Unveiling mysteries of aging: the potential of melatonin in preventing neurodegenerative diseases in older adults

In humans and non-human primates, melatonin treatment in acute form speeds up sleep onset, facilitates its maintenance, or both, and triggers brain waves characteristic of sleep, irrespective of the time of day (Cruz-Sanabria et al. 2023). Melatonin and associated compounds adjust the timing of circadian rhythms by shifting them when administered at specific times that affect the body’s internal clock according to phase response curves that remain consistent across mammals (Burgess et al. 2010). Completely blind people, who cannot perceive light, are able to effectively control their internal body clock by using melatonin (Hartley et al. 2018). Melatonin also helps to adjust the body’s natural sleep–wake cycle in individuals with seasonal affective disorders, leading to a reduction in depression levels (Walker et al. 2020). Melatonin’s distinct effects, resulting from its interactions with melatonin receptors in the central nervous system, are pertinent to the therapeutic objectives of melatonin medications. Difficulty initiating and/or maintaining sleep, as well as sleep that is unrefreshing, are key characteristics of insomnia or sleep–wake disorder, which frequently co-exists with daytime discomfort or emotional distress. A widespread disorder known as insomnia impacts roughly 10% of the global population (Riemann et al. 2022). Current insomnia treatments comprise benzodiazepines and their analogous nonbenzodiazepine medications, which exhibit considerable side effects that lead to impaired cognitive and psychomotor abilities, a heightened risk of falls, rebound, and the potential for dependence or abuse (Laudon and Frydman-Marom 2014). The pursuit of molecules with improved safety profiles has resulted in the creation of a slow-release melatonin formulation (such as Circadin) (Paulis et al. 2012) and artificial melatonin derivatives (including ramelteon, tasimelteon, and agomelatine) (Hardeland 2016). Insomnia is commonly linked to other related health conditions, particularly those affecting mood and the body’s natural circadian rhythms (Laudon and Frydman-Marom 2014). Melatonin and synthetic melatonin agonists typically do not exhibit the side effects (e.g., impairment of learning, memory, or motor function) commonly seen with other sleep medications.

According to the US National Institutes of Health, around 80 million Americans experience symptoms from various circadian rhythm disorders, which can lead to feelings of depression and changes in sleep patterns. Melatonin and melatonin receptor agonists have therapeutic uses in a range of circadian-related conditions, such as jet lag, shift work sleep disorders, delayed sleep phase syndrome, seasonal affective disorder and non-24 h sleep–wake disorder, and major depression (de Bodinat et al. 2010; Zhu and Zee 2012). Studies have shown that the mammalian suprachiasmatic nucleus expresses MT1 and MT2 receptors, as demonstrated by in situ hybridization with 2-[125I]-iodomelatonin and mRNA probes (Hunt et al. 2001). Activation of melatonin receptors decreases neuronal activity in the SCN and parts of the limbic system by stimulating the MT1 receptor, contributing to melatonin’s sleep-inducing effects (Singh et al. 2020).

Major depressive disorder stands as the most prevalent mental disorder in the U.S. and is the primary cause of disability impacting approximately 100 million adults globally (Zhao et al. 2024). The condition is marked by a variety of symptoms impacting emotional state, anxiety levels, neurochemical equilibrium, sleep cycles, and circadian and/or seasonal temporal patterns, as well as heightened neurodegenerative changes. The main treatments currently used are tricyclic antidepressants and selective serotonin reuptake inhibitors, which have been found to raise the levels of monoamine neurotransmitters outside the cells. These antidepressants do not address sleep disorders or disturbances related to a person’s natural rhythm and seasonal variations that accompany depressive conditions. Furthermore, prolonged use results in undesirable side effects like weight increase and the combination of cognitive, autonomic, and motor symptoms that characterise the serotonin syndrome (Pannu and Goyal 2024). As a result, researchers are in immediate need to develop antidepressants with new mechanisms of action and decreased side effects.

Melatonin receptors MT1 and MT2 are key targets for the creation of novel antidepressants. Initial evidence suggesting a role for the melatonin receptor in behaviors associated with depression stemmed from the antidepressant-like effects of melatonin and its agonists in rodent studies involving learned helplessness. The antidepressant-like effects of melatonin in the forced swim test were hindered by luzindole, indicating that MT1 and MT2 receptors may be involved (Wang et al. 2022). Melatonin treatment over a long period also increases the growth of new neurons in the hippocampus, a process crucial for the effectiveness of antidepressants in animal studies (Liu et al. 2013; Ramírez-Rodríguez et al. 2009). Mice lacking the MT1 receptor exhibit enhanced depressive-like behavior in a forced swim test (Adamah-Biassi et al. 2014; Weil et al. 2006). The increased presence of MT1 receptor activity in people with major depressive disorder indicates that this receptor type could be a potential target for alleviating some symptoms of depression (Wu et al. 2013). In summary, melatonin agonists may be effective in alleviating symptoms, neurochemical changes, or both associated with clinical manifestations of depressive disorders, primarily through activation of the MT1 receptor.

