Melatonin and the coordination of biological rhythms

Among all the functions attributed to melatonin, the one related to sleep is certainly the best known. However, defining melatonin simply as a hormone that promotes falling asleep would be reductive. Scientific evidence shows that this molecule plays a much more complex role, contributing to the regulation of the entire sleep architecture and the synchronization of the biological rhythms that govern the alternation between wakefulness and rest.

To understand its function, it is useful to imagine sleep as an orchestra composed of numerous musicians. Each instrument represents a different physiological system: the brain, metabolism, the endocrine system, the immune system, and the autonomic nervous system. Melatonin does not produce the music directly, but acts as the conductor who coordinates the exact moment each section must enter into action. When this coordination fails, sleep tends to become more fragmented, less efficient, and less restorative.

Clinical evidence gathered in recent years confirms this interpretation increasingly convincingly. A vast systematic review with meta-analysis that included twenty-three randomized controlled clinical trials demonstrated that melatonin supplementation significantly improves overall sleep quality in adults. Benefits have been observed in numerous clinical conditions, with effects particularly evident in subjects suffering from respiratory diseases, metabolic disorders, and primary sleep disorders. The analysis also showed a significant reduction in Pittsburgh Sleep Quality Index scores, indicating a clinically relevant improvement in the perceived quality of nocturnal rest. One of the most interesting aspects emerging from this meta-analysis concerns the fact that the improvement does not affect a single sleep parameter. Melatonin seems to act simultaneously on multiple dimensions of nocturnal rest, favoring faster sleep onset, better sleep continuity, and a reduction in nocturnal fragmentation. This suggests that its role is not limited to sleep induction, but involves the entire temporal organization of rest (Fatemeh et al., 2022) [7].

Particularly interesting confirmation comes from patients suffering from COMISA, a condition characterized by the coexistence of chronic insomnia and obstructive sleep apnea. This association is very frequent in clinical practice and represents one of the most complex forms of sleep disorder. The continuous micro-awakenings caused by apnea episodes profoundly alter the quality of rest, while insomnia in turn contributes to worsening sleep stability. In a randomized, placebo-controlled trial, the administration of 10 mg of melatonin for four weeks resulted in a marked improvement in sleep quality, a significant reduction in insomnia severity, and a decrease in daytime sleepiness. Patients also showed better adherence to CPAP therapy, an element particularly important for the control of sleep apnea (Motlaq et al., 2024) [8].

These results are particularly relevant because they demonstrate that melatonin does not act exclusively during the night. By improving sleep quality, it produces positive effects during the day as well, reducing fatigue, improving alertness, and promoting better functionality in daily activities. In other words, the benefit concerns not only sleeping better, but also living better during waking hours.

Another population in which melatonin has attracted great interest is that of patients suffering from Parkinson's disease. Sleep disorders represent one of the most frequent non-motor manifestations of the disease and can appear many years before the typical motor alterations. A recent meta-analysis that included randomized controlled trials highlighted that melatonin significantly improves sleep quality and reduces daytime sleepiness in subjects with Parkinson's. The best results were observed with dosages above 4 mg, with immediate-release formulations, and with relatively short-duration treatments. The data also suggest that the therapeutic response may depend on both the dose used and the pharmacokinetic characteristics of the formulation employed (Zrineh et al., 2025) [9].

The evidence in favor of melatonin does not only concern the adult population. In children with neurodevelopmental disorders, including autism, intellectual disabilities, and other neurological conditions, sleep onset problems represent one of the main causes of stress for the child and the entire family unit. The MENDS study, one of the largest randomized controlled trials conducted in the pediatric field, demonstrated that immediate-release melatonin significantly reduces the time required to fall asleep. On average, treated children fell asleep about forty-five minutes earlier than subjects who received a placebo. The increase in total sleep duration was more modest, suggesting that the main effect of melatonin is linked primarily to sleep onset rather than its prolongation (Appleton et al., 2012) [10].

This observation is particularly important because it helps to understand the true physiological nature of melatonin. Unlike traditional hypnotic drugs, which tend to force the body into a state of sedation, melatonin seems to facilitate the correct initiation of the biological processes that naturally lead to sleep. Once this process has begun, the maintenance and depth of rest depend on numerous other neurobiological systems.

Similar benefits have also been observed in the hospital setting. Hospitalization is indeed a particularly unfavorable condition for sleep due to noise, care procedures, pain, psychological stress, and alterations in normal circadian rhythms. A study conducted on hospitalized patients highlighted that evening administration of melatonin significantly improves sleep duration, reduces the time required to fall asleep, decreases the number of nocturnal awakenings, and increases the subjective quality of rest. These results take on particular relevance if one considers that sleep represents one of the main tools through which the body supports recovery and healing processes during illness (Ren et al., 2025) [11].

Considering the available evidence as a whole, an extremely coherent picture emerges. Melatonin should not be considered simply as a substance that induces sleep, but as a biological regulator capable of coordinating multiple aspects of nocturnal rest. Its effects are observed in very different populations—subjects with insomnia, patients with obstructive sleep apnea, people suffering from Parkinson's disease, children with neurodevelopmental disorders, and hospitalized patients—suggesting the existence of a common physiological mechanism. In all these contexts, melatonin seems to favor better synchronization of the processes that govern the transition from wakefulness to sleep, contributing to making rest more stable, more efficient, and more restorative.

Understanding the physiology of melatonin also means understanding the mechanisms through which this molecule communicates with cells. Like any hormone or signaling molecule, melatonin does not act alone. To exert its effects, it must be recognized by specific cellular structures capable of interpreting its message and translating it into a biological response. These structures are melatonin receptors, primarily identified as the MT1 and MT2 subtypes.

For many years, it was believed that both receptors performed substantially overlapping functions. More recent research, however, has revealed a much more complex reality. Although MT1 and MT2 are activated by the same molecule, they appear to participate in different and, in some cases, even opposite processes. This discovery has profoundly changed our understanding of the neurobiology of sleep and has opened new therapeutic perspectives for the treatment of sleep-wake rhythm disorders (Gobbi and Comai, 2019) [12]; (Gobbi and Comai, 2019) [13]; (Comai and Gobbi, 2024) [15].

The MT1 receptor belongs to the family of G protein-coupled receptors (proteins that transmit signals within cells) and is expressed in numerous brain areas involved in the regulation of sleep and circadian rhythms. Its presence has been documented in the suprachiasmatic nucleus (a small area of the brain located in the hypothalamus), the body's main biological clock, but also in the lateral hypothalamus, the pons, the amygdala, and the hippocampus. This anatomical distribution suggests that MT1 is not simply involved in receiving the melatonergic signal, but participates directly in the neurobiological organization of sleep (Comai and Gobbi, 2024) [15].

