Light, Obesity, and COVID-19 — The Melatonin Connection

By Doris Loh

The end of summer is approaching. Parents, schools and policy-makers are faced with the almost impossible task of weighing the benefits against risks of in-person education when virtual alternatives are available. What are the real risks facing children for attending in-person education?

Evidence accumulated so far seems to indicate that COVID-19 presents relatively lower risks to school-aged children.  Compared to adults, even when infected, children generally exhibit mild to no symptoms. Unfortunately, this observation is no longer applicable to many children around the world. Unlike the first three months of the pandemic, where no deaths have been reported in published literature [1], documentation of children infected by SARS-CoV-2 suffering from Multisystem Inflammatory Syndrome in Children (MIS-C) is now not uncommon in countries including the United States, Luxembourg, Spain, France, United Kingdom, Canada, Switzerland, Sweden, to name a few [2, 3].  Along with increased severity of COVID-19 disease symptoms, a recent report by The American Academy of Pediatrics showed a 40% increase of over 97,000 COVID-19 cases in children across 49 states in the USA [4]. 

What is MIS-C, and Why is it Important?

In April, U.K. pediatricians found an unusual inflammatory disease very similar to Kawasaki Disease in some children infected by SARS-CoV-2. Soon, many countries began to report similar cases. The term multisystem inflammatory syndrome in children (MIS-C) was given by the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) after releasing their definitions of the disorder. 

Although this condition is uncommon (approximately 2 in every 100,000 persons < 21 years of age), as of the end of June, more than 1,000 cases of MIS-C have been reported worldwide [5], whereas around 322 in 100,000 persons younger than 21 years of age during the same period were diagnosed with SARS-CoV-2 infections [6].

A recent report published by the New England Journal of Medicine reported 186 cases of MIS-C from 26 states in the USA. The patients had a median age of 8.3 years. 73% of these patients were previously healthy. Organ-system involvement revealed cardiovascular involvement in 80% of patients, hematologic involvement in 76%, gastrointestinal system in 74%, and respiratory in 70%. 80% of these patients required intensive care, and 4 of the patients (2%) died. 92% of these patients exhibited elevated levels in at least four biomarkers for inflammation [7]. 

The majority of MIS-C patients had high erythrocyte sedimentation rates or C-reactive protein levels. These patients often showed hematological involvement including anemia, lymphocytopenia, thrombocytopenia, neutrophilia, and elevated ferritin levels. Elevated fibrinogen, and d-dimer levels indicated dysfunctions in blood clotting [7]. Although uncommon, MIS-C is a hyperinflammatory condition that can inflict damage to multiple organs. MIS-C is now considered to be serious and life-threatening in young children and adolescents infected by SARS-CoV-2, even though most of them may be previously healthy [7].  

What is the most common underlying condition that affects disease severity and mortality in COVID-19?

An extensive country-level model that incorporated data from 50 different countries found that rapid border closures, full lockdowns, and wide-spread testing were not associated with mortality in COVID-19 patients. However, full lockdowns were significantly associated with increased patient recovery rates.  

In this country-level analysis, the authors found obesity to be the one variable that showed a  SIGNIFICANT positive correlation with death rates, while reduced income dispersion within the nation, smoking prevalence and the number of nurses per million population were negatively correlated with increased COVID-19 mortality [8].

Why is obesity an important determinant of disease severity in COVID-19, and what does melatonin have to do with obesity? To fully unravel this complex relationship, we need to first understand what has changed in the countries that reported higher levels of infection and MIS-C in children since Feb and March. 

High Levels of Melatonin in Young Children is Protective against COVID-19

Melatonin is now recognized to be an effective treatment for SARS-CoV-2 infection [9-17]. Children under the age of nine can produce up to TEN TIMES the amount of peak melatonin than healthy adults. Even then, the maximum levels recorded for children showed a rapid decline as age increased. Children between the ages of 1 to 5 had peak melatonin at 325 picograms/m (pg/ml), while melatonin levels in those between the ages of 5 to 11 already declined to 133 pg/ml [18].  

Normal healthy adults between the ages of 65 to 70 years produce only around 49.3 pg/ml. After the age of 75, maximum production levels can be further reduced by 44% to  27.8 pg/ml [19].

{Source: Grivas TB, Savvidou OD. Melatonin the “light of night” in human biology and adolescent idiopathic scoliosis. Scoliosis. 2007;2:6. Published 2007 Apr 4. doi:10.1186/1748-7161-2-6]

 

Melatonin is an Immune System Modulator

The ability of melatonin to regulate the immune system in not only animals but plants as well, has catapulted this ancient molecule into the limelight surrounding COVID-19 treatment [20-24]. 

The decrease in circulating melatonin in the elderly is also accompanied by a distinct shift in their cytokine profiles where there is often a decline in CD3+ and CD4+, and an increase in CD8+ cells. Melatonin can reverse this age associated shift by increasing CD3+, or natural killer-like T-cells, and CD4+ cells, while inhibiting CD8+ cells [25].  Melatonin can enhance immune function in both the elderly as well as patients with compromised immune systems. 

SARS-CoV-2 infection can cause deleterious cytokine storms by activating NLRP3 inflammasomes via different mechanisms including extracellular hemoglobin from damaged red blood cells, calcium influx, and viroporins activities  [15, 26].  Melatonin has been demonstrated to be able to modulate and inhibit the activation of NLRP3 inflammasomes, greatly alleviating kidney damage, acute lung injury, and sepsis in animal models [27-29].

If higher melatonin levels protected young children from developing severe symptoms like MIS-C from SARS-CoV-2 infections during the early months of the COVID-19 pandemic, what has changed since April that altered the effectiveness of melatonin protection in young children and adolescents?

Immune functions in humans and animals are influenced by seasonal changes. Those changes are mediated by the duration of melatonin secretion, acting as a photoperiodic signal. Increased melatonin production during shorter days is a part of an integrative system that enables animals to cope with energetic stressors during cold winters [30]. In humans, seasonal changes in cytokines and immune functions may also be mediated by the changes in the duration of melatonin secretion [25, 31, 32]. 

It is therefore possible that changes in photoperiodism affecting melatonin secretion may be the reason for increased disease severity in children and young adolescents. The seasonal changes in melatonin levels may also have caused the increased observation of neurological dysfunctions in COVID-19 patients [33-37].  

How do seasonal changes affect melatonin production?

Melatonin Production is Altered by Photoperiod 

The ability of plants and animals to alter their functional or behavioral response to changes in duration in daily, seasonal or annual cycles of light and darkness is known as photoperiodism [38].  Even though melatonin is synthesized in various tissues and organs of the human body at levels exceeding pineal production [39, 40], the pineal gland is the only organ responsible for melatonin circadian rhythm [41]. 