Changes in the synapses between brain cells store learning and memory (Abraham et al. 2019). Strengthening of the synapse between the two cells occurs when both cells are active simultaneously (Lisman et al. 2018). In 1973, long-term potentiation (LTP)—a mechanism that facilitates the storage of learning and memory in the hippocampus—was first identified by Tim Bliss and Terje Lomo. Research revealed that brief periods of high-frequency stimulation to the hippocampus’ excitatory pathways led to an enduring rise in synaptic excitability, which persisted for even several months, as noted by Rison and Stanton (1995). Further research revealed that LTP is also associated with a shift in ionic flow, resulting in an ionic flow that diverges from that seen during standard synaptic transmission (Morris 2003).

There is a connection between long-term potentiation and memory and learning. Changes in synaptic strength, defined as synaptic plasticity, are believed to be brought about by LTP and are thought to be the mechanism through which learning and memory are stored within the brain. Research findings indicate that synaptic weights are altered following the learning process, thereby establishing a link between learning and the phenomenon of LTP. Changing the mechanisms that underlie synaptic plasticity also alters the rate of learning. Even after the completion of learning, changes to synaptic weights continued to impact the experimental animals’ capacity for recalling what they had learnt. Research has shown that interfering with LTP also disrupts learning and memory functions, highlighting the significant role that LTP plays in these processes (Cantarero et al. 2013; Morris 2003).

Investigations into the hippocampus have been conducted to examine the impact of melatonin. Research findings by Roy et al. (2021) indicate that melatonin alters LTP by modifying synaptic transmission between neurons. A study conducted by Louisa M. Wang found that melatonin suppresses long-term potentiation in neurons. Wang demonstrated this in an experiment involving hippocampal slices of mice. Initially, LTP was triggered using high-frequency stimulation, and the outcome was documented for 60 min. Melatonin was then added to the hippocampal slices, and long-term potentiation was prompted once more. The slopes of field excitatory postsynaptic potential this time were significantly lower, indicating that melatonin had decreased the magnitude of LTP as reported in Wang et al. (2005). Yoshiyuki Takahashi conducted research on melatonin, focusing on its involvement in LTP. He investigated the impact of melatonin on long-term potentiation in the CA1 region of the hippocampus using hippocampal slices from rat brains. Melatonin significantly reduced LTP expression when compared to the control group, as noted by Takahashi and Okada in 2011. Two studies demonstrate that melatonin in the hippocampus acts to prevent LTP. In both experiments, following the addition of melatonin, the levels of LTP were significantly lower than those in the control groups. Melatonin suppresses LTP via the MT2 receptors, as reported by Liu et al. (2016). Previous research on melatonin’s effect on long-term potentiation suggests that melatonin may be impairing the brain’s capacity to form and retain memories. This suppression by the body’s own melatonin, produced by the pineal gland, is an integral component of the body’s natural circadian rhythm. Melatonin and LTP both exhibit a circadian pattern. LTP in the hippocampus is more pronounced during the day when melatonin levels are lower, and less pronounced at night when melatonin levels are higher (Takahashi and Okada 2011). The impact of melatonin on long-term potentiation is contingent upon concentration levels. Research has found that higher levels of melatonin are more effective at suppressing LTP than are lower levels (Shi et al. 2018). The significance of this information becomes apparent when examining the impact of melatonin on cognitive functions such as learning and memory. The natural fluctuation of melatonin levels influences the body’s innate circadian rhythms of learning and memory, which are a typical aspect of bodily function. Taking exogenous melatonin supplements results in higher than typical doses of melatonin entering our bodies, thereby causing a greater-than-normal suppression of LTP. Melatonin supplements may have a severe impact on LTP, thereby causing substantial impairments in an individual’s ability to learn and memory.

