Melatonin is a “synchroniser”
Melatonin is an ‘ancient’ molecule, its presence can be traced back to primordial photosynthetic unicellular organisms. Melatonin has a primitive and primary function as a scavenger of free radicals and as a broad-spectrum antioxidant. During evolution, melatonin has acquired other physiological functions, the most relevant of which are those related to chronobiotic activity.
Melatonin plays an important role in regulating the biological clock and circadian cycles, i.e., all the functions of the body that are related to and regulated by day-night alternation. Therefore, it can be said that melatonin has a fundamental role as a chronobiotic of biological rhythms and neuroendocrine activities. Examples of circadian rhythms are the sleep-wake alternation, the secretion of cortisol and various other biological substances, the core body temperature rhythm, etc.
The system consists of circadian clocks, which are biological structures located in specific areas of the central nervous system or in peripheral tissues. The organisation of the clocks is hierarchical: at the top we find the master clock, located in the suprachiasmatic nucleus of the hypothalamus, controlled mainly by light signals. Below this we find secondary encephalic clocks and peripheral clocks, distributed in various organs and tissues that are more sensitive to metabolic and nutritional signals.
Circadian rhythms, and more precisely the network of circadian ‘clocks’, allow the time organisation of biological functions in relation to periodic environmental changes (e.g., the alternation of day and night, or days becoming longer in summer) and thus reflect adaptation to the environment.
Melatonin’s synchronisation of peripheral clocks reflects the individual’s adaptation to his or her internal and external environment (e.g., melatonin’s synchronised effects on the secretion of hormones such as cortisol and insulin allow the individual to be fully awake at 8 o’clock in the morning and to be able to start the day by eating and gaining some energy from food). The daily rhythm of melatonin secretion conveys internal information that the body uses for both the circadian and seasonal time organisation of its neuro-endocrine functions.
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The physiological production of melatonin
The production and release of melatonin in the pineal gland follow a circadian rhythm that sees a peak in production during the hours of darkness and a low level during daylight hours. One of the functions of melatonin is the transfer and translation of photoperiodic information (such as time of day and length of day) into physiological and metabolic signals that activate multiple processes within the body in a synchronised manner. In mammals, melatonin regulates seasonal changes within the neuroendocrine and reproductive systems. Melatonin has been associated with the processes of puberty and ageing, control of blood pressure, free radical scavenging and regulation of antioxidant processes, particularly in tissues such as the retina, gastrointestinal tract, thymus, spleen, heart, skeletal muscle tissue, liver, stomach, intestines, skin, placenta, testes, ovaries, cerebral cortex and striatum.
Some physiological functions of melatonin
Circadian oscillation is regulated primarily by the light-dark cycle, detected by specialised cells located in the retina of the eye, which are not involved in the visual process. Regulation is also finely controlled by metabolic and behavioural inputs, such as nutritional status and sleep-wake rhythm. Circadian desynchronisation can lead to a worse metabolic status and favour multiple pathologies, which include obesity, metabolic syndrome, insulin resistance, type 2 diabetes mellitus, as well as certain forms of cancer, alterations of the microbiota, psychiatric and neurodegenerative pathologies and, as one can easily guess, sleep disorders.
In addition, melatonin is involved in blood pressure and the autonomic control of the cardiovascular system, regulation of the immune system, as well as in various physiological functions such as retinal functions, free radical detoxification and antioxidant actions by protecting against oxidative stress.
Finally, melatonin has physiological effects on reproduction and sexual maturation in mammals, through the under-regulation of gonadotropin-releasing hormone (GnRH), which is present in both males and females with essential functions on development, maturation, and maintenance of ovarian and testicular function.
Melatonin and Synchronisation
Melatonin is not only important for sleep-wake synchronisation. Many biological functions have phases of growth and decline according to cycles that repeat daily, monthly, seasonally or annually, some are linked to lunar phases, others to light and dark cycles. These patterns reflect the body’s biological rhythms, i.e., its ability to keep track of time and direct changes in biological functions accordingly. When animals switch between diurnal, nocturnal or seasonal modes of behaviour (e.g., hibernation), they respond to signals generated by a circadian pacemaker, which is written into their genes and is synchronised with the Earth’s rotational cycles, anticipates transitions between day and night and triggers appropriate changes in behavioural state and physiological substrates. In mammals, a high-level circadian oscillator is found in the suprachiasmatic nuclei (SCN) of the hypothalamus. This circadian master clock acts as a multifunctional timer to regulate the homeostatic system, including sleep and wakefulness, hormone secretions and various other body functions. (Cardinali 2006).
Melatonin and sleep
Evidence suggests that sleeping between 7 and 8 hours every night is optimal for the vast majority of adult humans. Longer or shorter sleep durations have been associated with increased health risks such as weight gain/increased BMI, reduced glucose tolerance/diabetes, hypertension, cardiovascular disease and stroke, and increased mortality risk.
The human body produces its own melatonin starting two hours before bedtime, provided lighting and external stimuli are reduced. This natural action is known as ‘dim light melatonin onset’ (DLMO) and helps keep the body on a regular sleep-wake schedule. In a normal subject, DLMO normally occurs around 9 pm.