The production of melatonin in pineal glands is associated with darkness. Melatonin is therefore, generally referred to as the ‘hormone of darkness’. More accurately, melatonin is a chemical expression of darkness [42]. Dopamine (DA)  is a critical neuromodulator controlling brain states, action, reward, learning, locomotor activity, and memory processes [43, 44]. Both melatonin and dopamine participate in the entrainment of the biological clock. Melatonin and dopamine are often found to act as mutually inhibitory signals representative of night and day respectively [45]. 

Changes in exposure to light or photoperiods are believed to be the major regulators of melatonin production in the pineal glands of vertebrates [46]. During winter, the shorter photoperiod (black bars in diagram) results in increased pineal melatonin production. In general, animals usually have significantly higher levels of melatonin in winter than in summer as a result of less sunlight in the day. 

[Source: Arendt J, Middleton B, Stone B, et al. Complex Effects of Melatonin: Evidence for Photoperiodic Responses in Humans?, Sleep, Volume 22, Issue 5, August 1999, Pages 625–635, https://doi.org/10.1093/sleep/22.5.625]

 

Both light and melatonin can modulate the dopaminergic pathways. 

Light, Dopamine, and Neurological Disorders — The Melatonin Connection

The suprachiasmatic nucleus or nuclei (SCN) is the central clock governing circadian rhythms [47]. The SCN generates many circadian signals via the production of melatonin (N-acetyl-5-methoxytryptamine) in the pineal gland [48]. These circadian signals may involve the inhibition of dopamine release in specific areas of the mammalian central nervous system, including the hypothalamus, hippocampus, medulla-pons, and retina by melatonin [45]. In other areas such as the striatum, dopamine can be modulated by light [48]. 

In Parkinson’s disease, melatonin could potentially exacerbate symptoms due to its ability to interfere with dopamine release. But interestingly, extensive research on melatonin indicates that this chemical of darkness plays an exceedingly protective role in neurodegenerative diseases, especially in Parkinson’s disease, and Alzheimer’s disease [49-53]. 

Melatonin Protects and Increases Dopamine in the Brain

The protective nature of melatonin in the brain is in large part attributable to its nature as a powerful antioxidant. In fact, melatonin is so important that this molecule is synthesized directly in the matrix of mitochondria in the brain [54]. 

It is no surprise to find that melatonin not only protects dopamine neurons, but enhances dopamine synthesis through the increase of tyrosine hydroxylase activity [55]. Tyrosine hydroxylase is the rate-limiting enzyme of catecholamine biosynthesis, by forming the critical step of hydroxylating the amino acid L-tyrosine to L-DOPA [56, 57]. Male syrian hamsters treated with melatonin for 9 weeks were able to significantly increase tyrosine hydroxylase and L-DOPA (dopamine precursor) levels [58]. 

Many people associate light, especially sunlight, with the ability to stimulate dopamine synthesis [59]. LIke everything in nature, light is also a double-edged sword in that it can inhibit melatonin synthesis in the pineal glands. The balance between light and dark is a major key to understanding the complex relationship between melatonin and dopamine. 

Neuromelanin is a Proxy for Dopamine Function in the Brain

The distinctive loss of pigmentation in substantia nigra neurons from the brains of patients with Parkinson’s disease (PD), an observation first made by Konstantin Tretiakoff in 1919, is a fundamental pathological manifestation in PD [60]. The substantia nigra (SN) is a region in the midbrain, and is considered a part of the basal ganglia. Neuromelanin, the abundant pigment found in SN, is the reason why these two structures on each side of the brainstem were named “black substance”, or substantia nigra, in Latin, because the pigment was so dark that it could be readily observed with just the naked eye [61]. 

Neuromelanin (NM) is a paramagnetic metabolic product of dopamine autoxidation. The pigment is first observable in humans at around 3 years of age and continues to accumulate over time. Neurons are unable to degrade or eliminate neuromelanin, which is only cleared from cells following cell death [62,63]. Excess dopamine in the cytosol can either be metabolized by monoamine oxidase and aldehyde dehydrogenase into the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), or the excess dopamine will auto-oxidize to form neuromelanin [64-67]. 

The concentration of neuromelanin in the brain has traditionally been used as a biomarker for neuronal loss in neurodegenerative diseases such as PD. Recent technological advances showed that in vivo MRI signals of neuromelanin correlates with dopamine functions in humans without neurodegenerative disease.

Neuromelanin is now accepted to be a proxy measure for the function of dopamine neurons, and as a clinically useful biomarker for non-neurodegenerative conditions associated with dopamine dysfunction [68]. 

SARS-CoV-2 May Target Cortical Neurons

Evidence is mounting that extensive neurological involvement may be associated with COVID-19 [69-73]. Even though ACE2 receptors are not widely expressed in neurons [74], CD147, which is another possible receptor for SARS-CoV-2 [75], is widely expressed in both cortical neurons as well as in the basal ganglia [76, 77]. Dysregulation of CD147 as a result of receptor binding to SARS-CoV-2 can be part of the cause for neurological disorders.   

Studies now show that SARS-CoV-2 can infect the brain with great affinity to specific cells and regions such as cortical neurons in the cerebral cortex [78, 79]. The cerebral cortex contains between 14 to 16 billion neurons [80]. The basal ganglia, where the substantia nigra is located, is strongly interconnected with the cerebral cortex [81]. It is highly plausible that COVID-19 infection can affect neuromelanin containing substantia nigra as well as locus coeruleus, leading to neurodegenerative development [78]. 

Melatonin may be able to protect the brain during COVID-19 infection, due to its intricate relationship with dopamine, tyrosine hydroxylase, and neuromelanin.

Dopamine, Toxins, and Neuromelanin — The Iron Connection

In Parkinson’s disease pathology, it appears that only neuronal loss in the pigmented areas is associated directly with classic symptoms such as the loss of locomotor activity [82,83]. What is the significance of pigmented areas that are abundant with neuromelanin? 

Even though neuromelanin is associated with the disease progression of PD [84], where the age-dependent increase of neuromelanin could exceed a pathogenic threshold of accumulation that ultimately leads to neurodegeneration and dysfunction in PD, neuromelanin actually have important, critical functions that are largely underappreciated [85, 86]. 

Neuromelanin functions in the cell not only as a toxin-binding agent, but as a vehicle for the binding, storage and release of dopamine. As such, neuromelanin has the important function of maintaining cellular dopamine function [87]. The ability of neuromelanin to bind iron with extremely high affinity [88], is the key to understanding why melatonin is able to protect dopamine neurons.