Alzheimer’s disease is an irreversible, progressive neurodegenerative condition that is marked by a decline in cognitive function, memory impairment, and irregular behavior patterns (Anwal 2021). Impairments in spatial learning and memory are an important clinical feature of this disease (Sun et al. 2020).Studies have shown that melatonin improves short-term memory in a mouse model of Alzheimer’s disease. Many studies have shown that MT prevents the progression of AD and improves the cognitive impairment associated with the disease through various mechanisms (Shen et al. 2016). For these effects, MT doses need to be approximately twice those required to affect sleep and circadian rhythms (Low et al. 2020). Clinical studies using MT in the range of 50–100 mg/day are needed to investigate the therapeutic validity of MT treatment in AD (Labban et al. 2021a, b). Labban et al. used the highest prophylactic MT dose (80 mg/kg) that did not produce any signs of toxicity in mice in their 2021 study (Labban et al. 2021a, b). They found that MT at this high dose was a potent antioxidant and anti-inflammatory that improved memory outcomes and locomotor activity in an animal model of multiple sclerosis (Abo Taleb and Alghamdi 2020; Alghamdi and AboTaleb 2020).

Research indicates that melatonin may play a part in shielding against neurodegeneration, apoptosis, and damage from ischemia/reperfusion (Zhang et al. 2024). It is widely accepted that melatonin’s neuroprotective properties are largely due to its ability to neutralize free radicals, as stated in Galano et al. (2013); nonetheless, current research indicates that the activation of MT1 and/or MT2 melatonin receptors may also be a contributing factor. Melatonin has been shown to decrease reactive oxygen species to nearly normal levels in hippocampal slice cultures lacking oxygen and glucose, a reduction that is prevented by luzindole as indicated in a study by Parada et al. (2014). The activity of melatonin receptors may be associated with the activation of antioxidant genes, such as superoxide dismutase and catalase, through a process initiated by receptor-mediated transcriptional regulation. Melatonin receptors could serve as potential targets for new treatments designed to combat the oxidative stress aspects of neuroinflammatory processes.

Melatonin blocks the pathways that lead to mitochondrial cell death in a laboratory model of Huntington’s disease that has a genetic mutation affecting striatal cells. Melatonin also prevents cell death in both cell lines and cultures of primary cerebrocortical and primary striatal neurons, a protective effect that is counteracted by luzindole (Wang et al. 2011). The effect is probably caused by the MT1 receptor, since blocking it makes neurons in culture more prone to dying, whereas producing too much of it has a protective effect (Wang et al. 2011). In the R6/2 mouse model of Huntington’s disease, melatonin reduces the rate of disease progression by preventing mitochondrial cell death. In R6/2 mice, a decrease in MT1 but not MT2 melatonin receptors is found in the brain; this reduction can be partially alleviated by administering melatonin (Wang et al. 2011). Research indicates that the creation of selective MT1 receptor agonists may result in neuroprotective medications that can treat individuals afflicted with Huntington’s disease.

Unlike other receptors, the activation of MT2 receptors has been associated with melatonin’s protective effects against neuronal damage in the aftermath of ischemic strokes, according to Mozaffarian et al. (2015). Melatonin treatment also provides protection against ischemia/reperfusion injury in a mouse stroke model by receptor-mediated pathways that are blocked by 4P-PDOT or luzindole. In addition, melatonin stimulates neurogenesis and cell multiplication via a mechanism that relies on the MT2 receptor (Chern et al. 2012). Consequently, these findings indicate that the MT2 receptor plays a part in mediating the neuroprotective effects of melatonin after ischemia/reperfusion and is associated with a significant increase in neurogenesis.

Ageing is a multifactorial process that results in degeneration and dysfunction at the genetic, cellular and organismal level, leading to the decline of maintenance mechanisms and the exponential accumulation of molecular damage. Senescent organisms exhibit genetically significantly reduced adaptive potential and are unable to overcome diverse stress factors and adverse external stimuli (Poeggeler et al. 1993). Ageing refers to post-maturational changes that underlie increased vulnerability to adversity; therefore, reducing the ability to survive. As age advances, and age-related diseases manifest or progress, the biosynthesis of melatonin, predominantly nocturnal, is significantly reduced in various species, including humans (Reiter 1992). Delaying the rate of aging and the onset of age-related diseases can be achieved through melatonin supplementation or therapeutic methods that sustain the high amplitude of the body’s natural melatonin production cycle (Poeggeler et al. 1993). Melatonin’s natural daily cycle amplitude diminishes in older adults and is nearly absent in certain neurodegenerative disorders, including Alzheimer’s disease (Wu and Swaab 2005). A disrupted melatonin circadian rhythm could have significant effects on the health and wellbeing of elderly individuals. Healthy young organisms display a significant circadian rhythmicity in various crucial physiological processes, including the sleep–wake cycle, core body temperature, performance, wakefulness, and the secretion of numerous hormones. These rhythms can have a significant impact on maintaining health and overall well-being. Old age is typically marked by the disturbance of the regular circadian patterns of these cycles, with decreased peak values, timing difficulties, disorganization of the temporal sequence, and impaired response to environmental time cues (Karasek 2004). Melatonin functions as a timekeeper signal, known as a Zeitgeber, according to Armstrong and Redman (1991).

