating neuronal functions by regulating the activity of N-methyl-D-aspartate (NMDA) receptors [ 66]. It is a primary route for tryptophan metabolism, yielding neuroactive intermediates such as quinolinic acid, which acts as an excitotoxic NMDA receptor agonist, and kynurenic acid, which serves as a neuroprotective NMDA receptor antagonist. Quinolinic acid, a biosynthetic precursor of NAD, functions as both an NMDA receptor agonist and a neurotoxin [ 66, 69, 70]. The disruption of energy metabolism leads to neuronal depolarization and overactivation of NMDA receptors, causing an uncontrolled rise in intracellular calcium levels and initiating apoptosis [ 70]. Furthermore, dysregulation of the kynurenine pathway results in a significant reduction in SIRT1 activity in astrocytes and neurons. Generally, dysfunction of the kynurenine pathway can lead to either hyper- or hypofunction of active metabolites, profoundly impacting the functioning of the central nervous system and exacerbating neurodegeneration, neurological disorders, and psychiatric illnesses like depression and schizophrenia [ 71, 72, 73]. 5. The Aging Brain The brain’s functional structures consist of postmitotic, differentiated neurons that have permanently exited the cell cycle, meaning they can no longer divide [ 74]. Almost all neurons become terminally differentiated postmitotic cells early in development. Their longevity and proper functioning depend on highly stable molecular mechanisms [ 74]. Depending on their activity levels, the protein and lipid structures within neurons can degrade relatively quickly, typically within days or weeks [ 75]. Studies suggest that the half-life of neuronal mitochondria is approximately 2 to 4 weeks, with excessively used mitochondrial proteins eliminated by a process called mitophagy [ 75]. Therefore, to maintain proper brain function over the long term, lipoprotein-based cellular structures must be continuously rebuilt, and the byproducts of repair processes must be effectively removed. This includes the continuous division and fusion of mitochondria, as well as the repair of membrane channels and receptors, which rely on post-translational modifications of lipids and proteins through glycosylation. Increasing age-related insufficiency of intracellular NAD salvage pathways and the disruption of the kynurenine pathway caused by chronic inflammatory processes do not allow for the supplementation of NAD deficiency and, at the same time, increase the production of excitotoxins such as quinolinic acid [ 76]. Elevated levels of quinolinic acid destabilize the cytoskeleton of astrocytes and blood vessel endothelial cells, which can degrade the blood–brain barrier [ 70]. Dysfunction of the kynurenine pathway leads to a rapid decline in NAD levels with a concomitant decrease in NAD-dependent SIRT1 activity, culminating in accelerated aging and ultimately neuronal death [ 61, 77]. The accumulation of Aβ peptide in the brain occurs decades before the onset of Alzheimer’s symptoms. Aβ is produced from the membrane-bound amyloid β precursor protein (APP) through proteolytic cleavage by β-secretase 1 (BACE1) and γ-secretase [ 77]. Growing evidence indicates that the intracellular trafficking of APP to each secretase determines the level of Aβ production [ 77]. Importantly, cleavage by the α-secretase ADAM10 and γ-secretase does not produce amyloid β [ 77]. Stress, which increases with age, is an inherent attribute of aging and especially of disturbing the energy balance of the brain. Chronically elevated cortisol levels can lead to glucocorticoid receptor resistance, inhibiting the activity of tryptophan 2,3-dioxygenase (TDO) in the liver. TDO catalyzes the first and rate-limiting step of tryptophan degradation, thereby impairing systemic tryptophan metabolism [ 73, 81]. This results in an increased production of quinolinic acid, at the expense of NAD synthesis [ 76]. Such disorders lead to a significant decrease in SIRT1 activity in astrocytes and neurons. Thus, dysfunction of the kynurenine pathway can worsen the dysfunction of the glutamate–GABA–glutamine cycle, profoundly affecting the central nervous system. This exacerbates neurodegeneration, neurological disorders, and psychiatric illnesses, including depression and schizophrenia [ 71, 72, 73]. Increased concentrations of quinolinic acid in cerebrospinal fluid have been observed in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, depression, epilepsy, and Huntington’s disease [ 82, 83]. 