Iron forms indispensable iron-dependent enzymes, including tyrosine hydroxylase, that are critical in the production and metabolism of neurotransmitters such as dopamine, norepinephrine, epinephrine and serotonin. An excess of iron can also initiate neurotoxic processes in addition to Fenton chemistry. Dopamine can be oxidized to extremely reactive and toxic quinones through the oxidation by ferric iron (Fe3+) [89].

Neuromelanin is formed by the autoxidation  of excess cytosolic dopamine [64]. Oxygen and light can also affect the oxidation of dopamine to produce neuromelanin. In vitro experiments have shown that 40% of dopamine oxidation can be accounted for by oxygen, while 20% of dopamine oxidation is caused by exposure to light [90].  

Light, Iron, and  Neuromelanin — The Melatonin Connection

A ground-breaking study by Romeo et al. (2013) showed that bright light not only significantly reduced dopamine neurons that express tyrosine hydroxylase (TH-positive), but substantially increased neuromelanin [91]. Tyrosine hydroxylase is considered to be a marker for dopamine. Reduced TH-positive dopamine neurons may result in reduced synthesis of dopamine and L-dopa [92]. 

Romeo and his team divided Sprague–Dawley albino rats into three different groups and raised them under different conditions of light exposure during a period of 90 days.  Group A were raised under dim light (0.5 lux) during the dark cycle (12 h/12 h) for the entire duration. Group B were raised under dim light (0.5 lux) during the dark cycle (12 h/12 h) for seventy days and then exposed to continuous bright light (3,000 lux, 24h) for 20 days. Group C were exposed to continuous  bright light (3,000 lux, 24 h) for the entire 90 days [91].

The rats were sacrificed at the end of the experiment period and examined for neuromelanin formation and tyrosine hydroxylase-positive neurons in the substantia nigra. This is what they found:

A Staggering 29% Decrease in TH-Positive Neurons in Rats Exposed to Continuous Light for 90 days

[Source: Romeo S, Viaggi C, Di Camillo D, et al. Bright light exposure reduces TH-positive dopamine neurons: implications of light pollution in Parkinson’s disease epidemiology. Sci Rep. 2013;3:1395. doi:10.1038/srep01395]

 

A Corresponding Decrease in Dopamine and its Metabolite DOPAC in the Striatum

[Source: Romeo S, Viaggi C, Di Camillo D, et al. Bright light exposure reduces TH-positive dopamine neurons: implications of light pollution in Parkinson’s disease epidemiology. Sci Rep. 2013;3:1395. doi:10.1038/srep01395]

A Substantial Increase in Neuromelanin in Substantia Nigra of Rats Exposed to Continuous Light 

[Source: Romeo S, Viaggi C, Di Camillo D, et al. Bright light exposure reduces TH-positive dopamine neurons: implications of light pollution in Parkinson’s disease epidemiology. Sci Rep. 2013;3:1395. doi:10.1038/srep01395]

Dopamine Complexed with Iron Absorbs Light at 437nm and 740 nm

Iron is often found in high levels in the areas of the brain that are rich in dopaminergic neurons. The conversion of dopamine to neuromelanin is facilitated by the iron in the oxidized ferric Fe3+ state [93]. When dopamine is bound to ferric iron, the complex is able to absorb visible light with peaks at 437 and 740 nm [91].  

Romeo and his team showed that the photon energy from the fluorescent lighting used in the experiment, crossed the scalps and skulls of the rats at ~0.1% energy at 436.6 nm peak and ~15% for the minor peaks around 710 nm. The external light that passed through the heads of the animals (~400 g body weight) was able to reach the substantia nigra, and was absorbed by the dopamine/Fe3+ iron complex. Light photons have been demonstrated to travel a 13.3 cm path from side-to-side of the human head [94]. 

The authors concluded that continuous light exposure facilitated autoxidation  of dopamine to create neuromelanin, because continuous exposure to light increased dopaminergic functions and also suppressed melatonin secretion, leading to the formation of excess dopamine that resulted in increased autoxidation  and reduction of TH-positive neurons[91]. It is also possible that the increased oxidative stress from the higher autoxidation  was responsible for the reduced TH-positive neurons, dopamine and DOPAC [95, 96]. 

Sunlight Increases Neuromelanin in Substantia Nigra of Animals

It is obvious that the fluorescent lighting used in the experiment cannot substitute sunlight.

Does sunlight also increase neuromelanin?

Sunlight is extremely bright, with direct sunlight delivering anywhere between 32,000 lux to 130,000 lux. A landmark study published in 1961 by Marsden examined the substantiae nigrae of 49 mammals in order to determine the effect of sunlight on neuromelanin formation [97].

Romeo et al. re-tabulated the results from the Marsden study into three  light exposure groups. Low light animals were animals living in cavities with nocturnal activities; medium light animals lived in dimly-lit environments such as woodlands, with nocturnal activities; while high light animals were diurnal animals living in open fields such as savannas and deserts.

Romeo et al. found that animals exposed to more light had substantially higher levels of neuromelanin [91]. Sunlight contains the full-spectrum of visible light, including 437 nm and 740 nm, absorbed by the dopamin/Fe3+ iron complex. Yet sunlight also contains the 670 frequency.

670 nm NIR Frequency Increases TH-positive Neurons and Dopamine

In animal models treated with MPTP to induce permanent symptoms of Parkinson’s disease, 670 nm frequency was able to rescue dopaminergic neurons and TH-positive neurons destroyed by MPTP in a dose-dependent manner [98]. Mice treated with saline (controls) or MPTP (50, 100 mg/kg body weight) received 670-nm light at an intensity of 40 mW/cm2 at the scalp for 90 seconds, 4 times spread over a period of 30 hours. The authors of the study determined that about 10% of the energy from 670 nm light exposure reaching the surface of the head was transmitted to the brain [98]. 

Mice treated with 50mg/kg MPTP+NIR (670 nm) showed significantly higher levels of TH-positive neurons. Whereas mice treated with 100mg/kg MPTP+NIR (670 nm) had lower levels of TH-positive neurons compared to controls, but the levels were still higher than mice treated with the same amount of MPTP without NIR exposure [98]. MPTP-NIR groups compared to MPTP groups also showed 35% to 45% increase in dopaminergic cells [98].

[Source:  Shaw VE, Spana S, Ashkan K, et al. Neuroprotection of midbrain dopaminergic cells in MPTP-treated mice after near-infrared light treatment. J Comp Neurol. 2010;518(1):25-40. doi:10.1002/cne.22207]

 

Why is 670 nm capable of neuroprotection, reducing MPTP-induced neuropathology?  The answer is simple. 