Research indicates that periodic melatonin administration can reset internal rhythms, synchronizing them and increasing their amplitude to normal levels in aged organisms (Armstrong and Redman 1991). A number of theories have been put forward suggesting a connection between the pineal gland and melatonin and the mechanisms of ageing and its associated conditions. The decrease in circulating melatonin levels over the course of a person’s lifetime, which coincides with a more general decline in many circadian rhythms as people get older, is a compelling indicator that melatonin, even at physiological levels, may have an important role to play in this process.

These geronto-protective effects can combine to result in a substantial improvement in well-being, as well as a decrease in the occurrence and severity of specific age-related health issues characteristic of the elderly (Reiter et al. 2002b). Research on animals has shown that low levels of melatonin, when taken over a prolonged period, may counteract the ageing process by reversing and stabilizing the negative effects it has on oxygen and energy metabolism (Okatani et al. 2003).

The electron transport chain inside mitochondria ensures a secure four-valent reduction of molecular oxygen to form water. The decrease in molecular oxygen’s valency due to electron loss leads to the formation of ROS (Watabe et al. 2007). Aging cells exhibit elevated electron leakage rates due to compromised electron transfer chain function. High levels of ROS can lead to an overactive response in redox signaling pathways, ultimately increasing inflammation, cancer, cell death, and contributing to accelerated aging, as noted in Schieber and Chandel’s 2014 study. Melatonin minimizes electron loss in mitochondria and acts as an antioxidant, providing a high electron supply to neutralize ¹O₂, O²∙-, O₂²⁻, and OH∙ radicals through reactions that do not follow a one-to-one ratio (Tan et al. 2000).Melatonin and its derivatives exhibit a reductase-modulatory effect on ROS and reactive nitrogen species (RNS) (Wang et al. 2019b). Melatonin-induced redox regulation may be achieved through direct ROS scavenging and the action of both enzymatic and non-enzymatic antioxidant systems, as described by He et al. (2017). Exogenous non-enzymatic antioxidants, which are derived from nutritional sources, include vitamins A, E, C, xanthophylls, polyphenols, and carotenoids, as noted by Okeke et al. (2022). Vitamin C functions as a hydrophilic antioxidant, whereas other compounds like vitamins A and E, polyphenols, and carotenoids are active in a hydrophobic environment, as reported by Kuciel-Lewandowska et al. (2020). The direct antioxidant properties of melatonin are dependent on its own electron-rich aromatic indole ring. Indole ring makes it a potent electron donor that can significantly reduce free radicals (Mannino et al. 2021). Melatonin neutralizes reactive oxygen species (ROS) and free radicals by donating electrons to them. This process converts melatonin into its radical form, N-acetyl-5-methoxytryptamine (AMT). The radical form is relatively stable and can react with additional ROS, leading to the formation of less harmful products. The oxidized form can be restored to its active state through enzymatic reactions. The primary enzyme involved in this regeneration is glutathione peroxidase, which reduces oxidized melatonin using reduced glutathione (GSH). The metabolism of the substance yields various metabolites, including 6-hydroxymelatonin, which exhibits antioxidant properties and plays a role in the body’s overall antioxidant protection mechanism. In essence, melatonin’s redox cycling involves its capacity to donate electrons to counteract oxidative stress, produce stable radicals, and be restored by antioxidant enzymes, particularly glutathione peroxidase, thereby enabling it to function effectively as an antioxidant. The enzyme glutathione peroxidase (Sies and Jones 2020) is responsible for maintaining melatonin within the oxidoreduction redox cycle. This enzyme is crucial for the replenishment of melatonin by converting its oxidized form back into its active state with the aid of reduced glutathione (GSH) as a co-factor. Glutathione peroxidase functions to facilitate the reduction of hydrogen peroxide (H₂O₂) and other peroxides through the utilization of GSH. During this process, GSH is converted into glutathione disulfide (GSSG). When melatonin donates electrons, it is converted into its oxidized form, helping to neutralise free radicals. Glutathione peroxidase enables the transfer of electrons from GSH to the oxidised form of melatonin, thereby restoring its active form. Maintaining redox balance in cells relies on this enzymatic action, enabling melatonin to act as a potent antioxidant that counteracts oxidative stress (Hasan et al. 2018; Rossi et al. 2023).