The Melatonin levels in a normal person go through this 24-hour cycle:
Today, DLMO is considered the best available test, a ‘gold standard’, for measuring melatonin levels. The DLMO test is very useful for discovering and understanding disturbances in the human biological clock and helps to better understand the effects of administering melatonin to healthy, normal subjects who may benefit from taking melatonin to cope with situations such as ‘jet-lag’ or a lengthening of the time it takes to fall asleep.
It is known that there is a kind of curve (called PRC, phase-response curve) of effects of (administered) melatonin with respect to one’s DLMO. The figure shows the PRC in a person who has a normal DLMO (usually around 9 pm) and the secretion of melatonin secreted by their body.
Looking at this curve, it can be seen that taking a dose of melatonin during the afternoon hours has an anticipatory effect on circadian rhythms, i.e., one goes to bed and wakes up earlier, whereas if it is taken between 8 pm and the early hours of the night, there is no interference with normal sleep-wake cycles. On the contrary, melatonin taken at the end of the night may have a delaying effect on natural circadian rhythms (i.e., one tends to go to bed and wake up later); this effect may also occur with ‘retard’ melatonin formulations in which there is a high blood level of melatonin even several hours after being taken.
Alteration of the sleep-wake cycle and chronic inflammation
Sleep disturbances are associated with increased levels of inflammation, and elevated levels of inflammation are believed to contribute to biological ageing and to an aggravation of the NF-κB/NLRP3 innate immune response, known as ‘inflammaging‘, a chronic, asymptomatic, low-grade form of inflammation that occurs in the absence of infection in advanced age. Sleep deprivation in healthy adults results in a non-specific immune response characterised by increased circulating monocytes and NK cells, and elevated plasma levels of pro-inflammatory cytokines (TNF- and IL-6) and increased PCR. Further evidence suggests that sleep is also involved in the regulation of the adaptive immune response.
Overall, these results provide a possible way through which sleep loss can influence inflammation and subsequent health. This chronic inflammatory state has detrimental effects on health and contributes to biological ageing and the development of age-related diseases.
Mean changes in plasma C-reactive protein (CRP) values in four subjects (red rectangles) who underwent partial sleep deprivation for 10 days (4.2 hours sleep/night) and five control subjects (blue rectangles) who had regular sleep (8.2 hours sleep/night).
(*) indicates a statistically significant difference between Day 1 and Day 10 values (P<0.05).
The horizontal dashed lines indicate cardiovascular risk levels correlated with PCR values according to Ridker Circulation. 2001;103:1813–1818
Melatonin and Age
The amount of melatonin produced by the mammalian pineal gland changes with age. The trend is that pineal melatonin production decreases with advancing age.
During childhood, nocturnal melatonin levels continue to rise until puberty, a time that coincides with the peak of endogenous melatonin production and during which the first and most significant decrease also occurs. This decrease causes an increase in other hormones: these, in turn, signal to the body that it is time to enter puberty. As time goes by, nocturnal melatonin levels continue to decline and drop significantly around the age of 40, also in relation to external factors, bearing in mind that the most rapid decline occurs from the age of 50 onwards, becoming minimal in elderly people. It is no mere coincidence that, as melatonin levels decline, the first serious symptoms of ageing appear.
In humans, melatonin production not only decreases in elderly people, but is also significantly lower in many age-related diseases, including Alzheimer’s disease and cardiovascular disease.
Melatonin in menopause
Melatonin production in women seems to differ between the ‘peri-menopause’ period and established menopause, and the two situations are each characterised by a series of different symptoms, as reported in an epidemiological clinical study. Menopausal women with sleep disturbances may have lower levels of endogenous melatonin than in the peri-menopausal period.
Thus, according to these findings, almost half of peri-menopausal women and more than half of post-menopausal women suffer from sleep disorders. Moreover, it appears that insomnia in peri-menopausal women is associated with altered 24-hour melatonin secretion, characterised by a shift in peak secretion from the night-time hours to the early morning hours, whereas there is a tendency for melatonin levels to generally decrease in post-menopausal women. Among post-menopausal women, an age-related sharp decline in nocturnal melatonin secretion was found up to 15 years after menopause, followed by an extremely gradual decline thereafter.
Changes in plasma melatonin in post-menopausal women, divided into homogeneous groups by years since the onset of menopause.
Melatonin and the retina
Melatonin can be an effective antioxidant in the retina, acting as a direct and indirect scavenger of free radicals. In the eye, melatonin is synthesised by the retina and modulates the daily renewal rate of photoreceptors and light sensitivity. In addition, the retina contains high concentrations of polyunsaturated fatty acids. The continuous bombardment of electromagnetic radiation (i.e., photons and UV) and the visual process that generates cascades of electrons make the ocular system extremely susceptible to oxidative stress.
Furthermore, it has been suggested that the accumulation of free radical damage in the eye over time could explain the high prevalence of ocular degenerative diseases in the adult and elderly population.
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