670 nm Increases Melatonin Synthesis

It is obvious that neuromelanin (NM) can protect neurons because of its ability to bind toxins, especially iron. NM may act in the capacity as an antioxidant, irreversibly sequestering reactive metabolites from dopamine oxidation [64]. However, NM can become dangerous when its antioxidant capacity is overwhelmed. In an environment high in oxidative stress, NM can easily become a dangerous prooxidant [99]. 

Melatonin Protects the Antioxidant Capacity of Neuromelanin.

Melatonin is an ancient molecule with powerful antioxidant properties [100]. Its ability to maintain higher antioxidant capacity in neuromelanin is probably the reason why it has been found to protect dopaminergic neurons. Dopamine autoxidation produces high amounts of reactive oxygen species, creating oxidative stress that may reduce dopaminergic neurons. 

Melatonin, with receptors in the substantia nigra, can dose-dependently counteract the effects of dopamine autoxidation. Studies found that the protective effect of melatonin against dopamine autoxidation was significantly higher than compounds tested, including vitamin C and vitamin E [101]. Ovariectomy animal models (OVX) often showed decreased TH-positive cells, as a result of the lack of estrogen [102].  OVX animals treated with melatonin exhibited higher levels of dopamine and TH-positive cells [103]. In animal models of Parkinson’s disease, melatonin-treated animals performed better in motor tasks and had no dyskinetic alterations compared to L-DOPA-treated animals. Melatonin-treated animals also showed much higher levels of TH-positive neurons and well-preserved striatal ultrastructures [104].

The healing powers of the 670 nm frequency have been associated with melatonin for many years. Two of the most well-known effects of red light therapy using 670 nm is wound healing, and improving energy production via modulation of mitochondrial functions. Melatonin is believed to be the principal component of 670 nm red light therapy [105]. 

Subjects exposed to 30 minutes of whole-body irradiation at 670 nm every night for 14 days almost doubled the amount of serum melatonin compared to control subjects who did not receive any light illumination. Subjects treated with 670 nm illumination also experienced better sleep quality, and improved endurance during athletic performances [106].

[Source: Zhao J, Tian Y, Nie J, Xu J, Liu D. Red light and the sleep quality and endurance performance of Chinese female basketball players. J Athl Train. 2012;47(6):673-678. doi:10.4085/1062-6050-47.6.08]

 

The ability of 670 nm to accelerate wound healing may be due in large part to an increased production of melatonin. Melatonin is well-known for its ability to significantly improve the quality of wound healing and scar formation [107],  The healing effect is not limited to skin tissues, but applies to the eyes as well. Melatonin receptors are widely expressed on corneal epithelial cells. When melatonin receptors are enhanced by agonists, the rate of wound healing in the cornea is significantly accelerated [108]. No wonder melatonin is present in tears [109]. 

 

Melatonin Concentration in Human Tears at Different Times of the Day

[Source: Carracedo G, Carpena C, Concepción P, et al. Presence of melatonin in human tears. J Optom. 2017;10(1):3-4. doi:10.1016/j.optom.2016.03.002]

Why is melatonin synthesized in ocular tissues in high amounts? And why are the amounts highest at night time?

 

Melatonin, Light, and Dopamine — A Story about Rods and Cones

Melatonin is synthesized in various ocular tissues, including the retina, ciliary body and even lens epithelial cells. The uptake of melatonin into various ocular tissues in different species is mediated by melatonin receptors MT1, MT2, and MT3. Melatonin receptors are widely distributed in various tissues of the eye, including cornea, lens, ciliary body, retina, choroid and sclera [110-113].  

 

Melatonin Receptors in Ocular Tissues of a Variety of Species (Xenopus laevis, Chicks, Rabbits, Rats, and Humans) 

[Source: Ostrin, L.A. (2019), Ocular and systemic melatonin and the influence of light exposure. Clin Exp Optom, 102: 99-108 doi:10.1111/cxo.12824 ] 

 

Melatonin exerts a wide range of protective functions in ocular tissues. Melatonin is able to reduce age-related macular degeneration [114]; protect corneal epithelial cells from ultraviolet radiation [115]; and reduce cataract formation in lens by improving transparency and lowering oxidative stress by decreasing lipid peroxidation and increasing antioxidant enzyme activity [116, 117]. 

The lens not only can synthesize melatonin, lens epithelial cells contain melanopsin. Melanopsin is a non-image forming photoreceptor that is only sensitive to the specific wavelengths between 465nm to 480 nm, otherwise known as blue light in the visual spectrum. The presence of melanopsin in lens epithelial cells led to the discovery that melatonin synthesis can be suppressed by the activation of melanopsin in lens epithelial cells [113].

 

Melatonin Synthesis in Human Lens Epithelial Cells is Suppressed by Blue Light (465-480 nm)

[Source: Alkozi HA, Wang X, Perez de Lara MJ, Pintor J. Presence of melanopsin in human crystalline lens epithelial cells and its role in melatonin synthesis. Exp Eye Res. 2017;154:168-176. doi:10.1016/j.exer.2016.11.019]

 

Why do ocular tissues increase melatonin at night but suppress its synthesis in the presence of blue light?

In the distant past, when the moon and stars were the only source of illumination at night, the ability to see well in the dark was a distinct survival advantage. Melatonin enhances night vision by promoting the rod system which is responsible for night vision in low light, and suppressing the cone system which is responsible for day vision in bright light. This specific function of melatonin in the eyes is the main reason why melatonin can inhibit retinal dopamine which is responsible for cone vision in bright light during the daytime [118, 119].

Melatonin and dopamine are under circadian control and have inhibitory effects on each other. In the inner retina, melatonin can modulate dopamine levels, inhibiting its release from amacrine cells [120, 121].  Dopamine is responsible for the mediation of light adaptation and changes in visual sensitivity [122, 123]. Therefore, light signals can stimulate the release of dopamine from amacrine cells, leading to the inhibition of melatonin production. The binding of dopamine to D2 and D4 receptors is required for the inhibition of melatonin synthesis [124]. 

In the eyes, by suppressing ocular dopamine, melatonin decreases the maximal cone response for photopic bright light vision, shifting the retina to night vision mode [125]. Essentially, ocular melatonin enhances night vision by promoting the rod visual system responsible for highly sensitive dim-light scotopic vision. 

[Source: Almut Kelber. Vision: Rods See in Bright Light Current Biology 28, R342–R366, April 23, 2018 DOI:https://doi.org/10.1016/j.cub.2018.02.062]

 

Night vision is an important ancient survival mechanism that may actually be one of the major determinants of circadian fluctuations in circulatory melatonin in humans. The suppression of ocular and pineal melatonin in the daytime could be a direct function for the regulation of photopic and scotopic vision. When there is no requirement for photopic vision, this circadian fluctuation of melatonin is terminated.  