Melatonin is oxidized when it provides electrons to ROS or RNS (Hardeland 2021). Typically, this process involves either the loss of hydrogen atoms or the addition of oxygen atoms to the melatonin molecule. The main oxidised form of melatonin is N-acetyl-5-methoxytryptamine (AMT), alongside other metabolites including 6-hydroxymelatonin. The oxidized forms of melatonin exhibit distinct chemical compositions when contrasted with the original melatonin molecule. Melatonin’s molecular configuration and functional groups are modified by oxidation, thereby impacting its reactivity, solubility, and biological effects. The introduction of hydroxyl groups to oxidized forms enhances their capacity for interaction with other molecules (Galano et al. 2011). Melatonin’s electron donation leads to structural changes, resulting in the formation of different oxidized metabolites that may retain some of the antioxidant properties, but are chemically distinct from the original hormone (Hardeland 2017).

Mitochondrial function decreases with age, with a notable impact on the activity of complexes I and III. These complexes are essential for the electron transport chain and ATP production, as noted by Miwa et al. (2022). The buildup of reactive oxygen species (ROS) can result in damage to mitochondrial DNA, proteins, and lipids, as found by Radak et al. (2011). Oxidative damage interferes with the operation of complexes I and III, thereby diminishing their capability for electron transfer (Choksi et al. 2007). Mitochondrial DNA mutations can accumulate over time, resulting in dysfunctional proteins that are essential components of the electron transport chain. Electron flow is consequently reduced and ATP synthesis is hindered as a result. The composition of mitochondrial membranes undergoes changes as people age, which impacts the fluidity and operational efficiency of electron transport chain complexes. The change in question hinders the correct formation and functioning of complexes I and III, as noted by Genova and Lenaz (2015; Gómez and Hagen 2012). Coenzyme Q10 (ubiquinone) plays a crucial role in facilitating electron transfer between complexes I and III. Reduced coenzyme Q10 levels in aging individuals can hinder electron flow and bioenergetic processes, as reported in the studies of Ebadi et al. (2001) and Banerjee et al. (2022). This can ultimately contribute to the destabilization of mitochondrial complexes I and III due to the combined effects of oxidative stress, genetic mutations, altered lipid composition, decreased coenzyme Q10 levels, and impaired mitochondrial dynamics. A disruption in electron flow ultimately compromises essential bioenergetic processes that are necessary for cellular function and contributes to the aging phenotype.

Research has demonstrated that melatonin affects the patterns of neurodegenerative genes and proteins, especially in cases of age-related disruptions to our internal body clock. The significance of this effect lies in the fact that disruptions to circadian rhythms can worsen neurodegenerative processes. The regulation of circadian rhythms is dependent on interconnected feedback systems that balance gene expression through continuous interaction and are comprised of transcriptional and translational elements. Alzheimer’s disease, the leading cause of dementia and a particularly severe psychiatric disorder (Barnes and Yaffe 2011), is distinguished by the formation of amyloid-β (Aβ) deposits outside cells, neurofibrillary tangles (NFTs) composed of abnormally phosphorylated tau, cell loss, and inflammation in the nervous system (Ballard et al. 2011). In addition to significant cognitive impairments, individuals with Alzheimer’s disease experience extreme disruptions to their body’s natural sleep–wake cycles and other related processes. Over the past few years, significant strides have been taken to gain a deeper understanding of the molecular and cellular causes of sleep disturbances and disrupted circadian rhythms that are commonly seen in AD patients (Bliwise et al. 2011). The clock pathway plays a vital role in maintaining rhythmicity, and research connecting this molecular group to brain and body functions in AD patients may help clarify the underlying causes of this prevalent form of dementia (Harper et al. 2004). A network of extra brain regions outside the SCN contains self-sustaining oscillators that facilitate circadian function, as noted in Cermakian and Boivin (2009). These secondary oscillators, similar to the SCN, depend on feedback loops that include clock genes and proteins.Research suggests that the function of the clock pathway in the suprachiasmatic nucleus (SCN) and other brain areas is thought to be distinct and related to the specific function of each region (Cermakian and Boivin 2009). Studies in rodents have found that age-related decline in circadian rhythm regulation occurs at the cellular level within the SCN, and is associated with altered expression of multiple genes crucial for circadian clock function (Asai et al. 2001). Additionally, it has been discovered that light-induced expression of clock genes is modified in the SCN of aging hamsters (Kolker et al. 2003), and that aging affects phase-shifts of the day-night cycle in the pineal gland and arcuate nucleus of aged rats (Davidson et al. 2008). Targeted deletions of Clock or Bmal1 genes significantly impact the rate of ageing by disrupting the circadian system, resulting in increased brain inflammation and neurodegeneration (Dubrovsky et al. 2010). In addition to regulating the circadian rhythm, clock proteins could have other roles (Kondratova and Kondratov 2012). Evidence from mouse models demonstrates accelerated neurodegeneration in mice with brain-selective or conditional Bmal1 knockouts, as observed in studies by Yang et al. (2016). It is therefore plausible that the upregulation of Bmal1 and the modified activation of the negative feedback loop, which takes place in all brain areas, acts as a counterbalancing mechanism to the neurodegenerative effect. Further investigation into these aspects is required, and this can be achieved using various circadian mutant models. Altered expression of the clock gene causes a loss of timely coordination among different brain areas, interferes with the regulation of basic cellular metabolic and homeostatic processes, and ultimately results in the disruption of connections among brain structures, ultimately leading to cognitive impairment and the characteristic chrono-disruption seen at the onset of early neurodegenerative diseases in patients.