To understand the role of this receptor, one can imagine melatonin as a communication sent every evening by the central biological clock. The MT1 receptor represents one of the main recipients of this message. When activated, a series of cellular and neuronal modifications are triggered that progressively prepare the brain for the transition from wakefulness to sleep.

The first indications of the specific role of MT1 emerged from studies conducted on genetically modified animal models. Through the selective elimination of the gene responsible for producing the receptor, researchers were able to observe the consequences of its absence. The results showed that mice lacking the MT1 receptor exhibit a significant reduction in REM sleep, the phase of sleep associated with intense dream activity, memory consolidation, and emotional regulation (Comai et al., 2013) [14].

This observation became even more significant when researchers analyzed brain electrical activity during sleep. In animals lacking MT1, a reduction in theta oscillations (rhythmic electrical waves produced by brain neurons) was documented during REM sleep. Theta waves represent one of the main neurophysiological signatures of this sleep phase and participate in the processes of memory consolidation and the reorganization of information acquired during the day. Their reduction suggests that MT1 influences not only the quantity of REM sleep but also the functional quality of this phase (Comai et al., 2013) [14].

Evidence collected subsequently has progressively strengthened the hypothesis that the MT1 receptor plays a fundamental role in the stabilization of REM sleep. Several literature reviews have highlighted how the activation of MT1 is associated with the consolidation of REM phases and the modulation of the neuronal circuits that regulate their onset and maintenance throughout the night (Gobbi and Comai, 2019) [12]; (Gobbi and Comai, 2019) [13]; (Comai and Gobbi, 2024) [15].

Another aspect of great interest concerns the relationship between MT1 and circadian regulation. Numerous pieces of evidence suggest that this receptor participates in the mechanisms through which the suprachiasmatic nucleus synchronizes the body's biological functions with the light-dark environmental cycle. In other words, MT1 could represent one of the main connection points between temporal information coming from the environment and the internal organization of sleep (Gobbi and Comai, 2019) [13]; (Comai and Gobbi, 2024) [15].

Observations from knockout models further reinforce this interpretation. Animals lacking MT1 show not only alterations in REM sleep but also greater sleep fragmentation, a reduction in the continuity of rest, and less stability in circadian organization. These results suggest that the receptor contributes to maintaining a stable and physiologically efficient sleep structure (Comai and Gobbi, 2024) [15].

From a therapeutic point of view, these discoveries have opened particularly interesting perspectives. Most currently available preparations activate both MT1 and MT2 simultaneously. However, if the two receptors perform different functions, it becomes plausible to imagine drugs capable of acting selectively on only one of the two targets. In this perspective, specific MT1 agonists could be useful in conditions characterized by REM sleep alterations, sleep fragmentation, and difficulty in initiating the physiological processes that lead to nighttime rest (Gobbi and Comai, 2019) [12]; (Gobbi and Comai, 2019) [13]; (Comai and Gobbi, 2024) [15].

Overall, the available evidence outlines the MT1 receptor as much more than a simple mediator of melatonin's effects. It appears as a sophisticated neurobiological regulator that connects the temporal signal of the night to the organization of sleep phases, the stability of alertness, and the control of the neuronal circuits involved in REM sleep. This modern view allows us to understand how melatonin does not act simply by inducing sleep, but by orchestrating a complex network of biological signals that prepare the brain and the body for nighttime rest.

To fully understand how melatonin influences sleep, it is necessary to delve into one of the most important neurobiological systems involved in the regulation of alertness: the locus coeruleus–noradrenaline system. If melatonin can be imagined as the signal announcing the arrival of night, the locus coeruleus represents one of the main brain centers that decide how alert, attentive, and ready to react to environmental stimuli the brain should remain.

The locus coeruleus is a small nucleus located in the brainstem that, despite its small size, exerts an extraordinarily broad influence on the entire central nervous system. Its neurons produce noradrenaline, a neurotransmitter fundamental for attention, alertness, memory, stress response, and the maintenance of the waking state. In recent decades, it has emerged that the locus coeruleus–noradrenaline system constitutes one of the main regulators of the sleep-wake cycle, participating not only in the maintenance of alertness but also in the organization of the different stages of sleep (Van Egroo et al., 2022) [17].

Electrophysiological recordings have shown that the activity of locus coeruleus neurons varies continuously throughout the day. During active wakefulness, the firing rate is high, allowing the brain to maintain high levels of attention and reactivity. As sleep approaches, noradrenergic activity decreases progressively, reaching even lower levels during non-REM sleep. The situation changes radically during REM sleep, when the neurons of the locus coeruleus become almost completely silent and extracellular levels of noradrenaline plummet to the lowest values observable in the entire sleep-wake cycle (Van Egroo et al., 2022) [17].

For many years, it was believed that the locus coeruleus was simply "turned off" during sleep. However, modern noradrenaline monitoring technologies have profoundly changed this view. Today we know that during non-REM sleep, the noradrenergic system continues to function through extremely precise rhythmic oscillations that contribute to the organization of sleep architecture. Noradrenaline levels rise and fall cyclically every thirty to fifty seconds, synchronizing with fundamental phenomena such as sleep spindles (brief electrical waves produced by the brain during light sleep), slow cortical oscillations, and heart rate variations. This behavior suggests that the locus coeruleus is not simply a wakefulness center, but a sophisticated regulator of sleep quality itself (Osorio-Forero et al., 2022) [20].

One of the most interesting aspects concerns the role of noradrenaline in memory consolidation. During non-REM sleep, the controlled oscillations of the noradrenergic system seem to favor synaptic plasticity and the transfer of information from the hippocampus to the cerebral cortex. Subsequently, during REM sleep, the almost complete disappearance of noradrenaline creates a completely different neurochemical environment that favors the reorganization of neuronal connections and the processing of emotional information accumulated during the day. This drastic reduction of noradrenaline during REM sleep does not represent a simple side effect of sleep, but a biological condition necessary for the brain to properly enter this phase. The most recent observations have in fact shown that the drop in noradrenaline levels begins several seconds before the start of a REM episode. In other words, the silencing of the locus coeruleus seems to represent one of the events that prepare the brain for entry into REM sleep (Osorio-Forero et al., 2022) [20].