6. Chemical Imbalances in the Aging Brain Neurons form intricate synaptic transmission networks that function under the influence of specific ions, neurotransmitters, neuromodulators, cytokines, and hormones. If neurons are lost, these connections cannot be restored [ 84]. Neuronal dysfunction and death are linked to the gradual degradation of multiple functional systems and neurotransmitters, particularly those in the glutamatergic, dopaminergic, serotonergic, GABAergic, histaminergic, adrenergic, and cholinergic systems within the cerebral cortex, brainstem, and basal ganglia [ 85]. The progressive decline in energy metabolism plays a critical role in neuronal aging, contributing to the failure of cellular processes and increased cell death [ 60, 61]. Metabolic dysfunctions and related inflammatory processes throughout the body are at the root of the pathogenic process known as inflammaging [ 86, 87]. Aging causes a shift in energy and metabolic resource allocation, shifting it toward combating chronic inflammation and supporting tissue regeneration and repair. This neuroimmune energy shift is regulated by the hypothalamic–pituitary–adrenal (HPA) axis [ 81]. 6.1. Glutamate–GABA–Glutamine Cycle The brain’s neocortex plays multiple roles in controlling human behavior, including sensory perception, working memory, and motor planning [ 8]. Its unique structure consists of repeating subunits known as macrocolumns, which generally have identical circuitry [ 8, 28]. The core of each column is made up of glutamatergic excitatorypyramidal neurons, surrounded by GABAergic neurons that form a local inhibitory network. Glutamatergic excitatory pyramidal neurons account for approximately 70–80% of the total neuronal population, while the inhibitory GABAergic short axonal interneurons make up only 15–25% [ 28]. Such modular column organization is typical in the somatosensory and visual cortices, as well as the primary motor cortex. Distal dendritic segments are capable of generating impulses autonomously, allowing pyramidal neurons to learn new activation patterns independently of somatic action potentials. In contrast, synapses connecting to the proximal basal dendrites are more readily modified alongside global neuronal activity [ 8, 81]. Calcium ions influxing through activated NMDA receptor channels play a critical role in long-term synaptic plasticity, which is essential for cortical memory processes [ 81]. Glutamate is the primary excitatory neurotransmitter in the human brain and is involved in numerous physiological functions such as cognition, memory, learning, neurodevelopment, cell migration, cell differentiation, and apoptosis [ 88, 89]. Disrupted glutamate signaling is associated with the development of several neurological disorders [ 82]. In particular, excessive activation of N-methyl-D-aspartate (NMDA) receptors can lead to cascades of neuronal death [ 82]. Glutamate excitotoxicity primarily results from excessive calcium ion influx into neurons, which is essential for synaptic transmission, combined with a deficiency in the energy needed for calcium removal, leading to the death of particularly aging and energy-inefficient neurons. Glutamine is utilized to recycle the neurotransmitters glutamate and GABA, while excess glutamine supports neuronal energy metabolism through the tricarboxylic acid cycle by oxidizing acetyl-CoA derived from glycolysis [ 90]. The glutamine-dependent increase in ATP provides the energy needed to restore ionic balance at resting potential and to remove excess calcium ions. Impaired energy metabolism in astrocytes leads to reduced glutamate uptake due to insufficient ATP production. Under pathological conditions, astrocytes may fail to meet the energetic demands of glutamate uptake, causing intracellular glutamate accumulation. Reduced levels of glutamate and GABA in aging neurons result in an increased concentration of glutamine in the cerebrospinal fluid, significantly affecting microglial activity. The accumulation of glutamine in the brain can disrupt excitatory signaling and is associated with brain dysfunction or disease, manifesting as mental disorders, disorientation, personality changes, or even coma [ 90]. The glutamatergic and GABAergic systems are vital for maintaining the excitatory-inhibitory balance within the neocortex [ 94]. This balance is closely regulated by metabolic coupling between neurons, astrocytes, and