Sirtuins and Melatonin: Linking Chronobiology to Inflammation and Aging

Abstract

In recent years, the intricate interplay between sirtuins and melatonin has emerged as a fascinating area of research, with profound implications on various aspects of human health. This comprehensive chapter delves into the complex relationship between sirtuins and melatonin, as well as their essential roles in the regulation of circadian rhythms, inflammation, and aging. The attention is primarily directed to their impact on a range of critical health focal points, including cardiovascular diseases, central nervous system disorders, metabolic imbalances, musculoskeletal disorders, neoplasms, and the overarching process of aging, detailing all the complex biochemical mechanisms and physiological pathways that validate the intimately tailored functional relationship between the indoleamine hormone synthesized in the pinealocytes and the NAD+-dependent histone deacetylases. These two components interact in complex ways, influencing processes such as cellular homeostasis, oxidative stress, and inflammatory cascade regulation. Age-related reductions in SIRT1 expression, influenced by melatonin levels, can deeply impact cellular functions. By elucidating the complex connections between sirtuins, melatonin, and chronobiological processes, we contribute to a deeper understanding of the fundamental mechanisms that trigger inflammation and aging-related diseases, and in the meantime underscore the promising avenues for future research and clinical interventions aimed at enhancing human health and extending the quality of life.

1. Introduction

Melatonin is mainly known for its involvement in sleep and circadian rhythm regulation, among other neuroendocrine processes [1], with reported anti-inflammatory, antioxidant, and antitumor effects [2, 3]. Melatonin is a hormone synthesized by the pineal gland that subsequently enters the bloodstream, enabling its distribution throughout various bodily systems. Moreover, it has the capability to penetrate the third ventricle of the brain via the pineal recess [4]. Melatonin receptors are mainly found throughout the central nervous system (CNS) and in immune cells, with various effects. Aside from its well-known role in circadian rhythm and sleep regulation, melatonin also acts as an anti-excitatory molecule in the CNS and is involved in the regulation of metabolic pathways, modulation of hormone secretion and of pro- and anti-inflammatory cytokines release, and it can even directly activate monocytes [4, 5]. Moreover, it maintains redox homeostasis by upregulating antioxidant enzymes, downregulating reactive oxygen- (ROS) and reactive nitrogen species (RNS)-generating enzymes, and also via its mitochondria-protective effects [4, 6, 7, 8].

Sirtuins are NAD⁺-dependent enzymes with numerous physiological functions, regulating energy metabolism, inflammation, stress response, DNA repair, cell survival, and also being involved in circadian rhythms [9, 10]. Moreover, recent literature data links the sirtuin family to neurodegenerative, inflammation, and aging-associated diseases [11]. In humans, this enzyme family comprises seven isoforms, with different subcellular distribution and functions. Three enzymes are nuclear—SIRT1, SIRT6 and SIRT7, three mitochondrial—SIRT3, SIRT4, and SIRT5, and one cytosolic—SIRT2 [9]. However, SIRT1 often shuttles to the cytoplasm, while SIRT2 and SIRT3 can migrate to the nucleus, under certain conditions [9, 11]. The nuclear sirtuins are transcriptional and epigenetic regulators, stabilizing chromatin and deacetylating histones and non-histone proteins, such as transcriptional factors or DNA repair proteins [12, 13, 14]. They also modulate stress and oxidative stress response, maintain telomere integrity, and regulate apoptosis [9]. SIRT2 intervenes in several cellular processes, including cell cycle, apoptosis, DNA repair, metabolism, and senescence [11]. The mitochondrial sirtuins are mainly involved in metabolic regulation, energy metabolism, and mitochondrial function, maintaining redox and energy homeostasis [11].