In this context, the direct link with melatonin and the MT1 receptor described in the previous paragraph emerges. A study published in 2024 demonstrated that the selective activation of MT1 receptors present on the noradrenergic neurons of the locus coeruleus reduces their electrical activity in a dose-dependent manner. This inhibition translates into a significant increase in REM sleep without altering non-REM sleep. When researchers pharmacologically blocked the MT1 receptor or genetically silenced its expression in the neurons of the locus coeruleus, the effect disappeared completely. This result provided one of the strongest pieces of evidence that melatonin can directly modulate the noradrenergic system through the MT1 receptor, facilitating the onset of REM sleep (López-Canul et al., 2024) [19].

This discovery allows for a better understanding of the role of melatonin in sleep physiology. Rather than acting as a simple sleep inducer, melatonin seems to intervene in specific neuronal circuits that control the transition between different states of alertness. Through the activation of MT1 receptors present in the locus coeruleus, it contributes to progressively reducing noradrenergic activity, creating the neurochemical conditions necessary for entry into REM sleep (López-Canul et al., 2024) [19].

The importance of the locus coeruleus emerges with particular evidence when sleep is chronically altered. An experimental study that simulated a condition very similar to that experienced by many people in modern life—a few days of insufficient sleep followed by short recovery periods—documented surprising consequences. After several weeks of intermittent reduced sleep, the animals showed a significant loss of noradrenergic neurons in the locus coeruleus, accompanied by persistent alterations of the sleep-wake cycle, reduction of neuronal projections, and biological markers compatible with accelerated cellular aging processes (Zhu et al., 2016) [18].

The vulnerability of the locus coeruleus to sleep loss is also confirmed by studies that have analyzed selective REM sleep deprivation. In these conditions, an increase in oxidative stress, apoptotic activation, and degeneration of noradrenergic neurons is observed. However, the administration of melatonin after sleep deprivation was found to be able to significantly counteract these phenomena. Researchers observed an increase in reduced glutathione levels, a decrease in caspase-3 activation, and a preservation of the noradrenergic neuronal population of the locus coeruleus. In other words, melatonin did not just promote sleep, but showed a true neuroprotective action toward one of the most important systems for the regulation of alertness (Jameie et al., 2019) [16].

This observation takes on particular relevance when considering that the locus coeruleus is now recognized as one of the first brain structures involved in neurodegenerative processes associated with aging and Alzheimer's disease. Numerous pieces of evidence suggest that the accumulation of pathological alterations in this region may begin many years before the appearance of cognitive symptoms. In parallel, chronic sleep fragmentation accelerates the loss of noradrenergic neurons and favors the accumulation of pathological proteins such as tau and β-amyloid, establishing a vicious cycle between sleep deterioration and neurodegeneration (Van Egroo et al., 2022) [17].

Overall, the available evidence describes the locus coeruleus–noradrenaline system as one of the main orchestrators of sleep physiology. Its activity regulates transitions between wakefulness and sleep, contributes to memory consolidation, coordinates important autonomic functions, and participates in neuroprotective processes that keep the brain efficient throughout life. Melatonin, through its interaction with the MT1 receptors present in the noradrenergic neurons of the locus coeruleus, seems to fit directly into this regulatory network, contributing not only to the organization of REM sleep but also to the long-term protection of one of the most important neuronal systems for brain health.

In the previous paragraph, we saw how the locus coeruleus represents one of the main brain centers responsible for the production of norepinephrine and the regulation of alertness. However, to fully understand how this system functions, it is necessary to go upstream and identify what controls the activity of the locus coeruleus itself. Research over the last few decades has shown that one of its most important regulators is a small group of neurons located in the lateral hypothalamus: the neurons that produce orexin, also known as hypocretin.

The discovery of orexin has profoundly changed our understanding of sleep physiology. Initially, this neuropeptide was primarily associated with the control of appetite and energy balance. Over the years, however, it has emerged that its main function is to coordinate the organism's state of alertness with its current biological needs. Orexinergic neurons act as a sort of integration center that collects information from metabolism, emotions, the reward system, and the external environment, transforming it into signals capable of modulating the level of brain activation (Sakurai, 2007) [24].

This function appears particularly logical from an evolutionary perspective. An organism that is in a state of energy deficiency, that perceives danger, or that must actively search for food resources cannot afford to reduce its level of alertness. In these circumstances, the orexinergic system increases its activity, favoring a state of sustained attention and promoting survival-oriented behaviors. Conversely, during sleep, and particularly during REM sleep, the activity of orexin neurons decreases drastically (Sakurai, 2007) [24].

Despite the relatively small number of orexinergic neurons present in the lateral hypothalamus, their projections reach numerous brain regions involved in the regulation of alertness. Among all these structures, the locus coeruleus is likely the most important target. Neuroanatomical analyses have shown that the locus coeruleus receives one of the densest orexinergic innervations in the entire brain. Fibers originating from the lateral hypothalamus form numerous direct excitatory synapses on the noradrenergic neurons of the locus coeruleus, creating an extremely robust anatomical connection between the two systems (Horvath et al., 1999) [21].

Electron microscope observations have highlighted that practically all noradrenergic neurons of the locus coeruleus receive synaptic contacts from terminals containing orexin. Even more interesting is the fact that these synapses exhibit characteristics typical of excitatory connections, suggesting that the orexinergic system is designed to directly increase the activity of locus coeruleus neurons; subsequent electrophysiological recordings have confirmed this hypothesis. When orexin is applied directly to locus coeruleus neurons, their firing rate increases rapidly and consistently. This effect is the result of both cell membrane depolarization and a reduction in the mechanisms that normally limit neuronal excitability. In other words, orexin makes noradrenergic neurons more active and more prone to maintaining high levels of alertness (Horvath et al., 1999) [21].

These results were further confirmed by subsequent studies that analyzed the role of orexin A, one of the two main biologically active forms of the peptide. Microinjections of orexin A directly into the locus coeruleus result in a marked increase in wakefulness, accompanied by a significant reduction in REM sleep and deep sleep. In some experiments, the increase in the state of wakefulness reached values exceeding 70%, demonstrating the extraordinary power of this neuronal activation system; it is particularly interesting that these effects are mediated primarily by the orexin receptor type 1 (OX1R). This suggests that communication between the lateral hypothalamus and the locus coeruleus occurs through a highly specialized mechanism, optimized to rapidly promote the state of wakefulness when physiological conditions require it (Hagan et al., 1999) [22].