Autophagosome formation rates may fluctuate with age, despite autophagy-related protein levels remaining stable in neurons over time. Phosphorylation and other post-translational modifications play a substantial part in the autophagy process. Protein modification changes can affect the rate of autophagosome formation without impacting the overall levels of protein production. The formation speed of autophagosomes can also be influenced by the cellular components’ location within the cell. In Caenorhabditis elegans, autophagy activity generally decreases as age advances. Age seems to influence neuronal autophagy to a greater degree of variability than it does other tissues (Chang et al. 2017). Modulating autophagy in neurons can have an impact on longevity and lifespan. In Drosophila, flies lacking the Atg8a gene exhibited shorter lifespans and a higher number of ubiquitinated protein aggregates in their neurons. Overexpressing dAtg8 in the CNS via the APPL-Gal4 driver resulted in the prevention of protein aggregate accumulation and a significant increase in lifespan. Overexpressing dAtg8 pan-neuronally with the aid of ELAV-Gal4, which drives earlier expression, did not lead to an increase in lifespan, indicating that the timing of autophagy induction is crucial (Simonsen et al. 2008). In the nematode C. elegans, blocking components of the initiation and nucleation complexes in neurons post-reproduction led to extended lifespan, whereas blocking these components in pre-reproductive animals resulted in decreased lifespan. Research data indicate that inhibiting the formation of partially completed autophagosomes is beneficial in post-reproductive animals (Wilhelm et al. 2017).

In mammals, the biogenic amine melatonin is synthesized from the aromatic amino acid L-tryptophane in many tissues; however, circulating levels are mainly of pineal origin with a pronounced nocturnal peak (Reiter 1980a, 1992). With respect to age-related diseases, such as AD, and advancing age, it was indicated that the melatonin concentrations in individuals reduce, which is highly correlated with disease progression and genotype (Reiter 1992; Wu and Swaab 2005).

Research conducted by numerous teams has revealed a decline in melatonin synthesis and release in older animals and humans along with a significant disturbance in the natural circadian cycle of circulating melatonin, resulting in an almost total disappearance of the typical nocturnal peak in melatonin levels, a phenomenon observed in many devastating age-related degenerative diseases. The physiological effects of an ageing pineal gland and its weakened capacity to produce melatonin with age could lead to melatonin deficiency in ageing animals, posing a severe threat to the old organism’s well-being.

Extensive research has been conducted on the decrease in melatonin levels that occurs during both normal ageing and pathological ageing processes in the pineal gland, the brain, and numerous other tissues outside of the pineal gland, as well as in bodily fluids such as cerebrospinal fluid, plasma, saliva, and urine (Wu and Swaab 2005; Reiter 1992). Almost all of the studies reported a highly significant drop in melatonin levels and the production of its primary liver metabolite 6-hydroxymelatonin; with a few exceptions, no statistically significant differences were shown, primarily due to methodological issues stemming from the significant variability of nocturnal melatonin production and 6-hydroxymelatonin excretion, as well as the timing of their age-related decline (Wu and Swaab 2005).

Recent research, which demonstrates the fact that preserving the circadian structure of melatonin production can serve as a significant indicator of biological age and has tremendous potential to use in assessing human health status, is of considerable interest and significance in the context of the present overview. The first reports based on observations that melatonin given to mice with potable water prolonged their lifespan and kept the organism in a younger state were initiated due to the strong immunomodulatory effects of indoleamine (Pierpaoli et al. 1991). Researchers who initially published their findings in the late 1980s and early 1990s have since revised and expanded their theory to propose that the pineal gland and its secreted substances, which may include melatonin and possibly other compounds, serve as an internal control and regulatory mechanism for “self-control”. Their theory posits that ageing is a direct outcome of the loss of "self-control", ultimately leading to the failure of the immune system. It is thought that melatonin and peptides originating from the pineal gland are crucial in controlling the immune system.