microglia [ 90]. In particular, the glutamate–GABA–glutamine cycle serves as the primary metabolic complex linking neurotransmission with cellular metabolism. In this cycle, astrocytes synthesize and release large quantities of glutamine, which neurons subsequently uptake to produce the neurotransmitters glutamate and GABA [ 90]. Most synaptic glutamate is recycled from the synapse via astrocytic uptake, thus preventing overstimulation. Glutamate uptake is considered one of the most energy-intensive processes within the central nervous system [ 89, 95]. A significant portion of the glutamate taken up by astrocytes is oxidatively metabolized to α-ketoglutarate, which then contributes to ATP production. In this way, oxidative glutamate metabolism leads to the production of massive amounts of ATP in astrocytes. 6.2. Glutathione Glutamine is also a crucial precursor for the body’s conversion to glutamate, which supports glutathione synthesis [ 96]. The metabolism of glutathione has a significant impact on glutamate synaptic activity [ 97]. Disturbances in glutathione/glutamate metabolism can be triggered by inflammation, which is marked by increased glutathione production in the liver. In the brain, glutamine serves as an energy enhancer, facilitating increased ATP levels during periods of intense neuronal activity. Accumulating deficiencies in glucose metabolism and the glutamate–GABA–glutamine cycle can lead to ion pump dysfunction and prolonged depolarization, rendering neurons vulnerable to uncontrolled spontaneous firing and death due to energy deprivation or excitotoxicity. This uncontrolled neuronal activity results in excessive glutamate release and sustained activation of glutamate receptors, which exacerbates neuronal death, particularly in the hippocampus and cerebral cortex [ 98]. Dysregulation of glutathione is recognized as a contributing factor in the development of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis [ 99]. 6.3. Glutamine Glutamine, alongside glucose, is a vital energy substrate in the body, especially in tissues under metabolic stress and in rapidly dividing cells like lymphocytes and enterocytes [ 90, 103]. Additionally, glutamine provides nitrogen necessary for the synthesis of purines, pyrimidines, and amino sugars. Consequently, a deficiency in glutamine can impair the function of various metabolic pathways and mechanisms reliant on its availability, leading to immune dysfunction and disturbances in the brain’s glutamatergic system [ 103]. Large amounts of glutamate, GABA, and glutamine are depleted through oxidative metabolism in both neurons and astrocytes. This deficiency can be compensated for by muscle-derived de novo synthesized glutamine, which can cross the blood–brain barrier (BBB) [ 104]. The BBB actively transports glutamine in both directions, regulating brain nitrogen levels, protecting against neurotoxicity, and maintaining astrocyte health. This barrier utilizes Na+-dependent glutamine transport across capillary endothelial cells, while also actively removing excess glutamine and ammonia from the brain into the bloodstream to prevent toxicity [ 104]. Early signs of cognitive and motor alterations may arise from a deregulation of the glutamate-glutamine cycle [ 105]. The availability and metabolism of glutamine in the body are closely tied to skeletal muscle mass and activity [ 103]. Muscle tissue is responsible for 90% of the body’s total glutamine production; thus, the role of skeletal muscle and its activity is fundamental in glutamine metabolism, significantly influencing brain function [ 103]. In physiological conditions, glutamine acts as an anaplerotic substrate in neurons, entering the tricarboxylic acid cycle as α-ketoglutarate. Alpha-ketoglutarate is a crucial intermediate for cellular energy production and amino acid metabolism, significantly influencing the rate of the body’s citric acid cycle [ 106]. It acts as a nitrogen scavenger and a source of glutamate and glutamine, which stimulate protein synthesis and inhibit protein degradation in muscle [ 106]. In the brain, alpha-ketoglutarate serves as a precursor for key neurotransmitters, including glutamate, GABA, and acetylcholine. Glutamine deficiency occurs early in the aging brain. Factors such as hypoglycemia, insulin resistance, and age-related NAD deficiency contribute to excessive glutamine oxidation in brain cells. This leads to reduced glutamine synthesis in