The role of the orexin–locus coeruleus circuit emerges with particular clarity when analyzing the transitions between wakefulness and REM sleep. As seen in the previous paragraph, the locus coeruleus is practically silent during REM sleep. Orexinergic activation, on the other hand, produces the opposite effect: it increases the activity of noradrenergic neurons and makes entering this phase of sleep more difficult. A study specifically dedicated to this phenomenon demonstrated that local administration of orexin A in the locus coeruleus suppresses REM sleep in a dose-dependent manner, while simultaneously increasing the duration of wakefulness. This effect is accompanied by marked neuronal activation documented both electrophysiologically and through the increased expression of a specific protein (Bourgin et al., 2000) [23].

These observations have helped clarify one of the mechanisms through which the brain stabilizes behavioral states. When the orexinergic system is active, the locus coeruleus continues to produce norepinephrine, keeping the level of arousal high and preventing the intrusion of REM phenomena during wakefulness. When orexinergic activity decreases, as occurs physiologically during the night, the locus coeruleus can progressively diminish its activity, favoring the transition to the different phases of sleep (Bourgin et al., 2000) [23].

The importance of this circuit becomes even more evident when observing what happens in narcolepsy (a neurological sleep disorder that causes severe daytime sleepiness). This pathology is characterized by the selective loss of orexinergic neurons in the lateral hypothalamus. In the absence of the stabilizing action of orexin, the brain loses the ability to maintain a clear separation between sleep and wakefulness. Consequently, daytime sleepiness, sleep fragmentation, and REM phenomena that inappropriately break through during wakefulness occur, as happens in episodes of cataplexy (a sudden and temporary loss of muscle strength) (Sakurai, 2007) [24].

A particularly elegant study allowed for the identification of the main circuits responsible for these phenomena. By selectively restoring orexinergic signaling in different neuronal populations of narcoleptic mouse models, researchers observed that the recovery of orexin transmission in the noradrenergic neurons of the locus coeruleus significantly improves the consolidation of wakefulness. The effect was directly proportional to the number of locus coeruleus neurons in which sensitivity to orexin had been restored. This result demonstrated that the locus coeruleus represents one of the main effectors through which the orexinergic system maintains a continuous and stable state of alertness (Hasegawa et al., 2014) [25].

Taken together, these findings describe the lateral hypothalamus as a sort of command center capable of continuously modulating the organism's level of alertness. Through the release of orexin, it activates the locus coeruleus, increases the production of norepinephrine, and supports the state of wakefulness when the organism must remain attentive to the surrounding environment. This system represents the physiological counterweight to the mechanisms that promote sleep described in the previous paragraphs. On one hand, melatonin and the MT1 receptor contribute to reducing the activity of the locus coeruleus and facilitating REM sleep; on the other, orexin exerts an opposite action, stimulating noradrenergic neurons and promoting alertness. The delicate balance between these opposing forces allows the brain to alternate between states of sleep and wakefulness in an orderly and stable manner.

In the previous paragraphs, we saw how the locus coeruleus and the orexinergic system represent some of the main promoters of alertness. However, a fundamental question remains: how does melatonin, the biological signal of the night, manage to counteract these powerful brain activation systems and promote sleep?

For many years, the answer remained incomplete. It was known that melatonin promoted sleep and that orexin supported wakefulness, but the direct link between these two neurobiological systems had not yet been clarified. More recent research, however, has identified an important anatomical and functional meeting point within the perifornical lateral hypothalamus, a region that houses most of the orexinergic neurons responsible for maintaining the state of alertness (Sharma et al., 2018) [26].

To understand the importance of this discovery, it is useful to remember that orexin neurons function as a sort of accelerator of consciousness. When active, they stimulate numerous arousal systems, including the locus coeruleus, the serotonergic raphe nuclei, the cholinergic systems of the brainstem, and other structures involved in alertness. Through these diffuse connections, they contribute to maintaining the brain in a state of activation that is stable and consistent with the demands of the surrounding environment (Hung and Yamanaka, 2023) [27].

Modern immunofluorescence techniques have shown that these neurons express MT1 receptors for melatonin. This observation suggests that the melatonergic system can exert direct control over the main wake-promoting neurons through a highly selective mechanism. Experimental verification of this hypothesis has produced particularly interesting results. When melatonin is administered directly into the perifornical lateral hypothalamus, a significant increase in non-REM sleep is observed, accompanied by a reduction in wakefulness. In parallel, the activity of orexinergic neurons decreases drastically, as demonstrated by the marked reduction in the expression of the neuronal marker c-Fos (a protein used as a marker of neuronal activation). In other words, melatonin seems to literally turn down the volume of one of the main brain systems responsible for maintaining alertness (Sharma et al., 2018) [26].

Particularly significant is the fact that the opposite effect is observed when melatonergic signaling is blocked. Pharmacological inhibition of melatonin receptors in the lateral hypothalamus indeed leads to an increase in wakefulness and a reduction in sleep propensity. This result suggests that the control exerted by melatonin over orexin neurons does not represent an artificial phenomenon observable only in the laboratory, but constitutes a physiological mechanism normally active during the night (Sharma et al., 2018) [26].

This discovery has helped to redefine how the action of melatonin is interpreted. For a long time, it was imagined that the hormone acted primarily as a circadian signal capable of informing the brain of the arrival of night. Today, it appears increasingly evident that melatonin also plays an active role in the modulation of the neuronal circuits that govern states of consciousness. In this perspective, sleep would not result solely from the presence of a favorable temporal signal, but also from the progressive deactivation of the systems that support wakefulness.

The importance of this mechanism becomes even more evident by observing the physiological behavior of orexinergic neurons during the sleep-wake cycle. Electrophysiological recordings and modern imaging techniques have shown that these neurons reach maximum activity during active wakefulness, exploration of the environment, exposure to new stimuli, and motivated behaviors. Conversely, their activity decreases progressively during quiet wakefulness and becomes minimal during non-REM sleep. This trend suggests that the inhibition of orexin represents one of the fundamental steps that allow the brain to transition from alertness to sleep (Hung and Yamanaka, 2023) [27].

Genetic evidence further reinforces this interpretation. Animal models lacking orexin or its receptors show a marked instability of states of consciousness, with fragmentation of wakefulness, episodes of early REM sleep, and manifestations similar to human narcolepsy. These observations demonstrate that the orexinergic system represents one of the main mechanisms through which the brain maintains the continuity of the state of wakefulness (Hung and Yamanaka, 2023) [27].