Thus far, two sirtuin isoforms, SIRT1 and SIRT3, seem to be essential for the normal functioning of the circadian system, via multiple cellular pathways [4]. SIRT1 was established as a secondary mediator of melatonin’s cellular actions, as numerous in vivo and in vitro studies confirmed its upregulation by melatonin [15]. Also, melatonin signaling in a SIRT1-mediated way is supported by the lack of melatonin effects in the case of SIRT1 inhibition or knockdown [16]. SIRT1 was reported to interact with the core circadian oscillator complex BMAL1:CLOCK (basic helix-loop-helix ARNT-like 1: circadian locomotor output cycles kaput), as to intervene in the positive feedback loop involving nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide adenine dinucleotide (NAD⁺), influencing the expression of the period circadian regulator 2 (Per2) gene, a central player in circadian rhythm regulation [17, 18, 19]. SIRT3 can also intervene in the NAD⁺ cycle, linking circadian rhythms to mitochondrial oxidative metabolism [20]. SIRT3 plays a pivotal role in mitochondrial antioxidant defense, increasing the expression of superoxide dismutase 2 (SOD 2) and catalase, two enzymes of paramount importance in counteracting the deleterious effects of oxidative stress [21, 22]. Moreover, intracellularly, melatonin is primarily concentrated in the mitochondria, its concentration in this organelle being higher than in any other [23]. Mitochondrial melatonin is not released in the systemic circulation and its synthesis is independent of light exposure [24]. Both melatonin and SIRT3 were reported to fight against oxidative stress by enhancing the expression of antioxidant enzymes [24, 25, 26, 27, 28], and melatonin’s antioxidant effects seem to be SIRT3-mediated [29]. Consequently, its mitochondrial accumulation goes hand in hand with its antioxidant and antitumor actions, contributing to the maintenance of redox homeostasis and combatting malignant cell transformation [23].

Melatonin can act both as a pro-inflammatory and an anti-inflammatory molecule. This duality might come as a surprise, however, just as with other hormones, its function may vary under different conditions and when concerning various cell types [16, 30]. Its pro-inflammatory effect can be deemed beneficial when considering its action as an immune stimulatory agent concerning leukocytes and their ability to fight off pathogens [30, 31, 32] while proving detrimental in autoimmune maladies. The anti-inflammatory effects usually take center stage as they can be the basis of melatonin-based therapies in diseases with a low-grade inflammatory component, such as neurodegenerative or metabolic diseases, or characterized by high-grade inflammation, such as ischemia-reperfusion or brain injury and sepsis [16, 33, 34].

In this chapter, we aimed to construct a summary of the current state of understanding on a wide topic concerning the link between melatonin’s effects and sirtuin signaling, concerning regulation of circadian rhythms, inflammation, and aging, in the most prevalent noncommunicable diseases currently associated with increased mortality and morbidity, selecting the most relevant, novel, and comprehensive research previously published by other scientists. The attention was primarily focused on their impact on cardiovascular diseases, central nervous system disorders, metabolic imbalances, neoplasms, and the process of aging, detailing the complex biochemical mechanisms involved.

2. Cardiovascular diseases

The imbalance of melatonin, which is one of the master regulators of the internal clocks in humans, is clearly associated with an increased risk of diseases, correlated with impaired sleep and aging-associated pathology, mainly cardiovascular, metabolic, and neurodegenerative disease [35, 36, 37, 38, 39, 40, 41, 42].

One of the main pathways responsible for the correlation between melatonin and age-related chronic disease is represented by sirtuins [36, 37]. The interplay between the circadian machinery and sirtuins promotes cardiac health in a complex biochemistry of regulatory systems, mainly by modulating metabolic homeostasis and cell death or survival genes and influencing energy metabolism [43]. Recent research suggested that sirtuins in general, but SIRT1 in particular, have a crucial role in connecting the cellular metabolism to the circadian/internal clock [43, 44].

SIRT1 is directly implicated in the mechanistic development of cardiomyocytes, being responsible for regulating the voltage-gated cardiac sodium ion channels, reducing the risk of atherosclerotic plaque build-up, protection against oxidative damage, and lowering thrombotic risk [43, 45].

Melatonin is an amphiphilic molecule, so it can be found in all subcellular components, with a high concentration in cellular and subcellular membranes [8, 24, 46, 47]. As a result, it has the ability to act as a stabilizer of membrane processes acting against lipid peroxidation and oxidative impairment of mitochondrial DNA [28, 48, 49]. Melatonin is concentrated in the mitochondria and, as a consequence, it improves the electron transport chain efficiency and stimulates ATP production [50]. Its subcellular localization is somewhat overlapping with SIRT isoforms, supporting the intertwining of their signaling pathways; for example, recent data argues that melatonin and SIRT3 may act synergistically in regulating free radical generation and shielding mitochondria from oxidative damage [24].