astrocytes, which directly impairs neuronal GABA signaling [ 107]. As a result, some glutamatergic neurons may become hyperactive in the early stages of Alzheimer’s disease, potentially causing seizures and accelerating disease progression. A significant reduction in hippocampal glutamine synthesis is also observed in patients with temporal lobe epilepsy, which results in excessive intracellular glutamate accumulation in astrocytes. This accumulation reduces synaptic glutamate uptake, leading to neuronal hyperexcitability and seizures [ 108]. As individuals age, glutamine deficiency can impair immune function, which subsequently disrupts the brain’s glutamatergic system. Particularly, during inflammatory states, brain glutamine needs are completely dependent on muscle resources [ 103]. Thus, in older adults, the accumulation of chronic inflammation and metabolic disturbances, combined with systemic glutamate deficiency, leads to muscle atrophy and sarcopenia [ 103]. This, in turn, further exacerbates inflammatory responses, leading to progressive neurodegeneration and deterioration of neuronal and mental functions. 6.4. Catecholamines Catecholamines include norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine. Norepinephrine plays a crucial role in regulating arousal, alertness, attention, and memory, forming a key element of the eustress response. By maintaining wakefulness, norepinephrine enhances the detection of sensory stimuli, improves concentration, sustains attention, and supports memory formation and recall. Loss of these functions is common in neurodegenerative diseases, contributing to cognitive and behavioral deficits [ 109]. Almost all norepinephrine in the brain is produced in the locus coeruleus, a small brainstem nucleus that sends signals to nearly all brain regions, including the prefrontal cortex, hippocampus, and amygdala. Notably, norepinephrine is the only neurotransmitter synthesized in the synaptic vesicles of locus coeruleus neurons [ 110]. Noradrenergic neurons in this area are also among the first to develop α-synuclein inclusions [ 110]. As a result, many early symptoms of brain neurodegeneration, such as sleep disturbances, anxiety, and depression, have been linked to locus coeruleus dysfunction [ 110]. During states of high alertness, noradrenaline released from the locus coeruleus acts on astrocytes, where it works together with glutamate to activate intracellular inositol trisphosphate (IP3) messenger, facilitating calcium release from the endoplasmic reticulum [ 111]. In response, the activated astrocytes release gliotransmitters, including D-serine, which coactivates NMDA receptors in the noradrenaline varicosity, modulating synaptic plasticity and information transfer [ 112]. The cellular population of the locus coeruleus consists of over 95% noradrenergic neurons [ 109]. The distribution of locus coeruleus projections is uneven throughout the neocortex, with axonal varicosities serving as sites for synaptic vesicle storage and neurotransmitter release. These projections primarily target key motor structures, such as the cerebellum, inferior olive, and motor cortex, as well as the olfactory bulb, frontal cortex, visual cortex, thalamus, midbrain, and spinal cord. The noradrenergic system of the locus coeruleus influences several fundamental behavioral processes and executive functions that depend on the prefrontal cortex, including synaptic plasticity and memory formation. Activity in the locus coeruleus during sleep features periodic switches between activity and silence, playing a crucial role in memory consolidation. The intense neural activity within limbic circuits during sleep enhances synaptic plasticity [ 110]. Adrenergic neurons, primarily located in the medulla oblongata, regulate key functions such as cardiovascular control, respiration, and stress responses. These neurons contain the enzyme phenylethanolamine N-methyltransferase (PNMT), which catalyzes the final step in catecholamine biosynthesis by converting noradrenaline into adrenaline. In this manner, they send signals to the hypothalamus and spinal cord, serving as central modulators. The hypothalamus executes these functions by controlling the pituitary gland, thereby regulating most endocrine responses [ 114]. Age-related declines in noradrenergic activity impair the regulation of neural plasticity, thus contributing to memory and learning difficulties in older adults [ 110]. Dysfunction