Immunosenescence is typically linked to autoimmune diseases and inflammation, and it can significantly speed up the aging process. Experimental data available thus far suggest that melatonin and other pineal products with potential secretory functions play a significant role in immune regulation in rodents (Pierpaoli et al. 1991). Low melatonin levels in the blood may severely compromise this role and put the organism at risk of developing an autoimmune or inflammatory disorder. Melatonin and indole metabolites could potentially be highly effective anti-inflammatory substances. Melatonin and its oxidative byproducts may significantly contribute to its anti-ageing effects, particularly in mitigating the inflammatory conditions commonly found in older adults.

Generally accepted clinical research has shown that melatonin and its derivatives have a well-documented safety profile and are associated with minimal side effects when used as supplements or therapeutic agents for short-term periods (Bonomini et al. 2018). Individual responses may differ significantly, and the available long-term safety data is currently restricted, thereby necessitating a cautious approach and further research for distinct populations or particular conditions (Besag and Vasey 2022).

Melatonin is commonly employed for a range of short-term purposes, including the treatment of sleep disorders, managing jet lag, and addressing circadian rhythm irregularities. Studies have demonstrated that it is effective in enhancing sleep quality and shortening the time it takes to fall asleep (Zisapel 2018). Most research suggests that melatonin is generally easy to tolerate, with mild and uncommon side effects reported in the majority of studies. Side effects commonly reported include drowsiness, dizziness, and headaches, as documented by Givler et al. (2023). Research suggests that doses as high as 12 mg or more are typically safe for brief use, provided that individual thresholds for tolerance are taken into account (Besag and Vasey 2022). Long-term ingestion of melatonin is considered safe in the short term, but the long-term effects of taking melatonin remain unclear. Research indicates possible hormonal impacts, especially among youngsters and teenagers, necessitating vigilance (Libowitz and Nurmi 2021). Some studies suggest potential hormonal effects, particularly in children and adolescents, which warrant caution (Libowitz and Nurmi 2021). Safety of melatonin in pregnant and nursing women is not thoroughly documented, and usage should be approached with caution, as noted in studies by Andersen et al. (2016) and Kennaway (2022). Older adults may be more sensitive to melatonin and may need their dosages altered (Anghel et al. 2022). Melatonin may react with a variety of drugs, including anticoagulants, immunosuppressants, and medications impacting the central nervous system (Laurindo et al. 2025). It is crucial to seek advice from a healthcare professional prior to commencing melatonin, particularly if other medications are being concurrently administered.

Evidence from laboratory and animal-based studies that were part of the research showed melatonin has potential for protecting the nervous system. Melatonin therapy has been demonstrated to improve Aβ aggregation, reduce tau hyperphosphorylation, alleviate oxidative stress, decrease neuroinflammation, inhibit neuronal apoptosis, and enhance neuroplasticity impairments. The success of melatonin treatment in animal studies relied on the extent of the disease and the length of the treatment periods. Melatonin administration in young Tg2576 mice inhibited amyloid accumulation and decreased levels of the oxidative stress indicator, nitrotyrosine (Matsubara et al. 2003), whereas no such effects were seen in older Tg2576 mice (Quinn et al. 2005). The efficacy of melatonin appears to be influenced by the severity of Alzheimer’s disease. Additionally, research has indicated that melatonin may be relatively ineffective, potentially due to treatment periods being either too brief or too prolonged. Behavioral improvements were not seen in Aβ-induced Wistar rat models treated with melatonin for a brief period of 10 days, as reported in Eslamizade et al. (2016), and neither were they observed in aluminum-treated Tg2576 mouse models given melatonin for a period of six months, as found in García et al. (2009). Results from animal studies showed a correlation between the ineffectiveness of melatonin therapy and disease severity and treatment duration, which is consistent with findings in patients with Alzheimer’s disease. Melatonin treatment did not demonstrate any advantages in alleviating cognitive impairments and psychiatric and behavioral problems in people with AD at all stages of the condition, although sleep disturbance was only somewhat alleviated in individuals with mild to moderate AD. Additionally, neither short-term nor long-term melatonin therapy was effective in improving symptoms in AD patients. In contrast, melatonin therapy demonstrated beneficial outcomes for sleep, cognitive function, depression, and behavioral symptoms in individuals with mild cognitive impairment. Despite melatonin treatment generally being ineffective in some patients, it remains worthy of further investigation due to its distinct functions in regulating circadian rhythms and mitigating oxidative stress. It is widely acknowledged that melatonin levels decline with typical aging, and that the risk of neurodegenerative diseases escalates with advancing age (Roy et al. 2022). It is thought that a low level of melatonin could be a significant risk factor for the advancement of Alzheimer’s disease as stated in Lahiri et al. (2004). Melatonin treatment may enhance patients’ circadian rhythms and sleep quality, and also lower the likelihood of disease progression. Melatonin’s antioxidant properties differ significantly from antioxidant supplements like vitamins C and E. Antioxidant supplements could produce pro-oxidant by-products as they neutralize free radicals, potentially offsetting the benefits of antioxidants in preventing aging and disease, resulting in antioxidant insufficiency and increased mortality rates (Bjelakovic et al. 2007). Melatonin does not produce pro-oxidant intermediates when neutralizing free radicals (Poeggeler et al. 2010), suggesting its antioxidant activity is even more effective. Further research on this beneficial property is warranted due to its possible relevance in neurodegenerative diseases.