A fascinating study on two adult human subjects kept in complete darkness for 10 days revealed that night-time melatonin decreased from ~26 to 16 pg/ml, while daytime melatonin levels actually increased from 3 to 18 pg/ml. At the end of the study, there was basically no difference between night-time and day-time melatonin production [126].  Daytime melatonin was increased because of the need to enhance night vision, while night-time melatonin was decreased because there is probably less requirement to inhibit dopamine levels. 

Since changes in the length of daylight and darkness can affect melatonin levels, what will happen when photoperiod is abolished?

The Absence of Photoperiod Changes in Modern Society

In the very distant past, blue light is only present during the daytime when light is bright. That is why melanopsin in lens epithelial cells and retina use blue light as a signal to inhibit melatonin production, and to promote dopamine synthesis for the enhancement of photopic vision in the daytime. Since the advent of electricity, blue light has become ubiquitous even at night time. 

Light at night abolished the photoperiod changes in melatonin levels. Every day of the year, regardless of season or natural light duration, is effectively ‘summer’, with artificial light at night (ALAN) suppressing melatonin production. 

 

Representative Human Melatonin Profiles in Long/Short Days Reinforced by Artificial Light

 

[Source: Arendt J, Middleton B, Stone B, et al. Complex Effects of Melatonin: Evidence for Photoperiodic Responses in Humans?, Sleep, Volume 22, Issue 5, August 1999, Pages 625–635, https://doi.org/10.1093/sleep/22.5.625]

 

Many people believe that dim light and/or candles are safe to use at night because they do not interfere with melatonin synthesis at night. Is this true?

Exactly How much light is required to inhibit melatonin production? 

Light, Melatonin, and Melanopsin — A Story About Lux

Melatonin suppression by light is mainly processed by melanopsin. The question is, at what level is melanopsin activated to inhibit melatonin? 

A landmark study by Prayag et al. in 2019 was able to use melanopic lux as an extremely accurate standard of measurement to show the exact amount of phototic light that can trigger the inhibition of melatonin via melanopsin [127]. Melanopic lux is a new photometric measurement of light intensity relevant for melanopsin photoreceptors. Melanopic lux is now regarded as  a more accurate predictor of melanopsin response to light of different spectral compositions [128, 129]. 

Light intensity is usually measured in units called lux. 1 lux is the amount of light required to illuminate one square meter surface area by one candle placed 1 meter away. Lumen is the total amount of light produced by a light source. 1,000 lumens in an area of 1 square meter has an illuminance of 1,000 lux. If you spread 1,000 lumens out over 10 square meters, then the illuminance level will be 100 lux per square meter.  A 100W incandescent bulb has an illuminance of 1,700 lumens. A 32W fluorescent tube has an illuminance of 1,600 lumens.

Direct sunlight can put out 32,000 to 130,000 lux. An overcast day has about 1,000 lux. Sunrise or sunset is about 300-500 lux, or typically what is found in a well-lit office. A full moon on a clear night gives out 0.27 to 1 lux [130]. 

Prayag et al. measured the amount of phototic light (lux) required to inhibit melatonin at different melanopsin illumination saturation levels of 10%, 50% and 90%, corresponding to melanopic lux of 1.5, 21, and 305 respectively [127]. The results discovered by Prayag’s team were quite revealing.

A mere 3.8 lux from candle light could initiate a 10% suppression of melatonin at 1.5 melanopic lux; while only 1.6 lux from an iPAD Pro had a similar effect. The complete saturation of melanopsin at 305 melanopic lux inhibits 90% of melatonin synthesis, and requires 771.2 lux from candles, but only 269.5 lux from an iPhone X [127]. 

 

Melatonin Suppression as a Function of Melanopsin Stimulation (melanopic lux)

[Source: Prayag AS, Najjar RP, Gronfier C. Melatonin suppression is exquisitely sensitive to light and primarily driven by melanopsin in humans. J Pineal Res. 2019;66(4):e12562. doi:10.1111/jpi.12562]

Photopic Lux Equivalence of Different Melanopic Lux Thresholds for Melatonin Suppression Response

[Source: Prayag AS, Najjar RP, Gronfier C. Melatonin suppression is exquisitely sensitive to light and primarily driven by melanopsin in humans. J Pineal Res. 2019;66(4):e12562. doi:10.1111/jpi.12562]

 

From the results obtained by Prayag et al., it would not be incorrect to assume that there is a high level of melatonin suppression during the winter months with short photoperiod. Even though the daylight hours are shorter, the exposure to artificial light at night is more than enough to suppress melatonin synthesis at night. 

If melatonin levels had been the same during the winter and the summer, because there is no extended darkness, why were children spared during the winter months from the more severe symptoms of  SARS-CoV-2, such as MIS-C?

The reason is simple. It is also the same reason that increases the risks of disease severity and mortality in obese individuals infected by COVID-19.

Cold, Obesity, and Melatonin — A Story About BAT

According to data collected by NOAA, 2020 will likely rank as the earth’s 2nd hottest year since 1880 [131].

[Source data: https://www.ncdc.noaa.gov/cag/global/time-series/globe/land_ocean/ytd/12/1880-2020]

 

Why is this important? 

 

Cold Temperatures Increase Melatonin

Cold temperature may be a major regulator of melatonin production in addition to photoperiod. For example, cold stress has been shown to significantly upregulate the gene expression of melatonin enzymes and melatonin synthesis in both plants and microorganisms as protective mechanisms [132, 133].  In animals such as hamsters, cold temperature alone can upregulate the expression of enzymes critical for melatonin biosynthesis. Elevated melatonin induced by cold exposure in turn improved immune responses [134].  

In 2018, Xu et al. reported that cold temperature alone could induce increased melatonin production in hamsters. Gene expressions of both AANAT and ASMT, responsible for the production of enzymes critical during the synthetic process of melatonin in the pineal glands of hamsters, were increased under cold temperatures [134]. 

Hamsters raised in natural climatic conditions reflecting local environmental temperature, photoperiod, and humidity for one month were sacrificed separately on the day of winter and summer solstice. The melatonin levels in hamsters examined on the day of winter solstice were significantly higher than those examined on the day of summer solstice six months later[134].

 

More than 50% Increase in Melatonin Levels of Hamsters Raised Naturally During Winter Solstice

[Source: Xu X, Liu X, Ma S, et al. Association of Melatonin Production with Seasonal Changes, Low Temperature, and Immuno-Responses in Hamsters. Molecules. 2018;23(3):703. Published 2018 Mar 20. doi:10.3390/molecules23030703] 

 

Xu et al. continued to test their hypothesis by changing housing temperatures of hamsters kept in environments with fixed humidity, and  regular 12/12 h light/dark cycles. Compared to controls, hamsters examined 72 hours after temperature treatments produced higher levels of melatonin in response to both rapid (RTD) and constant (CTD) temperature decreases. No changes in melatonin levels were detected in hamsters exposed to temperature increases, rapid or constant [134].  

