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Melatonin at 700 million years: On one of the oldest biologically active molecules

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As dusk sets and the dark night follows, these conditions set in motion a chain of molecular actions from your eyes to the pineal gland, necessary to stimulate the production of melatonin.

At the moment that melatonin is released in the brain and binds to neurons, the electrical rhythm changes and body temperature decreases. This directs your brain and body toward sleep. When getting up again in the morning, sunlight turns off the production of melatonin. Daytime signals come in again and the brain comes out of its sleeping mode.

This is the rhythm that for millions of years has been taking root in various forms of life. Melatonin has evolved approximately 500-700 million years ago in our earliest ancestors, in tiny organisms that lived in the sea.

It has long been thought that the enzyme needed to make melatonin can also be traced back to this period. The origin of the enzyme Timezyme seems to have taken place in the period of evolution which took place around the time of the transition from invertebrate to vertebrate life.

More recently, scientists at the European Molecular Biology Laboratory in Germany solved another piece of this puzzle and pushed back the rise of melatonin in the evolutionary timeline even further. They did this by looking at the activity of specific genes involved in the production of melatonin and of other sleep-related molecules.

They not only showed that the simple sea worm Platynereis dumerilii has the same melatonin-regulatory and light-trapping cells as humans have in their eyes, but also that they make use of the same type of gene-network as do us humans, whereby melatonin is similarly produced only at night, and answers to a 24-hour cycle.

Because of the similarity between the two gene networks, they are thought to have evolved from a shared invertebrate ancestor. This is a completely new and surprising theory that eventually leads back to probably the first primordial forms of sleep.

Melatonin is a clock and calendar

Because melatonin has been present early in evolution, it has been, as DHA, intertwined with our lives in the deepest possible way and therefore remains a very important substance in the body.

And all this for a molecule that emerged as a waste product of eye cells. It was gradually formed into a signal of the night because of its piling up in cells overnight. With the advancing complexity of life forms on earth, the need for more melatonin also increased. The pineal gland arose from this growing demand. The latter is a structure separate from the eyes to keep serotonin, and other toxic substances required in order to make melatonin, away from the sensitive eye tissue.

Step by step there will be more clarity about the evolutionary origin of the main functions of our brain. The fascinating thing is that many of these fundamental discoveries are being made by looking at life forms that occur in the sea. This is not surprising, however, because life in the oceans and seas have dominated the earth since the very beginning.

Melatonin is thus one of the oldest biologically active molecules on earth and, as previously mentioned, very deeply intertwined with mammalian biochemistry. Animals are not alone in producing melatonin: even bacteria and plants make use of this mysterious neuro-hormone.

As "hormone of the night" melatonin concentrations change over a 24-hour cycle with the function of circadian clock. But that is not all. It is also known that the melatonin concentrations change according to lunar and seasonal cycles. Melatonin is not only a clock for the body but also its calendar.

For example, the body knows on the basis of melatonin concentrations when it is winter. As night falls earlier, melatonin production takes place over a longer period of time. The body picks up this signal of surplus melatonin, thus affecting the thermoregulation set point. You'll be more resistant to cold as a consequence. This is obviously an adaptive adjustment in wintertime.

Melatonin - N-acetyl-5-methoxytryptamine

Melatonin has many functions throughout the body and these are not just hormonal. Beside the Zeitgeber (time-setting) function and master regulator of sleep, for example, melatonin controls the biorhythms and release curves of many other hormones, promotes cellular autophagy, and is a unique and powerful antioxidant.

The first functions of melatonin were paracrine, affecting only those cells present in the direct cellular environment. Later, with the emergence of the melatonin peak during sleep, melatonin was also released into the blood stream, turning its efficacy endocrine. From that moment onward, other tissues could also make use of melatonin.

Melatonin - N-acetyl-5-methoxytryptamine - is synthesized from the essential amino acid tryptophan and ultimately serotonin, via a multi-step chemical process. Production mainly, but not exclusively, takes place in the pineal gland. Melatonin is also produced in other parts of the brain such as the retina, the gastro-intestinal tract, the testicles and ovaries, and the skin.

Pineal gland

The pineal gland (epiphysis) acts as a link between the nervous system and the limbic system of the brain. Until 1958 little was known in the western world about the pineal gland until Aaron Bunsen Lerner claimed that it produced melatonin. In Oriental medicine, on the other hand, the pineal gland’s reputation has been established for thousands of years in terms of what came to be called the third eye.

The mystery of sleep

From a scientific point of view, follow-up studies addressing the above assumptions may also provide basic information about the role of sleep, because even today this still holds a host of mysteries. It seems that sleep cannot be properly explained biologically because of the more complex mechanics of the quantum world where different rules apply than biochemical ones. We might well get insights into the mysteries of sleep from biophysics, a field in which people are more aware of phenomena such as magnetism, electricity and other laws of physics, in dialogue with biology.

Recent information about sleep points to this direction. The significant difference between brain activity during wakefulness as compared to brain activity during sleep turns out to importantly lie in the degree to which areas of the brain communicate with each other. It is hypothesized from this that the function of sleep is not determined by the activity of individual brain regions, but by the interaction between these regions and the degree to which these interactions develops over space and time.

We may in fact consider sleep as a specific configuration of the neuronal network that is our brain. Supporting this theory is the discovery that during sleep electrical signals, used by brain cells to communicate, are seen to run in the opposite direction. This deletes unimportant information, and the cells are rendered susceptible again to new learning experiences. This discovery illuminates the biophysical basis of the formation of new memories.

It is not only the configuration of the direction of electrical signals that changes during sleep, but also the cellular structure of brain cells. The brain has a unique method of removing harmful waste through what is called the glymphatic system (or glymphatic clearance pathway). The most interesting thing about this is the way in which this occurs. Brain cells shrink in volume by about 60% during sleep so that waste can be disposed of easily. Sleep thus also changes the cellular structure of the brain, effectively bringing it in a completely different state.

No real nights anymore

A totally different configuration of the brain … backward electric signals … an altered cellular structure: it all sounds quite "quantum-like". In today’s world in which artificial light has done away with dark nights one should not forget that the basis for proper physical functioning is deeply rooted in our natural biorhythms.

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