Research into melatonin has been conducted to explore its impact on the clinical manifestations of neurodegenerative disorders, largely due to its demonstrated benefits in various experimental cell and animal studies. The initial case study involved a pair of twins afflicted with AD and demonstrated that melatonin therapy resulted in improved cognitive dysfunction, behavioral problems, sundown syndrome, and sleep quality during the treatment period (Brusco et al. 1998). A condition known as sundown syndrome or sundowning, characterised by its occurrence in the late afternoon or early evening, is typically found in patients with Alzheimer’s disease (Khachiyants et al. 2011). A case study of a man experiencing typical sundown syndrome found that taking a dose of 2 mg of melatonin at 8 p.m. nightly for one week yielded improvements in sleep and behavior, and further gradual improvements were observed when an additional 2 mg dose was taken at 3 p.m. for two weeks, as documented by Lammers and Ahmed (2013). The incidence of rapid eye movement sleep behavior is also decreased by melatonin, as found in the study by Anderson et al. (2008). Other research indicates that melatonin may not alleviate symptoms for all individuals with Alzheimer’s disease. Evidence suggests that melatonin can enhance a patient’s natural sleep–wake cycle, decrease daytime drowsiness, and promote a more positive mood in at least one case. While melatonin had a positive impact on cognitive impairment in one patient, it did not alleviate other symptoms in that individual. Various clinical studies (Cardinali 2019; Pandi-Perumal et al. 2013) have yielded evidence supporting the benefits of melatonin in addressing sleep issues and cognitive decline. Furthermore, research has found that combining exposure to bright light and taking melatonin supplements can enhance sleep–wake rhythms, reduce sundowning symptoms and improve sleep quality in people with Alzheimer’s disease (Uddin et al. 2020). Melatonin, which has been found to stabilise circadian rhythms, diminish daytime drowsiness, enhance sleep quality and slow the advancement of cognitive decline in the majority of case reports and clinical trials, does not yield noticeable benefits for some AD patients in certain research studies. Additional research is required to verify the effectiveness of melatonin for treating clinical symptoms in patients with Alzheimer’s disease. Adjuvant therapies that can be used in conjunction with melatonin supplementation are also worthy of consideration. Studies have found differences in the natural levels of melatonin in patients with PD who are taking melatonin supplements (Kakhaki et al. 2020). Clinical investigations have been conducted to examine the effects of external melatonin on the symptoms exhibited by patients suffering from Parkinson’s disease. Two double-blind and placebo-controlled clinical trials demonstrated an improvement in sleep disruptions among patients with Parkinson’s disease following melatonin therapy, as documented by Sugumaran et al. (2024). A limited number of clinical studies were conducted to examine the effectiveness of melatonin in other neurodegenerative conditions, including ALS and MS. The initial melatonin treatment for ALS took place in three participants who received 30–60 mg of slow-release melatonin orally each night for 13 months. Studies have demonstrated that a patient with advanced ALS experienced a slowed progression of the disease after receiving melatonin, while two other patients exhibited decreased rates of decline at a subsequent evaluation, as reported by Jacob et al. (2002). A clinical trial was conducted among 31 ALS patients who were given 30 mg of melatonin daily, at bedtime, for a period of 24 months as part of their adjunctive treatment. Researchers found that a high dose of melatonin could be used in clinical trials to decrease oxidative stress in ALS patients, but it does not appear to have a neuroprotective impact on the symptoms of the disease (Chen et al. 2020a). In addition, a number of clinical trials investigating the effectiveness and safety of administering melatonin to people with MS have been conducted by Skarlis and Anagnostouli (2020).