Melatonin acts through different signaling pathways, either membrane- or organelle-focused, influencing the dynamics of physiological processes and protecting from pathological shifts. One of the key pathways modulated by melatonin concerning its protective actions is represented by modulating SIRT1 expression [9, 11]. Melatonin induces the transcriptional activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and, consequently, antioxidant response element (ARE) through a SIRT1-dependent mechanism [51, 52]. Nrf2 is transcription factor that is able to bind to DNA and regulate the gene expression concerning antioxidant defense, as part of a master antioxidant and cytoprotective pathway, also inhibiting inflammation-enhancing signaling, such as the NLR family pyrin domain containing 3 (NLRP3) inflammasome [53, 54, 55].

Moreover, melatonin as well as its metabolites acts as ROS scavengers, stimulating the synthesis of antioxidant enzymes [7, 25, 28, 56]. Owing to its antioxidant action, melatonin was able to protect against ischemia-reperfusion injury in all organs, the activation sirtuins being most likely involved [10]. In a model of ischemia-reperfusion injury, the protective effects exerted by melatonin were dependent on the mitochondrial SIRT3. Melatonin’s action was correlated with the stimulation of the adenosine monophosphate-activated kinase (AMPK)—peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)—SIRT3 signaling, the activation of mitochondrial SOD and the enhancement of Nrf2 and mitochondrial transcription factor A (TFAM) expression [24, 57]. AMPK has a pivotal role in energy metabolism and homeostasis, adapting cell response to stress and nutrient availability. Recently, it was reported that AMPK functions as a redox sensor, also influencing autophagy, cell proliferation, and apoptosis, seemingly being involved in cardiovascular health and disease [58, 59]. PGC-1α is a key regulator of mitochondrial metabolism, being central to quite a few cellular pathways combating oxidative stress and inflammation [60]. This molecule is a crucial factor in the cellular stress response in the ischemic myocardium [60, 61]. TFAM is a mitochondrial DNA-binding protein vital for the maintenance of the mitochondrial genome, involved in the inflammatory stress response. An altered TFAM function was linked to pathological changes, especially in neurodegenerative diseases and aging [62, 63]. SIRT3 inhibition hinders mitochondrial SOD2 upregulation, leading to oxidative stress, which prevents melatonin’s ability to protect the myocardium from free radical destruction [64].

Melatonin attenuates sepsis-induced myocardial injury by inhibiting caspase-3-induced apoptosis via SIRT1 activation [65]. Caspase-3 is a protease involved in tissue differentiation and regeneration, neural development, and, most famously, cell apoptosis, being possible target in the therapy of cardiovascular diseases, neurodegenerative disorders, and malignancies [66, 67]. Melatonin also exerts anti-inflammatory SIRT1-dependent effects, as the downregulation/inhibition of SIRT1 was reversed under the effect of melatonin in a H₂O₂-induced pro-inflammatory cell model [68]. On the other hand, experimental research shows that melatonin upregulates sirtuins, with a consequent downregulation of transcription for pro-inflammatory proteins and kappa-light-chain-enhancer of activated B cells (NF-κB) by suppressing the activation of toll-like receptor 4 (TLR4) and NLRP3 inflammasome [4, 69]. TLR4 activation leads to pro-inflammatory signaling (i.e., NF-κB) and synthesis of pro-inflammatory cytokines [70, 71]. NLRP3 inflammasome is a protein complex that assembles in response to cellular stress, promoting inflammation; its chronic aberrant activation is part of the etiopathogenesis of numerous diseases characterized by low-grade inflammation [72].

Furthermore, melatonin downregulates inflammation-associated enzymes such as inducible nitric oxide synthase (NOS) and cyclooxygenase 2 (COX-2), leading to lower levels of pro-inflammatory molecules, also contributing to an increase anti-inflammatory cytokines (e.g., interleukin 10, IL-10), thus exerting a protective effect against cardiovascular, metabolic, and autoimmune disease, which are all associated with oxidative stress and inflammation [73, 74, 75, 76]. In a model of apolipoprotein E-deficient mice, melatonin decreased endothelial impairment, as well as the loss of SIRT1 and endothelial NOS activities, lowered tumor protein p53 and endothelin-1 expression. Administering melatonin formulated as a long-release dose and was more effective in counteracting endothelial dysfunction through multiple mechanisms, including SIRT modulation [46, 77].