 

Elevated Melatonin Synthesis During Rapid or Constant Temperature Decreases

[Source: Xu X, Liu X, Ma S, et al. Association of Melatonin Production with Seasonal Changes, Low Temperature, and Immuno-Responses in Hamsters. Molecules. 2018;23(3):703. Published 2018 Mar 20. doi:10.3390/molecules23030703]

 

Why does cold temperature increase melatonin? What happens if this annual natural rhythmic change is abolished?

Light at Night and Obesity — The BAT Connection 

Melatonin is a chronobiotic molecule that provides important signals in changes in the environment, including circadian cycles, and the changing of the seasons over the year. In that sense, melatonin acts in the capacities as both a ‘clock’ and a ‘calendar’, where the annual history of daily melatonin production in organisms can prepare for upcoming seasonal changes. During gestation, fetuses rely on maternal melatonin to program physiological response to environmental light/dark cycles and seasonal changes after birth [135, 136]. 

Melatonin receptors are widespread in the human embryo and fetus. Maternal melatonin easily diffuses across the placenta, and is also transferred to the infant during breastfeeding. During pregnancy, melatonin levels may increase after week 24, and reach extremely high levels after week 32 [137]. Disturbances in maternal melatonin during gestation can cause metabolic alterations in the fetus [138].

Infants depend on high levels of brown adipose tissue (BAT) to maintain body temperature through non-shivering thermogenesis. Infants rely mainly on BAT to generate high core body temperatures because they lack sufficiently developed skeletal muscle mass to keep warm through shivering thermogenesis [139]. 

Despite earlier understanding that BAT disappears after infancy, the discovery over a decade ago that a substantial amount of functional BAT is retained in adults [141] shed new light on the cause for the dramatic increase in the prevalence of obesity in both children and adults since the introduction of light at night.

Dramatic Increase of Obesity in Children and Adults in the Past 100 Years

An analysis of the records from the West Point Military Academy showed that over 100 years ago, 19-year-old caucasian cadets had an average BMI of 20.5. A surge in body weight began after the first world war, and a total weight increase of 13 kg took place over the course of the 20th century, with half of the increase observed in those  born before World War II [142, 143].

[Source: https://voxeu.org/article/100-years-us-obesity]

 

Data obtained from surveys (2001-2008) involving 42,200 military members showed that only 25% of all subjects surveyed had normal body weight. 20% of service members were obese, while 32% of veterans suffered from obesity and associated comorbidities of hypertension, diabetes and sleep apnea [144].

In the USA, childhood obesity is also a recent phenomenon of less than 100 years. Since there were no national surveys of child obesity before 1963 (probably because very few children were obese in the early 1900s), researchers took data from an Ohio local study and extended the history of childhood obesity back to the 1930s. What they discovered was that obesity was rare in the early days, and the prevalence only began to increase in children born after the year of 1970 [145].

In the United States, childhood and adolescent obesity have reached alarming epidemic proportions. In the past three decades, childhood obesity has more than doubled, and adolescent obesity more than tripled [146]. Light at night is now generally accepted to be able to suppress melatonin production and interrupt circadian rhythms in animals [147].  

 

Why would reduced melatonin levels increase the prevalence of obesity in children and adults?

Melatonin Increases Brown Adipose Tissue (BAT)

Short photoperiod with extended darkness has been shown to dramatically stimulate the growth of BAT and heat-producing thermogenic activity in animals [148]. BAT is responsible for energy expenditure that may be unrelated to physical activities. BAT can contribute as much as 60% of non-shivering thermogenesis in small animals, allowing them to stay warm in the cold without having to rely on shivering to produce heat [149]. 

BAT has critical functions in energy expenditure and energy homeostasis. The presence of metabolically active BAT is associated with reduced adiposity, especially during aging, where BAT activation is often reduced to 10% in those between 50 to 60 years of age [150]. 

Obesity can be simply explained as a condition where there is a disproportionate increase in white adipose tissue (WAT) relative to the total body weight. In elite athletes, WAT can account for merely 3% of total body weight, whereas in the morbidly obese individual, WAT can take up as much as 70% of total body weight [151].

In the distant past where cold winters meant less availability of food sources, Nature used obesity to ensure the survival of mammals, including humans. Cold temperatures can, therefore, easily activate and stimulate BAT activity to protect humans and animals from the cold [152]. Take a look at the difference in energy expenditure as a result of BAT thermogenic activity in room temperature and in mild cold conditions.

 

BAT Increases Total Body Energy Expenditure by ~70% Upon Mild Cold Exposure

[Source: Carpentier AC, Blondin DP, Virtanen KA, Richard D, Haman F, Turcotte ÉE. Brown Adipose Tissue Energy Metabolism in Humans. Front Endocrinol (Lausanne). 2018;9:447. Published 2018 Aug 7. doi:10.3389/fendo.2018.00447]

 

BAT is responsible for higher resting energy expenditure and with less ectopic fat accumulation in the liver. BAT contributes to cold-induced heat generation by taking up glucose, fatty acids, and other energy substrates from the circulation [153-155]. 

In obese individuals, the activities of BAT is dramatically reduced. Under cold stimulation, BAT in lean individuals irrespective of age and gender, showed activity levels doubling those of obese individuals. Even after weight loss, BAT activity levels in previously obese subjects did not increase [156]. 

Under conditions when only a portion of BAT is fully activated, BAT is estimated to be able to burn an amount of energy equivalent to about 4.1 kg of fat over the course of one year [157].  The excess body weight in obese individuals may be caused by having less functional BAT than leaner individuals, and BAT-positive individuals have lower BMI than those who are BAT-negative [153, 158].  

Why do obese individuals have blunted BAT responses?

Melatonin can influence the accumulation of brown fat during fetal life [159]. Newborn lambs from mothers kept in constant light during the last third of gestation period were unable to regulate central body temperatures. These newborns were also unable to produce heat after 1 hour of cold exposure. The BAT mass of these pups were much lower than those of controls whose mothers were kept in 12:12 photoperiod. Interestingly, the effects on the pups from mothers exposed to constant light were completely abolished when the mothers were treated with 12 mg melatonin during the experiment [160].