of the locus coeruleus–noradrenaline system is associated with various stress-related neuropsychiatric disorders and neurological diseases [ 113]. Significant neuronal loss in the locus coeruleus is considered one of the early features of Alzheimer’s disease and dementia in Parkinson’s disease [ 115]. The combined deficits in cholinergic and dopaminergic systems appear to contribute to cognitive impairment in Parkinson’s disease, supporting the dual syndrome hypothesis [ 115]. When comparing cases of Parkinson’s and Alzheimer’s diseases, the loss of cholinergic signaling is either comparable to or more severe in Parkinson’s disease. However, this effect is particularly pronounced in patients with both Parkinson’s disease and dementia [ 115]. Consequently, patients with dementia tend to respond better to anticholinesterase drugs, such as rivastigmine and galantamine, which are used for the symptomatic treatment of mild to moderate dementia in both Alzheimer’s and Parkinson’s diseases [ 115]. The decrease in acetylcholine levels in the cerebral cortex observed in dementia may be linked to cell death within the nucleus basalis of Meynert (nbM) [ 115]. In Alzheimer’s disease, there is a loss of 8% to 87% of magnocellular neurons in the nbM compared to the control group, while in Parkinson’s disease, this loss can reach up to 80% [ 115]. Dopamine, the third catecholamine, plays a crucial role in regulating various aspects of human life, including motor behavior, memory, and learning, as well as the perception and processing of emotional and motivational stimuli [ 116]. Dopamine is a key reward neurotransmitter responsible for the feeling of pleasure. The mesolimbic dopaminergic system connects the ventral tegmental area to the nucleus accumbens, amygdala, and hippocampus, significantly influencing reward-motivated learning and behaviors [ 117, 118]. The nucleus accumbens is a key node in the mesolimbic pathway that increases dopamine levels in the ventral tegmental area, inducing positive reinforcement, which is essential for engaging in physically demanding activities [ 119]. Adenosine receptors are primarily expressed on GABAergic medium spiny neurons in the striatum and nucleus pallidus, co-expressing dopamine and enkephalin receptors, which link motor behaviors with motivation and reward [ 120]. Beyond motor control, these pathways also regulate cognitive, limbic, and reward functions, playing a critical role in the development of cortical circuits [ 120]. 6.5. Acetylcholine In the central nervous system, acetylcholine is the excitatory neurotransmitter, predominantly found in the basal forebrain. Acetylcholine is synthesized solely in the cytoplasm of neurons from choline and acetyl-CoA, with ATP being an essential component of this process [ 125]. It functions as a neuromodulator critical for arousal, memory, and learning. The cholinergic neurons have extensive projections that provide the primary input to the cerebral cortex and hippocampus [ 126]. Acetylcholine, also a key excitatory neurotransmitter in the peripheral nervous system, is responsible for skeletal muscle contraction. The activity of human skeletal muscles is controlled by the largest nerve cells, known as motor neurons, which are distinguished by their long axon fibers that can reach over 1 m in length and a highly developed axonal tree. A single motor neuron can control several hundred to nearly 2000 muscle fibers via cholinergic synapses. At the neuromuscular junction, released acetylcholine is quickly degraded by the enzyme acetylcholinesterase into choline and acetate, thereby terminating cholinergic synaptic transmission. Choline is then reabsorbed by the presynaptic neuron, where it combines with acetyl-CoA to form acetylcholine via the action of choline acetyltransferase [ 125]. Choline plays a direct role as a precursor to acetylcholine and phospholipids, serving as a key building block for structural lipids like phosphatidylcholine and sphingomyelin, which are vital for maintaining the structure and function of cell membranes [ 128].Choline deficiency can lead to muscle damage, cognitive deficits, and fatty liver [ 128]. These adverse effects are worsened by the age-related decline in NAD levels, leading to a significant reduction in neuronal glycolysis and oxidative phosphorylation [ 60, 61, 129, 130]. Thisdeficiency contributes to motor neuron death and a progressive loss of muscle mass (sarcopenia) in older adults, creating a vicious cycle of inflammation. 