Human studies confirm the correlation between melatonin, sirtuins, and the risk of cardiovascular disease. A clinical trial published in 2017 showed that the time of day (morning vs. afternoon) when patients underwent isolated aortic valve replacement interventions clearly influenced the overall survival, with a direct advantage of patients involved in afternoon intervention, who were characterized by fewer post-interventional events; also, that hypoxia-reoxygenation tolerance of the human myocardium is higher in the afternoon [35, 78]. These results confirm the observations regarding the higher incidence rate of cardiovascular events (myocardial infarction, stroke, arrhythmias, and sudden cardiac deaths) in the morning than in the evening. Also, from a chronotherapeutic perspective, the efficacy of antihypertensive treatments is higher when administered in the afternoon, according to both animal and human studies [41, 79, 80, 81].

There are several studies supporting the synergistic effects of melatonin and sirtuins, with cardiovascular beneficial outcome through antioxidant and anti-inflammatory mechanisms; in experimental/preclinical studies mimicking severe pathology, such as cardiac ischemia-reperfusion of normal and diabetic rats, endoplasmic reticulum stress in cardiomyocytes, lipopolysaccharide (LPS)-treated microglial cell lines, in brain injury by cecal ligation/puncture in mice, these results are confirmed [10, 51, 69, 82, 83]. This synergy is also supported by results showing that melatonin effects are antagonized by sirtuin inhibitors or by silencing the protein.

3. CNS disorders

CNS disorders encompass a wide variety of diseases from neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or multiple sclerosis, to neuropsychiatric disorders, such as depression, anxiety, or substance abuse, all being associated with a decreased quality of life [84, 85, 86]. Their etiopathogenesis is very complex, with multiple processes and alterations being involved, including neuroinflammation, disruption of autophagy, protein and lipid metabolism, redox, and energy and circadian homeostasis [86, 87, 88].

SIRT1 is widely expressed in the CNS, with anti-inflammatory and neuroprotective actions in numerous neurodegenerative diseases experimental models [1], and its recent link to melatonin signaling opens a new research path in the therapy of neurodegenerative diseases [89].

One of the mechanisms of melatonin’s neuroprotective effect involves the increase of SIRT1 expression and the activation of SIRT1/Nrf2 pathway and the inhibition of the NLRP3 inflammasome [90, 91]. These might prove pivotal in the melatonin-based therapeutic approaches of some CNS disorders, seeing as the NLRP3 inflammasome is involved in the development or progression of neurodegenerative diseases [92], ischemia-reperfusion injury [93], traumatic brain injury [94], and cerebral tumors [95].

Neuroinflammation can be triggered by numerous factors, such as cellular damage or pathogens, and results into extracellular matrix damage and immunological reactions that can ultimately lead to neuronal oxidative damage and neurotransmitter dysfunction [1]. Further, the decrease in melatonin results in circadian dysregulation, decreased antioxidant defense, and alteration of normal mitochondrial functioning [26].

Inflammation is central to the pathogenesis of major depressive disorder (MMD) [91]. SIRT1 plays an important role in numerous cellular processes, including inflammation, in the hippocampus and central cortex [11], being recently linked to depression [96]. Mediation of inflammation by SIRT1, mainly via NF-κB and NLRP3 inflammasome downregulation, was shown to alleviate depression and anxiety-related behavioral deficits [91, 97, 98]. The NF-κB family of transcription factors is a key regulator of inflammation, immune responses, and cell proliferation, which, along with the NLRP3 inflammasome, contributes to amplifying inflammation [99, 100, 101].

Mitochondrial changes seem to play a crucial role in the development of MDD [26], and sirtuins are key regulators of mitochondrial processes, seeing as three of the seven family members are mitochondria-based [9]. The enhancement of the SIRT1–PGC-1α pathway is another signaling route via which melatonin exerts its protective effects, this time mitochondria being the main target, as PGC-1α is known as the master mitochondrial regulator, increasing their biogenesis and function [26]. SIRT1 enhancement by melatonin as a secondary signaling pathway [89] could correct some of the oxidative, mitochondrial, and neurotransmitter imbalances characteristic for depression and other neuropsychiatric disorders [102, 103], and contribute to uncovering more of the cellular pathways involved in melatonin’s antidepressant-like effect [104, 105].

Neurodegenerative disease diagnosis had a sharp escalation in the last decades, increasing elderly morbidity and mortality [35]. Inflammation is part of normal aging; however, it is also part of the pathogenesis of several maladies, including neurodegenerative diseases [4]. This type of neuroinflammation is not of an infectious cause but entails moderate, slowly progressing microglia activation, supported by oxidative stress and mitochondria dysfunction, encompassing immune cells, astrocytes, and neurons [4].