 

Melatonin Levels in Sheep Kept in 12:12 Photoperiod (LD), Constant Light (LL), and Melatonin Treatment During Gestation 

 

[Source: Seron-Ferre M, Reynolds H, Mendez NA, Mondaca M, Valenzuela F, Ebensperger R, et al. (2015) Impact of maternal melatonin suppression on amount and functionality of brown adipose tissue (BAT) in the newborn sheep. Front. Endocrinol. (Lausanne). 5: 1–12.]

 

The significant reduction of melatonin levels by light at night in modern society can cause epigenetic changes that affect the metabolic health of infants, with lasting changes into adulthood [161,162]. 

BAT, UCP1, and Mitochondria — The Melatonin Connection 

Melatonin is able to regulate energy balance by exerting a wide array of effects over brown adipose tissues (BATs). Melatonin supplementation can increase gene expressions of proteins and enzymes associated with non-shivering thermogenesis. The effects of melatonin treatment are even observed in mitochondrial complexes I, II and IV protein and enzyme activity. Melatonin supplementation could reverse impaired BAT responses to metabolic challenges in pinealectomy animal models that were deficient in melatonin [163]. 

Melatonin Increases BAT Mass and Functions

Diabetic models of Zücker fatty rats were demonstrated to reduce obesity without making any changes to their food intake when supplemented with melatonin for 6 weeks [164]. To put into perspective the length of time required to achieve these physiological changes, 6 weeks in the life of a rat is equivalent to about 3 human years [165]. 

The generation of heat during BAT thermogenesis is largely dependent upon the actions of uncoupling protein 1 (UCP1). UCP1 is widely expressed in the inner mitochondrial membranes of BAT. To generate heat, UCP1 dissipates the proton gradient across the inner mitochondrial membrane so as to uncouple electron transfer from adenosine triphosphate (ATP) synthesis. Instead of making ATP, BAT mitochondria generates heat because of activated UCP1 [166, 167]. Without UCP1, BAT mitochondria would have great difficulty in generating heat [168]. 

Both cold and darkness can increase melatonin synthesis [126, 134]. Cold and darkness also can activate and stimulate BAT thermogenesis [148, 152]. 

Could the thermogenic effects of BAT be mediated by melatonin?

Expression of UCP1 mRNA and protein levels in BAT tissues from diabetic Zücker obese rats were found to be 50% lower than their lean counterparts. Melatonin treatment in obese rats completely restored the expression levels of UCP1 mRNA and protein to the same levels found in BAT from lean rats [164]. 

 

10 mg/kg Body Weight Melatonin Supplementation in Diabetic Rats Normalized UCPI Gene and Protein Expression Levels

[Source: Fernández Vázquez G, Reiter RJ, Agil A. Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control. J Pineal Res. 2018;64(4):e12472. doi:10.1111/jpi.12472]

Melatonin Increases Mitochondrial Protein and Activity Levels

Zücker diabetic fatty rats had three times less mitochondrial protein in their BAT tissues. Obese rats treated with melatonin were able to increase their Interscapular BAT (iBAT) weight by about 31%, and mitochondrial protein by ~40%. In diabetic fatty rats, their BAT mitochondrial functions were severely impaired. Melatonin  improved mitochondrial function in complex I and complex IV in BOTH diabetic and lean rats.  Melatonin restored complex I function in diabetic rats from 17% of normal to 76%. In lean rats with normal complex I activity, melatonin improved functions by a staggering 41%.  

 

Complex I Activity Levels in Melatonin-treated and Control non-treated Lean (ZL) and Diabetic Fatty (ZDF) Rats

[Source: Fernández Vázquez G, Reiter RJ, Agil A. Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control. J Pineal Res. 2018;64(4):e12472. doi:10.1111/jpi.12472]

 

Complex IV Activity Levels in Melatonin-treated and Control non-treated Lean (ZL) and Diabetic Fatty (ZDF) Rats

[Source: Fernández Vázquez G, Reiter RJ, Agil A. Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control. J Pineal Res. 2018;64(4):e12472. doi:10.1111/jpi.12472]

 

Melatonin treatment in diabetic fatty rats not only normalized functions and expressions of UCP1 and mitochondria, thermogenic temperature responses to acute cold challenges were also vastly improved in both lean and diabetic fatty rats [164].

 

Baseline and Cold-Challenge Skin Temperatures of Melatonin-treated and Control non-treated Lean (ZL) and Diabetic Fatty (ZDF) Rats

[Source: Fernández Vázquez G, Reiter RJ, Agil A. Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control. J Pineal Res. 2018;64(4):e12472. doi:10.1111/jpi.12472]

 

The role of melatonin in energy homeostasis and metabolic health has gained tremendous attention in the past several years due to its immense potential in addressing the current obesity epidemic. In a landmark proof-of-concept study in 2019, Halpern et al. evaluated BAT activities in four patients with melatonin deficiency from radiotherapy or surgical removal of pineal glands, before and after the daily administration of 3 mg of melatonin, 30 minutes before sleep for 3 months [169]. 

In all four patients, melatonin supplementation increased both BAT volume and activity. There was also an improvement in total cholesterol and triglyceride blood levels.  Fasting insulin levels and HOMA of insulin resistance decreased in all four patients [169]. 

 

PET-MRI Showing BAT Activity in Response to  Cold Exposure — Before and After Melatonin Supplementation.

[Source: Halpern B, Mancini MC, Bueno C, et al. Melatonin Increases Brown Adipose Tissue Volume and Activity in Patients With Melatonin Deficiency: A Proof-of-Concept Study. Diabetes. 2019;68(5):947-952. doi:10.2337/db18-0956 ]

Melatonin Decreases Obesity — The Dopamine Connection

Melatonin may have an inhibitory/modulatory effect on dopamine in the brain [45]. In the context of obesity, the inhibition of dopamine by melatonin is especially critical for maintaining energy homeostasis. If extra caloric intake is not dissipated as heat, it will be converted and accumulated as body fat [170]. Overfeeding leading to excess nutrition is one of the causes for obesity [171].

A shocking study released in April, 2020 by Grippo et al. reported that dopaminergic signaling within the central pacemaker, suprachiasmatic nucleus (SCN), can disrupt feeding rhythms that result in the overconsumption of food. The dopamine receptor D1 was found to be responsible for overconsumption, and diet-induced obesity. Mice bred without D1 dopamine receptors were found to be resistant to diet-induced weight gain, disease and circadian disruption associated with energy-dense foods [172]. 

During summer months with long photoperiods, dopamine production is increased. Nature uses dopaminergic signaling as a tool to augment food intake, especially in hibernating animals like the grizzly bear. Obesity in grizzly bears are natural adaptation to survive months of fasting [173]. However, if the animal is unable to burn fat during the cold months, obesity becomes a disease and not a survival mechanism. 