From this perspective, a particularly elegant picture of sleep physiology emerges. During the day, the activity of orexinergic neurons helps to support alertness and activate systems such as the locus coeruleus and noradrenergic transmission. With the arrival of the night, the increase in melatonin secretion allows this activity to be progressively reduced through the MT1 receptors expressed on orexin neurons. The decrease in orexinergic activity therefore translates into less stimulation of arousal systems, facilitating the entry into sleep and its stabilization (Sharma et al., 2018) [26].

The clinical importance of this relationship has also been confirmed by recent pharmacological studies. The observation that melatonin receptor agonists and orexin receptor antagonists produce similar benefits in various pathological conditions suggests that both therapeutic approaches may converge on the same neurobiological circuits. In a study conducted on elderly patients hospitalized for stroke, the early administration of a melatonin receptor agonist or orexin receptor antagonists was associated with a significant reduction in the incidence of delirious symptoms. The authors hypothesized that this benefit derives at least in part from the improvement in sleep quality and the normalization of the sleep-wake rhythm, confirming the importance of the balance between the melatonergic system and the orexinergic system in the stability of cognitive functions (Miyoshi et al., 2024) [28].

These observations open up particularly interesting therapeutic perspectives. If melatonin promotes sleep by reducing the activity of orexin neurons and if orexinergic receptor antagonists produce similar clinical effects through a different mechanism, it becomes plausible to consider these two systems as complementary parts of the same biological network. In such a model, melatonin would represent the physiological signal that communicates the arrival of the night, while orexin would constitute the main system that must be progressively silenced so that sleep can emerge in a stable and effective way.

Overall, the available evidence indicates that the relationship between melatonin and orexin represents one of the main meeting points between the circadian system and the neuronal circuits of alertness. Through the activation of MT1 receptors present in the lateral hypothalamus, melatonin appears to directly inhibit one of the most powerful promoters of wakefulness present in the brain. This mechanism allows the biological signal of the night to be linked to the reduction of neuronal arousal, creating the necessary conditions for sleep to develop in a physiological and coordinated manner.

Up to this point, we have followed the path of melatonin within the brain circuits that regulate sleep, observing how it interacts with the locus coeruleus, norepinephrine, and the orexinergic system of the lateral hypothalamus. At this stage, a common misconception might arise: imagining that MT1 receptors are confined almost exclusively to the brain and that their primary function is to regulate sleep. In reality, research in recent years has revealed a much more fascinating and complex reality. MT1 receptors are distributed across numerous organs and tissues of the body and participate in the regulation of biological processes involving metabolism, the cardiovascular system, immunity, endocrine function, and even cellular protection against oxidative stress (Jockers et al., 2016) [29]; (Slominski et al., 2012) [31].

From a structural standpoint, the MT1 receptor belongs to the large family of G protein-coupled receptors. When melatonin binds to this receptor, a cascade of intracellular signals is activated, modifying the cell's behavior. Among the most important effects are the reduction of intracellular levels of cyclic AMP (a molecule that transmits signals within cells, regulating important functions), the modulation of protein kinases (enzymes that regulate the activity of other proteins by adding phosphate groups), the control of ion fluxes (the movement of electrically charged particles (ions) across the cell membrane), and the regulation of gene expression. In some tissues, the receptor can also activate the phospholipase C pathway (an enzyme that transforms certain cell membrane fats into chemical signals) and protein kinase C, further expanding the variety of possible biological responses (Jockers et al., 2016) [29]; (Tripathy and Bhattamisra, 2025) [33].

One of the peripheral systems richest in melatonergic signaling is the gastrointestinal tract. For many years, it was believed that the pineal gland was the body's main source of melatonin. Today, we know that the gut produces extremely high quantities of melatonin, often exceeding those present in the bloodstream. Studies conducted on human tissues have identified the MT1 receptor throughout the entire gastrointestinal tract, including the intestinal epithelium, the myenteric plexus, the submucosal plexus (a network of neurons located between the muscle layers of the intestine), and the vascular structures of the intestinal wall (Söderquist et al., 2015) [30].

This distribution suggests that melatonin participates directly in the regulation of intestinal motility, digestive secretion, barrier function, and communication between the enteric nervous system and the digestive tract. In other words, the gastrointestinal tract does not represent merely a target organ for melatonin, but a true peripheral melatonergic system endowed with significant functional autonomy (Söderquist et al., 2015) [30]; (Slominski et al., 2012) [31].

Particularly interesting is the presence of MT1 receptors in the endocrine pancreas as well. Cells of the pancreatic islets, in fact, express complete components of melatonergic signaling. This observation has attracted the attention of researchers because it directly links melatonin to the control of glucose metabolism. Through its receptors, melatonin contributes to the modulation of insulin secretion and the circadian synchronization of energy metabolism. Alterations in melatonergic signaling have been associated with insulin resistance, impaired β-cell function, and an increased risk of type 2 diabetes (Söderquist et al., 2015) [30]; (Tripathy and Bhattamisra, 2025) [33].

The cardiovascular system also possesses significant expression of MT1 receptors. These receptors have been identified in the wall of blood vessels, both in smooth muscle cells and in the endothelium. Research indicates that MT1 activation is generally associated with vasoconstrictor phenomena mediated by the reduction of cyclic AMP and the modulation of calcium-dependent potassium channels. This mechanism contributes to the fine-tuning of vascular tone and blood pressure, integrating circadian signals with the hemodynamic needs of the body (da Rocha-Carvalho et al., 2025) [32]; (Slominski et al., 2012) [31].

Interest in these effects has increased upon observing that MT1 receptor expression tends to decrease with aging and in various pathological cardiovascular conditions. Some researchers have hypothesized that the progressive loss of sensitivity to melatonin may contribute to age-related vascular alterations, promoting endothelial dysfunction, increased arterial stiffness, and reduced capacity to adapt to circadian rhythms (da Rocha-Carvalho et al., 2025) [32].

Another particularly relevant area concerns the immune system. Numerous immune cells express MT1 receptors and respond directly to the presence of melatonin. Through these mechanisms, melatonin can influence lymphocyte proliferation, cytokine production, and the regulation of inflammatory responses. In particular, the MT1 receptor appears to be involved in the modulation of adaptive immunity, contributing to the production of interleukin-2 (a protein of the immune system that stimulates the growth and multiplication of T lymphocytes) and the control of T lymphocyte activity (Jockers et al., 2016) [29]; (Slominski et al., 2012) [31].

The peripheral distribution of MT1 also extends to the kidney, bone tissue, skin, reproductive organs, and the placenta. In the kidney, it contributes to the regulation of hydro-electrolytic homeostasis and protection against inflammatory processes. In bone tissue, it promotes osteoblast activity and the maintenance of skeletal mass. In the skin, it participates in protection against oxidative stress and the regulation of cell proliferation. During pregnancy, the presence of melatonergic receptors in the placenta and uterus contributes to fetal protection and the regulation of gestational processes (Slominski et al., 2012) [31].