Brain inflammation is a hallmark of neurodegenerative diseases, most notably Alzheimer’s disease (AD) [4]. Both AD and Parkinson’s disease (PD) are associated with an altered circadian rhythm, alongside impaired homeostasis of redox and inflammatory processes [4, 106]. AD is the most prevalent form of dementia in the elderly, being characterized by modified sleep patterns, abnormal melatonin secretion, and circadian dysregulation [26, 107, 108], shifting sleeping habits being reported early in its progression [35]. SIRT1 is an important link between circadian rhythm and redox homeostasis [35]. Melatonin is intimately linked to SIRT1 function in aging cells [109, 110]. Age-associated NAD⁺ and SIRT1 deficiency, changes which are observed in neurodegenerative diseases also, are associated with mitochondrial dysfunction, autophagy, and circadian rhythm alterations, which can be reversed by melatonin [4, 111]. In preclinical and in vitro neurodegenerative diseases models, melatonin proved beneficial [112], while in clinical settings results varied [112], but the majority of studies reported improved sleep quality and reduced daytime sleepiness, stabilizing the circadian rhythm, and slowing down the progression of cognitive impairment [113, 114, 115, 116, 117].

Traumatic brain injury is a worldwide leading cause of mortality and morbidity, with debilitating long-term sequels. Sleep alterations are among the most common long-term post-injury implications. Animal studies showed that melatonin improved cognition as well as behavior; it also reduced post-injury cognitive decline and the risk of developing dementia, while human studies are scarce [118, 119]. The development of secondary injury following traumatic brain injury is dependent on the inflammatory response in the cerebral cortex, the NLRP3 inflammasome playing a central part [120, 121, 122]. SIRT1 was reported to have a protective role against traumatic brain injury, seeing as it mitigates oxidative stress and ROS production, which can, in turn, activate the NLRP3 inflammasome [1]. Further, resveratrol, a well-known SIRT1 activator [11], attenuated inflammation and oxidative stress by suppressing the NLRP3 inflammasome in a SIRT1-dependent manner [120]. Taking into consideration the melatonin-SIRT1 relationship, this neurohormone is a possible candidate as an additional therapeutic option in traumatic brain injury [118, 119].

4. Metabolic imbalances

Metabolic diseases, such as diabetes mellitus, metabolic syndrome, and obesity, have exponentially increased in the last decades, posing a serious threat to human health. They are characterized by inflammation and oxidative stress, along with impairments of cell metabolism, energy homeostasis, insulin secretion and function, and microbiota alterations [123, 124, 125, 126].

Melatonin is involved in energy metabolism pathways and regulates epigenetic processes in neuronal cells, being biochemically interconnected with signaling pathways responsible for adjusting energy metabolism, such as insulin/insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxO), and sirtuin pathways [110, 127, 128, 129, 130, 131]. Alterations of the expression and activity of circadian rhythm components are commonly found in patients with neurodegenerative, metabolic disorders, and cancer [37, 127, 132]. Also, melatonin levels and CLOCK expressions are reduced in patients with neurodegenerative and metabolic disorders [133, 134, 135, 136, 137, 138, 139].

All these pathological impairments have an underlying component of oxidative stress and mitochondrial function failure. Sirtuins, and especially SIRT1, as well as the peroxiredoxin protein family, are directly involved in the relationship between redox homeostasis and circadian rhythm, regulated by melatonin [37, 127, 132, 133, 134, 135, 136, 137, 138, 139].

Metabolic syndrome and diabetes are associated with oxidative stress and inflammation, reunited under the umbrella of inflammaging, and would clearly benefit from the melatonin/SIRT synergy [69], seeing as melatonin is a key player in energy sensing/energy expenditure and body weight regulation. Animal studies showed that removing the pineal gland from rats led to a body weight increase that could be reversed by exogenous melatonin administration, along with a decrease of visceral fat; the results were found in animals fed either high fat or high fructose diets [140, 141]. Also, rat pinealectomy was associated with decreased insulin sensitivity and reduced glucose transporter type 4 (GLUT4) gene expression [142, 143]. In animal models, melatonin, as well as selective melatonin receptor agonists, induced a reduction of body weight and blood pressure, increased insulin sensitivity, and restored lipid homeostasis [34, 144]. These preclinical reports, among others [145, 146], highlight the potential of melatonin therapy in improving glucose metabolism and contribute to diabetes mellitus prevention [145, 146].