Obese mice on high-fat diets that were supplmented with melatonin (1 mg/kg body weight) during the dark phase for 10 weeks were able to prevent weight gain through the reduction of lipogenesis and the increase of lipolysis in white adipocytes. Melatonin supplementation also lowered serum triglyceride levels and total and LDL cholesterol. But most importantly, melatonin treatment attenuated the increased expression of leptin and other pro-inflammatory cytokines often associated with obesity [174]. 

Inadequate melatonin as a result of indoor temperature controls during cold seasons, and light at night may be the reason for the dramatic increase in obesity during the past decades.  The fact that 2020 has shown to be one of the hottest years on record also contributed to lowered melatonin production in both children and adults [131].  Reduced melatonin as a result of seasonal changes could be a primary reason for more severe symptoms in very young children infected by SARS-CoV-2 beginning in March.

Why is obesity a high risk factor in COVID-19 patients regardless of age?

The metabolic and inflammatory disorders in obesity are the main reasons why obesity may present greater risks for individuals during COVID-19 infections. Even though obese individuals have low BAT activity, surprisingly, most obese individuals actually have higher melatonin levels. 

Melatonin, Obesity, and Oxidative Stress — The Hemoglobin Connection

Obese individuals usually have high levels of free radicals such as reactive oxygen or nitrogen species. The excess oxidative stress in obesity is associated with impaired antioxidant defenses and increased production of inflammatory adipokines. Oxidative stress in obesity also drives the formation of pro-inflammatory cytokines. When the level of white adipose tissues increase to a non-physiological level, these adipocytes no longer function as energy storage organs that can mediate energy homeostasis.  Accumulation of excess fat in heart, muscle, liver and other important internal organs can result in insulin resistance, lipotoxicity, and organ dysfunctions [175]. 

It is widely accepted that obesity is directly linked to changes in redox state, whereby abnormal production of free radicals can cause obesity-associated pathologies including NAFLD (Nonalcoholic fatty liver disease), diabetes, hypertension, cardiovascular diseases and cancer [175]. 

Excess oxidative stress can lead to the reduction of bioavailability of antioxidants, such as ascorbic acid. The expression of transporters for ascorbic acid (SVCT1, SVCT2) can be modulated by metabolic and/or oxidative stress, preventing the normal cellular uptake and homeostasis of ascorbic acid [176]. 

Certain obese subjects have been found to hypersecrete melatonin. Scientists believed that the elevated levels of melatonin in this subgroup of obese individuals are protective measures that can reduce free radicals and increase vasodilation [177]. Obese patients on calorie-restriction diets exhibited elevated levels of oxidative stress and lower melatonin levels. Supplementation with 10 mg melatonin for 30 days together with a calorie-restriction diet produced significant reduction in body weight, and inflammatory adipokines, together with a dramatic improvement of antioxidant defenses in obese subjects [178]. 

COVID-19, Oxidative Stress and Glycated Hemoglobin — The Melatonin Connection

Researchers now believe that microvascular disease and endothelial dysfunction may underlie adverse outcomes in COVID-19 [179]. Endothelial cell dysfunction is now recognized as a key pathophysiological factor that can cause severe disease progression in COVID-19 disease. 

Endothelial dysfunction can activate coagulation, resulting in venous thromboembolic events (VTE) including deep vein thrombosis, pulmonary emboli, digital ischemia, arterial thrombosis, microvascular thrombosis and strokes [180]. Endothelial cell dysfunction may also be responsible for causing multisystem inflammatory syndrome in children (MIS-C) [181]. 

Hyperglycemia expressed as glycated hemoglobin (HbA1c) is used as a clinical marker to predict endothelial cell dysfunction in diabetic patients [182]. HbA1c is also found to correlate with worse outcomes in COVID-19 [179]. Obese individuals are also found to have high levels of HbA1c [183]

Why is glycated hemoglobin important in COVID-19 disease progression?

SARS-CoV-2 can infect hemoglobin (Hb) via CD147 receptors expressed on red blood cell membranes [15]. Elevated glycation of Hb can weaken erythrocyte membranes, increasing osmotic fragility in erythrocytes that ultimately results in hemolysis of Hb [184]. Glycosylated Hb can render erythrocytes easy targets for the SARS-CoV-2 virus because the membranes are damaged and thus easier to destroy and penetrate [15, 185]. 

Erythrocytes with fragile or damaged membranes lose their ability to change shapes (deformability) and thus cannot pass through extremely small capillaries without inducing hemolysis [186]. Erythrocyte deformability is measured in terms of elongation index (El). El are extremely sensitive to changes in hyperglycemia levels, and is well correlated with levels of glycated hemoglobin. Diabetic patients have decreased El (low deformability) compared to healthy controls. In patients with complications of chronic renal failure, end stage renal disease, retinopathy, their Els are significantly decreased compared to diabetic patients without these pathological complications [187]. 

Melatonin Protects Red Blood Cells, and Prevents Glycation of Hemoglobin

Melatonin has the ability to attenuate pathologies from endothelial cell dysfunctions caused by SARS-CoV-2 infection [15]. The high antioxidant capacity of melatonin allows it to protect erythrocytes from oxidative stress under many physiological and pathological conditions [188-190]. 

In animal models of ethanol toxicity, the administration of melatonin protected liver, kidney and muscle tissues from severe oxidative stress damages. Melatonin supplementation was able to reduce the significantly elevated HbA1c levels, returning glycated Hb to normal, while diminishing free radical production [191]. 

A complete analysis of how melatonin exerts protective effects against red blood cell injuries during COVID-19, please read “The potential of melatonin in the prevention and attenuation of oxidative hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor binding” [15].  

A significant reduction in melatonin production in children and adults during late spring and summer may partially explain increased infection rates and disease severity in a subgroup of COVID-19 patients with high risk comorbidities such as obesity, diabetes and hypertension. It is not unreasonable to assume that the situation may be greatly attenuated as summer ends and cold winter approaches. Therefore, if in-person school attendance can be delayed until the weather cooled significantly in countries like the United States, COVID-19 may not assert the same degree of malice in young children going into the colder months. 

Conclusion

The pandemic caused by SARS-CoV-2 is a poignant wake-up call to humanity. The disease highlights the disturbance of Nature’s protective mechanisms, such as melatonin and ascorbic acid, as a result of changes in our light and food habits. It will not be easy to reduce the exposure to light at night, electromagnetic radiation in communication devices, or to change our lifestyles and eating habits. However, adding appropriate levels of melatonin and ascorbic acid to our daily maintenance especially during COVID-19 pandemic, may be the simplest, safest, most cost-effective solution not only for the protection against SARS-CoV-2 infections, but for the optimization of health in our modern, high-tech society.

Have you had your AA and MEL today?

 

 

 

 

 

 

 

 

 

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