An aspect that is sparking growing interest concerns the role of MT1 receptors in chronic diseases. Alterations in receptor expression have been observed in Alzheimer's disease, Parkinson's disease, Huntington's disease, and some neurodevelopmental disorders. In many of these conditions, alterations in sleep, circadian rhythms, and metabolic function are observed simultaneously, suggesting that dysfunction of melatonergic signaling may contribute to disease progression (Jockers et al., 2016) [29].

Overall, the body of available evidence profoundly changes the traditional image of melatonin as a simple sleep hormone. The MT1 receptor emerges, in fact, as a component of a vast biological network distributed throughout the body. Through its presence in the brain, gut, pancreas, blood vessels, immune system, and numerous other tissues, it helps coordinate functions ranging from circadian regulation to energy metabolism, and from immunity to cellular protection. This systemic view allows us to understand how the nocturnal signal of melatonin is not destined exclusively for the brain, but represents a global biological message capable of synchronizing the entire organism with the rhythm of the day.

To fully understand many of the functions attributed to melatonin, it is necessary to introduce a biological process fundamental to cellular survival: autophagy. The term derives from Greek and literally means "self-eating," but this definition can be misleading. Autophagy is not a self-destructive mechanism, but rather an extraordinary internal maintenance system through which the cell identifies, sequesters, and degrades damaged components, misfolded proteins, and non-functional organelles, subsequently reusing their constituents to produce new cellular structures (Coto-Montes et al., 2012) [34]; (Boga et al., 2019) [35].

This process could be compared to what happens in a well-organized city. Every day, waste is collected, damaged materials are removed, and useful raw materials are recovered for new construction. If this collection and recycling system were to stop, the streets would progressively fill with debris, compromising the functioning of the entire city. Similarly, when autophagy is impaired, cells accumulate damaged structures that promote inflammation, metabolic dysfunction, aging, and disease (Coto-Montes et al., 2012) [34].

In recent years, it has emerged that melatonin is one of the most important physiological regulators of this system. Initially, it was believed that its role was limited to the direct neutralization of free radicals and the regulation of the sleep-wake cycle. More recent evidence has shown that melatonin intervenes at a much deeper level, coordinating numerous cellular mechanisms involved in intracellular quality control (Boga et al., 2019) [35]; (Lei et al., 2024) [38].

One of the elements that closely links melatonin and autophagy is oxidative stress. During normal cellular metabolism, reactive oxygen species—commonly called ROS—are continuously generated. In physiological amounts, these molecules perform important signaling functions. However, when their production exceeds the cell's defensive capacity, damage to proteins, lipids, DNA, and mitochondria accumulates. Under these conditions, autophagy is activated as an emergency mechanism to eliminate compromised structures and restore cellular homeostasis (Coto-Montes et al., 2012) [34]; (Lei et al., 2024) [38].

Melatonin actively participates in this process through numerous molecular pathways. Among the most important are the activation of AMPK, one of the main cellular energy sensors, and the inhibition of mTOR, a protein that normally suppresses autophagy when energy resources are abundant. Through this regulation, melatonin promotes the activation of ULK1 (a protein that initiates autophagy) and the start of autophagosome formation, the structures that engulf the material to be degraded (Qiu et al., 2026) [40]; (Zhu et al., 2025) [39].

Among the various forms of autophagy, one of the most important is mitophagy, a selective process dedicated exclusively to the removal of damaged mitochondria. Mitochondria constitute the main energy powerhouses of the cell, but they are also one of the largest intracellular sources of free radicals. When they become dysfunctional, they can transform from energy producers into generators of cellular damage. For this reason, the organism has developed sophisticated mitochondrial quality control systems that allow for the selective elimination of compromised organelles and their replacement with new, functional mitochondria (Coto-Montes et al., 2012) [34]; (Lei et al., 2024) [38].

The most recent evidence suggests that melatonin plays a particularly important role in mitochondrial quality control. In addition to directly protecting mitochondria from oxidative damage, it regulates mitochondrial fusion and fission, promotes the biogenesis of new organelles, and stimulates mitophagy through specific systems. This coordinated set of mechanisms allows for the preservation of cellular energy efficiency and limits the accumulation of dysfunctional structures (Lei et al., 2024) [38]; (Zhu et al., 2025) [39].

A particularly fascinating aspect that has emerged from research is that melatonin does not act as a simple switch that always activates autophagy. On the contrary, it acts as an adaptive regulator: when the autophagic flux is insufficient and the cell accumulates damaged structures, melatonin tends to enhance it; when, however, autophagy becomes excessive and risks turning into a self-destructive mechanism, melatonin can limit it. In other words, its goal is not to increase or reduce autophagy indiscriminately, but to maintain the optimal balance necessary for cellular survival (Boga et al., 2019) [35]; (Zhu et al., 2025) [39]; (Lei et al., 2024) [38].

This bidirectional nature appears particularly evident in the nervous system. Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterized by the progressive accumulation of aggregated proteins and damaged mitochondria. In these contexts, melatonin promotes autophagy and mitophagy, facilitating the removal of pathological structures, improving mitochondrial function, and reducing neuroinflammation. In other neurological scenarios, however, excessive activation of autophagy can contribute to neuronal death; in such conditions, melatonin appears to exert a moderating effect, helping to restore cellular balance (Zhu et al., 2025) [39]; (Boga et al., 2019) [35].

The same regulatory capacity has been observed in the liver. In a mouse model of steatohepatitis associated with obesity and chronic intermittent hypoxia—a condition frequently observed in subjects suffering from obstructive sleep apnea syndrome—melatonin reduced liver damage by restoring autophagic activity. The recovery of autophagic flux was associated with a reduction in inflammation, an improvement in liver structure, and a slower progression of metabolic disease (Ren et al., 2019) [36].

Bone tissue also seems to benefit from this regulation. In models of diabetic osteoporosis, chronic hyperglycemia compromises the regenerative capacity of mesenchymal stem cells (immature cells capable of transforming into different types of cells, such as those of bone, cartilage, and adipose tissue) and promotes a persistent inflammatory state. Melatonin was found to be capable of activating the NRF2-autophagy pathway, reducing oxidative stress, and promoting the polarization of macrophages toward the anti-inflammatory M2 phenotype. This change in the cellular microenvironment favored osteogenic differentiation and improved bone formation (Zhang et al., 2026) [41].