Impairments of melatonergic signaling due to genetic polymorphism support the development of a prediabetic status, type 2 diabetes, elevated cholesterol, triglycerides, and coronary heart disease; mice knocked out for the melatonin receptor MT1 or with pinealectomy exhibit insulin resistance [137, 142, 143, 147]. These metabolic alterations were reversed by melatonin, which decreased pro-inflammatory signaling (TNF-α, IL-1β) and inducible NOS by suppressing NF-κB expression in a SIRT-dependent manner [44, 148, 149].

Human studies confirm the metabolic protective action of melatonin, reporting antihyperlipidemic effects and a reduced insulin release (via pancreatic β-cells receptors), also contributing to alleviating metabolic syndrome via SIRT regulation, enhancing antioxidant and anti-inflammatory pathways [139, 150]. In type 2 diabetic patients low-circulating levels of melatonin were found, as well as increased mRNA for the melatonin membrane receptor [150, 151], while genetic variations of melatonin receptors are associated with impaired levels of fasting blood glucose and increased risk of type 2 diabetes, and also with polycystic ovary syndrome [45, 152, 153, 154]. Also, coronary artery disease patients show decreased melatonin levels; exogenous melatonin was effective in reducing blood pressure and cardiovascular rhythm alterations, preserving the availability of nitric oxide and yielding anti-remodeling cardiac effects, thus providing cardiovascular protection in metabolic syndrome patients [45, 137, 155]. Controlled clinical studies confirmed the antihypertensive properties of melatonin, and also underlined its ability to improve lipid profiles, with an increase of HDL, in metabolic syndrome patients [156].

5. Musculoskeletal disorders

Skeletal muscle is essential for posture and movement, but it is also directly involved in glucose uptake, thermal regulation, and nutritional balance, among other important physiological roles [157, 158, 159]. Therefore, deterioration of skeletal muscle mass is associated with impaired glucose homeostasis, and not only with posture/movement-associated difficulties (falls, fractures, disability) [160]. Moreover, skeletal muscle ailments are considerably increasing in aging, thus bringing up the costs of healthcare and having a negative impact on the quality of life [159].

Melatonin was reported to support muscle activity through its ability to maintain mitochondrial function, alongside oxidative stress reduction and inhibition of cardiolipin peroxidation [15, 24, 69]. Cardiolipin is a dimeric phospholipid found in the inner mitochondrial membrane that undergoes oxidation and translocation to the cytosolic side of the outer mitochondrial membrane under oxidative stress conditions, signaling a dysfunctional mitochondria [161, 162]. In Refs., [163, 164] dystrophic muscle diseases are biochemically characterized by inflammation, redox imbalance, and mitochondrial dysfunction, and could benefit from melatonin treatment [160, 165]. This is attributable to its lipophilic nature, making it possible to pass through cells and mitochondrial membranes and the blood-brain barrier, as well as its effect as a calcium homeostasis regulator during muscle contraction [166, 167]. When administered as a nutraceutical in preclinical, but also in clinical studies, it improved muscle metabolism and strength [163, 164]. These positive effects are also pointed out in age-related sarcopenia and muscle weakness [160].

Chronic melatonin administration in rat and mouse models of muscle injury reduced apoptosis, increased twitch force, and accelerated the regeneration of satellite cells. Women with fibromyalgia benefit from melatonin administration which induces reduction of symptoms such as chronic muscular pain, cognitive dysfunctions, and sleep disorders [159, 168, 169].

Calpain is a receptor of calcium, found in the cytoplasm of skeletal muscle cells in an inactive form, being controlled by intracellular calcium ion concentration and calpain inhibitory protein. An increase in the skeletal muscle cells’ cytoplasmic Ca²⁺ concentration activates calpain, resulting in the hydrolysis of skeletal muscle fibers, leading to reduced contractility. Melatonin was reported to inhibit calpain, but more in-depth studies are required to establish its clinical potential [170, 171, 172].