6.6. Serotonin 6.7. Neuropeptides 6.8. Monoamine Oxidases Monoamine oxidases (MAO) are a family of enzymes located in the outer mitochondrial membrane of neurons and astrocytes that catalyze the breakdown of neurotransmitters. They play a key role in regulating levels of serotonin, dopamine, and norepinephrine [ 136]. The isoform MAO-A is primarily found in dopaminergic, noradrenergic, and adrenergic neurons, while MAO-B is predominantly located in astrocytes. The activity of both isoforms helps maintain the neurochemical balance that affects mood. Increased MAO-B activity enhances GABA production, leading to excessive tonic inhibition, which impacts neuronal excitability and synaptic function. Furthermore, metabolism through MAO-B generates reactive oxygen species (ROS), including hydrogen peroxide, exacerbating oxidative stress and neuroinflammation. Overexpression of MAO-B and depletion of dopamine are considered pathological factors in neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease [ 137]. Conversely, MAO-B deficiency may lead to a hyperdopaminergic state and behavioral disinhibition in schizophrenia [ 138]. Importantly, skeletal muscle also exhibits significant monoamine oxidase activity, primarily MAO-B, and serves as the main source of this enzyme in healthy humans. However, under chronic stress conditions, high glucocorticoid levels and increased MAO-A expression can promote protein degradation and inhibit protein synthesis, contributing to muscle atrophy and mitochondrial damage through heightened production of reactive oxygen species [ 138]. 6.9. Calcium N-methyl-D-aspartate (NMDA) glutamate receptors are vital for excitatory synaptic transmission in the central nervous system, playing a significant role in synaptic plasticity [ 139]. In the adult brain, over 80% of neurons and more than 90% of synapses release glutamate [ 140]. NMDA receptors function as key calcium ion channels essential for learning and memory [ 139]. Voltage-gated sodium-calcium channels are crucial for the activity of cells with variable activity levels. They trigger action potentials in neurons and muscle cells, coupling plasma membrane depolarization to intracellular events such as secretion, contraction, synaptic transmission, and gene expression [ 141]. The sodium-calcium exchanger serves as a transporter, removing intracellular Ca 2+ ions by using the electrochemical gradient to exchange them for Na + ions. In astrocytes, calcium in the cytosol acts as a universal messenger, responding to various stimuli and triggering a range of cellular responses. Astrocytic calcium levels change dynamically with sleep and wake states [ 142]. During sleep, activity in the locus coeruleus is low, resulting in suppressed or absent astrocyte calcium responses. In contrast, pronounced astrocyte calcium responses, driven by norepinephrine released from the locus coeruleus, occur during locomotion [ 143]. Under conditions of high arousal, glutamate transfer to active synapses enhances local norepinephrine release from locus coeruleus axons [ 144]. Large-scale calcium waves in the aroused brain are primarily inositol trisphosphate IP3-dependent, primarily evoked by sensory input, and contribute to reliable sensory transmission. Localized calcium spikes appear to be IP3-independent and are associated with decreased extracellular potassium (K +) levels, hyperpolarization of neurons, and suppression of sensory transmission. In the aging brain, several secondary complications, such as impaired calcium signaling and stem cell depletion, lead to dysfunction in neural networks [ 66]. Calcium and phosphate signaling play fundamental roles in these processes. 7. Gut–Brain Axis Dysfunction in the Aged The gut–brain axis is a bidirectional communication network linking the enteric nervous system with the brain. It enables constant, bidirectional signaling via neural, immune, and hormonal pathways, profoundly influencing mood, digestion, and immunity [ 147]. The gut microbiota plays a crucial role in this axis, with gut health directly affecting brain function. Gut microbiota can influence the brain, neurochemistry, physiology, and behavior [ 49]. The microbiota plays a role in this process, in part by generating short-chain fatty acids, which help regulate microglial homeostasis and are essential for their maturation and function [ 148]. Human studies have shown a link between ir