Particularly interesting is the role of autophagy in oncology as well. Tumor cells frequently use autophagic mechanisms to survive in hostile environments characterized by nutrient deficiency, hypoxia, and metabolic stress. In some contexts, melatonin appears to exploit this very system to counteract neoplastic growth. In neuroblastoma cells, for example, it induces a form of cytotoxic autophagy through the activation of the Pak2/AMPK/mTOR axis and the modulation of endoplasmic reticulum stress, contributing to the suppression of tumor growth (Qiu et al., 2026) [40].

Similar results have been observed in colorectal carcinoma. In this model, melatonin increases the production of reactive oxygen species, activates the endoplasmic reticulum stress response, and induces the expression of specific autophagic proteins. Modifications of the AMPK and PI3K/AKT/mTOR pathways have also emerged. The final outcome is an activation of autophagy associated with the death of tumor cells, suggesting a possible role for melatonin as an adjuvant in oncological therapeutic strategies (Chok et al., 2021) [37].

Overall, the currently available evidence shows that melatonin represents much more than a simple sleep regulator. Through the control of autophagy and mitophagy, it intervenes in some of the most important mechanisms for maintaining cellular homeostasis. The ability to modulate AMPK, mTOR, and numerous other signaling pathways allows melatonin to adapt the cellular response to the specific needs of each tissue and each pathological condition. In this perspective, autophagy appears as one of the main tools through which melatonin protects the organism from aging, metabolic dysfunction, neurodegeneration, and chronic cellular damage.

In the previous paragraph, we saw how melatonin can influence autophagy through numerous intracellular signaling pathways, including AMPK and mTOR. To fully understand this mechanism, it is necessary to focus on one of the most important metabolic sensors present in the organism: AMP-activated protein kinase, better known as AMPK.

Every cell in the human body is constantly faced with a fundamental challenge: balancing energy consumption and production. When available energy is abundant, the cell can invest resources in growth, protein synthesis, and proliferation. When energy reserves decrease, however, it becomes necessary to adopt conservation and recovery strategies. In this context, AMPK acts as a true metabolic control center, capable of continuously monitoring the ratio between AMP and ATP (two molecules linked to cellular energy availability) and adapting cellular behavior to the energy conditions of the moment (Smiles et al., 2024) [43]; (Mandic et al., 2025) [45].

AMPK could be compared to a sophisticated emergency management system installed in a large city. When energy resources are sufficient, activities proceed normally. If, however, there is an energy shortage, the system intervenes immediately by reducing non-essential consumption and activating mechanisms designed to restore balance. This principle represents the biological foundation of AMPK's action (Mandic et al., 2025) [45].

To perform this function, AMPK works in close collaboration with another important metabolic regulator: mTORC1. If AMPK represents the sensor of energy scarcity, mTORC1 can be considered the promoter of cell growth. When nutrients and energy are abundant, mTORC1 promotes protein synthesis, proliferation, and anabolism. When energy decreases, however, AMPK intervenes by suppressing mTORC1 activity and orienting metabolism toward resource conservation and recovery processes (Smiles et al., 2024) [43]; (Al-Kuraishy et al., 2025) [46].

This antagonistic relationship represents one of the most important metabolic checkpoints in the entire organism. Through the phosphorylation of proteins such as TSC2, AMPK is able to reduce mTORC1 activity, temporarily interrupting high-energy-consuming cellular programs and favoring the activation of catabolic pathways oriented toward survival (Smiles et al., 2024) [43]; (Mandic et al., 2025) [45].

Among the main targets of this regulation is ULK1, a kinase considered the starting point of the autophagy program. ULK1 represents the convergence node through which AMPK and mTOR communicate with the autophagy system. In the presence of abundant nutrients, mTORC1 phosphorylates ULK1 at inhibitory sites, preventing the initiation of autophagy. When energy resources decrease, however, AMPK modifies ULK1 through different phosphorylation events that allow for the activation of the autophagy program and the beginning of autophagosome formation (Smiles et al., 2024) [43].

For many years, this relationship was interpreted according to a relatively simple model: energy deficiency, AMPK activation, mTOR inhibition, ULK1 activation, and consequent induction of autophagy. This paradigm dominated the scientific literature for over two decades and has been confirmed by numerous experimental studies conducted on cells, animal models, and human tissues (Kim, 2024) [44]; (Mandic et al., 2025) [45].

According to this classic view, autophagy represents a tool through which the cell recovers nutrients and energy substrates during periods of metabolic stress. By eliminating damaged organelles, protein aggregates, and other non-functional components, the cell can recycle precious materials and use them to support its vital functions (Mandic et al., 2025) [45].

From these observations, a new interpretative model has emerged. According to this perspective, AMPK would not simply be an activator of autophagy, but a dynamic regulator capable of deciding when and to what extent the process should be activated. During an initial phase of severe energy depletion, AMPK could preserve the autophagy machinery by keeping proteins like ULK1 in a functionally ready but temporarily inactive state. Once more favorable energy conditions are restored, autophagy could be initiated in a more efficient and sustainable way (Kim, 2024) [44].

This concept has been defined by some authors as the maintenance of "autophagic competence." In other words, AMPK would not only control the switching on or off of autophagy, but would ensure that the entire system remains ready to respond when metabolic conditions allow it (Kim, 2024) [44]; (Mandic et al., 2025) [45].

The AMPK/mTOR/autophagy axis also plays a central role in skeletal muscle. During physical exercise, the increase in energy consumption leads to the activation of AMPK, the suppression of mTORC1, and the coordinated stimulation of autophagy and lysosomal biogenesis (the process by which cells produce new lysosomes, small organelles that degrade and recycle waste substances). This process promotes the removal of damaged proteins and dysfunctional mitochondria, improving cellular quality, insulin sensitivity, and metabolic flexibility. In sarcopenic obesity, these adaptations contribute simultaneously to the preservation of muscle mass and the reduction of adipose accumulation (Zhang et al., 2026) [42].

The importance of AMPK also emerges in cardiovascular diseases. In atherosclerosis, chronic activation of mTOR and the impairment of autophagy promote endothelial dysfunction, vascular inflammation, and the progression of atherosclerotic plaque. Conversely, AMPK activation improves lipid metabolism, reduces the production of inflammatory cytokines, and promotes the restoration of physiological autophagy, contributing to the protection of the vascular wall (Al-Kuraishy et al., 2025) [46].