In Refs., [159, 168, 169] literature data reveal melatonin to be a promising agent for muscle regeneration and maintenance, with a possible use in chronic diseases, especially those associated with aging, sirtuins being just one of the signaling pathways involved. Nevertheless, further studies, both preclinical and clinical, are needed to establish its muscle-protective mechanisms and clinical use aspects.

6. Neoplasms

Malignancies have an ever-increasing prevalence and a cancer diagnosis has a severe impact on the quality of life and mental well-being of patients [173]. The antitumor effect of melatonin was reported in different types of cancer, interfering with various cancer hallmarks, mitigating cancer initiation, progression, and metastasis [174, 175].

The disruption of circadian rhythm due to exposure to excessive light or frequent long-distance travel entails an alteration of melatonin synthesis and secretion, with an associated increased risk of cancer development [176, 177]. In vitro studies in breast cancer cells showed that exposure to white fluorescent light led to decreased melatonin levels and increased tumor growth [178], while the blood of volunteers exposed to white fluorescent light during nighttime had lower melatonin levels and proved a better tumor growth medium [178].

Melatonin administration decreased proliferation parameters and induced a reduction in tumor growth, concomitantly downregulating SIRT1 [179]. The downregulation or inhibition of SIRT1 led to increased pro-oxidant and antitumor activity [180, 181], while its activation decreased melatonin’s anticancer action [182].

The relationship between SIRT1 and melatonin in cancer cells is opposite to that in nontumor cells, melatonin acting as an inhibitor of SIRT1 activity [44]. This might come as a surprise, but seeing as SIRT1 is overexpressed in some types of cancer [183, 184], a context-specific role for melatonin in regulating the activity of this sirtuin is plausible [185]. The dual role of melatonin concerning SIRT1 regulation in normal and malignant cells seems to entail its ability to either stimulate or inhibit the activity of SIRT1. Moreover, this regulation might not only target cell proliferation but also the control of circadian regulation genes, such as BMAL1 or Per2, which are key players in maintaining tissue homeostasis [90, 185].

7. Aging

Aging is a ubiquitous phenomenon that encompasses numerous biological changes that, in time, lead to the decline of an organism [186]. In humans, aging entails a gradual accumulation of physical and cognitive alterations, with an increased risk of developing various maladies, such as cardiovascular, metabolic, or neurodegenerative diseases and malignancies [186, 187, 188]. These often cause a marked decline in the quality of life, being associated with higher morbidity and mortality.

Aging is associated with an alteration of circadian rhythm synchrony and reduced secretion of melatonin [1, 35]. Also, a reduction of SIRT1 activity was observed in senescence, while its inhibition abolished a number of melatonin’s cellular effects [69]. Lower SIRT1 levels were observed in the suprachiasmatic nucleus (SCN) of aging mice, affecting the functioning of the core circadian oscillator BMAL1:CLOCK, while its overexpression prevented aging-depending circadian rhythm alterations and its silencing in young animals decreased BMAL1 and Per2 gene expression [189].

Low-grade inflammation is a major component of physiological aging, especially considering its association with the alteration of brain function, neurodegeneration, and mood disorders [137, 190]. The contribution of inflammation to the aging process is known as inflammaging [4, 16]. Apart from playing a central role in longevity, regulating cellular processes as cell cycle, apoptosis, or DNA repair, SIRT1 is involved in modulating antioxidant and anti-inflammatory processes [11]. SIRT1 seems to be an important factor in trying to assess the extent of melatonin’s effects on aging and aging-associated low-grade inflammation [1]. Moreover, melatonin enhances the antioxidant defense of senescent cells, regulating redox homeostasis. A central player in this effect is SIRT1, whose upregulation results in the increased expression of antioxidants via Nrf2 and FOXO pathways, modulating mitochondrial ROS production and autophagy, while inhibiting NF-κB signaling [35].

Despite all these, some conflicting results regarding the effect of melatonin treatment on SIRT2 activity were reported in preclinical models of aging. One research group found no effect on SIRT2 in neurons from the dentate gyrus [191], while another group observed that melatonin treatment led to a decrease in SIRT2 activity in the hippocampus of adult rats [192], and in the colon and hippocampus of aged rats [193, 194], reducing oxidative stress parameters and pro-apoptotic proteins.

Both the pro-inflammatory effect of melatonin, as well as the anti-inflammatory, must be considered when addressing its potential use in mitigating some aging-associated signs and symptoms [69]. Most data are supportive of its beneficial, anti-inflammatory actions. However, some reports concerning autoimmune diseases, such as rheumatoid arthritis or multiple sclerosis, bring to the fore its possible detrimental effects [195, 196, 197]. Its protective actions fall mainly under the umbrella of the above-mentioned and well-documented antioxidant and anti-inflammatory effects, along with its stimulation of the immune system, promoting healing and maintaining homeostasis [187, 188, 198, 199]. A special melatonin-mediated pathway, central to the aging process, is the enhancement of SIRT1 activity.

8. Discussion

Melatonin, a hormone primarily synthesized in the pineal gland, has emerged as a critical regulator of circadian rhythms and a multifunctional molecule with antioxidant, anti-inflammatory, and neuroprotective properties, involving numerous cellular signaling pathways (Figure 1).

Figure 1.

An overview of the SIRT1-mediated melatonin effects in noncancerous and malignant cells. ROS-reactive oxygen species, AO-antioxidant, BMAL1:CLOCK-basic helix-loop-helix ARNT-like 1: circadian locomotor output cycles kaput, Per2-period circadian regulator 2 gene, PGC-1α-peroxisome proliferator-activated receptor gamma coactivator 1-alpha, Nrf2-nuclear factor erythroid 2-related factor 2, FOXO-Forkhead box O, NF-κB-kappa-light-chain-enhancer of activated B cells, NLRP3-NLR family pyrin domain containing 3 inflammasome.

The anti-inflammatory activity of melatonin involves both immunological and non-immunological processes [16]. The latter mainly includes protection against oxidative stress by promoting antioxidant defense and decreasing the formation of reactive oxygen and nitrogen species, and the preventing mitochondrial dysfunction [16]. It contributes to an anti-inflammatory pathway involving sirtuin activation, namely SIRT1, Nrf2 upregulation, and nuclear factor NF-κB downregulation [1, 69]. Also, it was reported to downregulate COX-2 and neuronal NOS, to prevent TLR4 and NLRP3 inflammasome activation [16]. These resulted in an increased secretion of anti-inflammatory cytokines and decreased production of ROS and pro-inflammatory cytokines [1, 16].

Exploring the melatonin-sirtuins interaction holds significant promise in advancing our understanding of their joint impact on human health. On the other hand, sirtuins, a family of deacetylase enzymes, play fundamental roles in cellular processes such as gene expression, DNA repair, and stress response. The interplay between melatonin and sirtuins has been implicated in a spectrum of biological phenomena, ranging from circadian rhythm regulation to cellular homeostasis and physiological aging. Investigating the intricate crosstalk between melatonin and sirtuins has the potential to unlock novel insights into the mechanisms governing these processes and different pathological milieu modulation.

Moreover, understanding how melatonin influences sirtuins activity and vice versa could pave the way for the development of innovative therapeutic strategies targeting a wide array of health conditions, including sleep disorders, cardiovascular and metabolic diseases, neurodegenerative disorders, and cancer. These melatonin-sirtuins studies not only shed light on the fundamental principles of circadian biology and cellular physiology but also offer promising avenues for enhancing human health and well-being.

9. Outlook

Melatonin is considered one of the master regulators of the circadian rhythm, being intensively studied for its pleiotropic effects concerning redox imbalance, inflammation, immune response, aging, cell proliferation, and even fertility. The present chapter aims to critically analyze the latest scientific information regarding the interplay between sirtuins and melatonin in order to better understand the role of this complex system and its potential modulation in preventing/treating various afflictions. As a result, we pointed out that sirtuin signaling is directly involved in the cardio- and neuroprotective effects attributed to melatonin, as well as its ability to support musculoskeletal function and regeneration and to restore metabolic and energy homeostasis. Regarding malignancies, the relationship between SIRT1 and melatonin in cancer cells is opposite to that in non-tumor cells, with an overall antitumor action. All these reported effects are integrated as important pathways, justifying the protective effect of melatonin in aging-associated pathology through SIRT-mediated pathways. In this complex picture, there is an acute need for further studies to substantiate all these scientific claims, since there is a great imbalance between in vitro, preclinical and clinical studies, for each of the above-mentioned effects. Also, a systematic review of the latest literature data, encompassing the cellular pathways through which melatonin modulates physio-pathological processes, focusing on the interconnection with sirtuins, is highly needed considering the current heterogeneous research output.

Conflict of interest

The authors declare no conflict of interest.