Overall, current evidence shows that AMPK represents much more than a simple energy sensor. It constitutes one of the main conductors of cellular homeostasis, capable of coordinating growth, survival, metabolism, and autophagy through an extremely sophisticated regulatory network. The modern view no longer describes AMPK as a simple activator of autophagy, but as a contextual regulator that continuously adapts the cellular response to the energy conditions of the moment. Through its dialogue with mTOR, AMPK contributes to maintaining that dynamic balance that allows cells to survive, adapt, and function correctly even in the presence of significant metabolic stress.

In the previous paragraphs, we saw how melatonin is much more than just a hormone involved in sleep regulation. Scientific evidence shows that it participates in the control of energy metabolism, autophagy, mitochondrial function, the response to oxidative stress, and cell survival. At the heart of many of these functions emerges a common signaling pathway, consisting of the MT1–AMPK–mTORC1 axis, which represents one of the main mechanisms through which melatonin translates the circadian rhythm signal into concrete biological adaptations.

When melatonin binds to its receptors, particularly MT1, a cascade of intracellular events is initiated that leads to the activation of AMPK, the main cellular energy sensor. AMPK activation signals to the cell the need to optimize the use of available resources, reducing high-energy-consuming anabolic processes and favoring mechanisms of adaptation and cellular maintenance. One of the main targets of this regulation is mTORC1, a protein complex that promotes growth, protein synthesis, and nutrient accumulation when metabolic conditions are favorable (Chen et al., 2020) [47]; (Zhang et al., 2019) [50].

In simple terms, one could imagine AMPK and mTORC1 as the two ends of a metabolic scale. When mTORC1 prevails, the cell invests energy in growth and the construction of new structures. When AMPK is activated, however, the organism prioritizes resource conservation, the recycling of damaged components, and cellular protection. Melatonin appears to possess the ability to shift this balance toward metabolic programs more oriented toward cellular resilience, especially during nighttime hours (Wang et al., 2019) [51]; (Chen et al., 2020) [47].

One of the clearest examples of this mechanism comes from studies on vascular calcification. In this pathological condition, the smooth muscle cells of blood vessels tend to progressively take on characteristics similar to those of bone cells, promoting the deposition of calcium in the arterial wall. Chen and colleagues demonstrated that melatonin activates AMPK, inhibits mTORC1, and increases the activity of ULK1, promoting autophagy and simultaneously reducing calcium deposition and the apoptotic activity of vascular cells. When researchers blocked AMPK or artificially reactivated mTOR, most of the protective effects of melatonin disappeared, confirming the central role of the AMPK–mTORC1 axis (Chen et al., 2020) [47].

The same molecular architecture has also been observed in the nervous system. In neuroblastoma cells, a particularly aggressive form of tumor, melatonin was found to be able to increase the expression of the Pak2 protein, which in turn activates AMPK and suppresses mTOR signaling. In this context, autophagy does not perform a protective function for the tumor cell, but contributes to its elimination, suggesting that melatonin can exploit the AMPK–mTORC1 axis to limit neoplastic growth (Qiu et al., 2026) [40].

The evidence gathered in the reproductive system shows remarkable consistency with these results. In the corpus luteum of sheep, the phase characterized by the highest progesterone production coincides with the highest expression of MT1 and MT2 receptors and the most intense autophagic flux, suggesting that melatonin may support steroidogenesis (the process by which the organism transforms cholesterol into steroid hormones) precisely through the modulation of autophagy mediated by the AMPK–mTOR axis. In this scenario, autophagy does not appear as a degradation mechanism for its own sake, but as a tool with which the luteal cell optimizes its metabolism to support hormone synthesis (Duan et al., 2024) [48].

A similar picture emerges in the senescent ovary. With advancing age, the accumulation of reactive oxygen species, the deterioration of mitochondrial function, and the alteration of homeostasis progressively compromise oocyte quality. Studies conducted on murine models have shown that chronic administration of melatonin increases the number of retrievable oocytes, improves embryonic quality, and increases fertility. These effects are strictly dependent on the activation of the MT1 receptor and the AMPK pathway, as demonstrated by the marked reduction in fertility observed in animals lacking the MT1 receptor. The activation of this axis is also associated with a reduction in oxidative stress, greater antioxidant activity, and better preservation of mitochondrial function (Zhang et al., 2019) [50].

The male reproductive system also seems to benefit from the same biological regulation. During sperm cryopreservation, freezing and thawing cause a massive production of reactive oxygen species that compromises motility, cellular integrity, and fertilizing capacity. Zhu and colleagues observed that melatonin significantly increases AMPK phosphorylation, reduces intracellular ROS levels, limits lipid peroxidation, and improves sperm survival after thawing. The fact that these effects are attenuated by blocking melatonin receptors suggests once again the existence of a functional connection between MT1, AMPK, and cellular protection mechanisms (Zhu et al., 2019) [49].

One of the most interesting aspects that emerged from the research concerns lipid metabolism. In bovine mammary epithelial cells, melatonin induces an increase in MT1 receptor expression and a marked reduction in the phosphorylation of mTOR and its main effectors. This change is accompanied by a decrease in the synthesis of triglycerides, the formation of intracellular lipid droplets, and the accumulation of fat in milk. When mTOR is experimentally reactivated, the effects of melatonin are nullified, demonstrating that the suppression of mTOR represents the crucial step of this mechanism (Wang et al., 2019) [51].

Considering these results as a whole, a surprisingly consistent biological model emerges. In very different tissues and conditions—blood vessels, brain, ovary, corpus luteum, sperm, and mammary gland—melatonin tends to converge on the same regulatory nodes. The activation of MT1 receptors favors the activation of AMPK; AMPK reduces the activity of mTORC1; the decrease in mTORC1 signaling allows for the activation of adaptive programs such as autophagy, mitochondrial protection, control of oxidative stress, and metabolic regulation.

This observation suggests that melatonin does not act simply as a signal of darkness, but as a systemic coordinator of cellular energy economy. During the night, when the organism reduces many of the activities associated with the external environment, melatonin seems to favor processes of maintenance, repair, recycling, and metabolic optimization. Through the MT1–AMPK–mTORC1 axis, it helps maintain the balance between growth and conservation, between synthesis and recycling, between energy consumption and cell survival.

In light of the currently available evidence, the MT1–AMPK–mTORC1 pathway can be considered one of the main biological mechanisms through which melatonin exerts its systemic effects. The extraordinary conservation of this axis in different tissues suggests that it represents a central element of melatonergic physiology and a possible therapeutic target for numerous conditions characterized by metabolic dysfunction, altered autophagy, oxidative stress, and cellular aging.