Page 26 - SAM 0625

SAN ANTONIO
MEDICINE

Melatonin: Its expanding universe

By Russel J. Reiter, PhD
alternate source of melatonin is the mitochondria of perhaps every cell.
elatonin was isolated from the bovine pineal gland seven-
and-a-half decades ago by the dermatologist, Aaron Lerner Phylogenetically, melatonin is an extremely ancient molecule hav-
Mand colleagues, hoping it would be useful to treat abnormal ing evolved in prokaryotic organisms such as bacteria 3-2.5 billion
skin pigmentations. This assumption was based on a study published years ago.3 Subsequently, with the advent of single cell eukaryotes,
50 years earlier, which reported that the consumption of minced ani- which came into being about 2 billion years ago, they fed on the pro-
mal pineal tissue profoundly changed pigment distribution in the skin karyotes by engulfing/phagocytizing them for their nutrient value.
of tadpoles. The observations reported for amphibian skin, however, Over additional eons, the engulfed bacteria established a permanent
proved not to directly apply to the pigment distribution in the human residence and evolved into mitochondria, and they carried with them
epidermis. the ability to produce melatonin. The transformation of engulfed bac-
Shortly after the seminal discovery by Lerner, a physiologist, Wil- teria into mitochondria in eukaryotes is known as the widely accepted
bur Quay, observed that the synthesis of melatonin in the pineal gland endosymbiotic theory. Even today, mitochondria in every human cell
of mammals exhibited a circadian rhythm, which was driven by the have many molecular characteristics of bacteria, attesting to their ori-
light:dark cycle to which the animals were exposed with high levels of gin from these prokaryotes.
this molecule being produced and released at night and virtually none The early melatonin synthesizing single cell eukaryotes eventually
during the day. This observation set the stage to what is usually known became multicellular with the earliest vertebrates only appearing about
about melatonin by most individuals today. 525 million years ago during the Cambrian Explosion. Vertebrates are
In humans, the blood melatonin rhythm, which is initiated in the the only species that have a pineal gland, so melatonin was present for an
newborn at 4 to 6 months of age and is like that in all other mammals estimated 2 billion years before vertebrates and the pineal gland existed.
such that during the day circulatory levels are barely measurable, while Additional data supporting the synthesis of melatonin in human
at night they increase 10 to 20-fold. Noteworthy is that the cerebro- mitochondria comes from experiments that examined the melatonin
spinal fluid exhibits a melatonin cycle like that in the blood except the synthetic activity of recently ovulated oocytes from two mammalian
nighttime increase is an order of magnitude greater than the levels in species. When provided the necessary precursor, serotonin, melatonin
the circulation; the cycle of melatonin in the cerebrospinal fluid may production was quickly activated. This is relevant given that during
be the one that drives the circadian rhythms of the body by interacting embryo development, oocyte mitochondria are the exclusive anteced-
with neurons situated in the master circadian clock, the suprachiasmat- ents of all mitochondria of every cell in the body.
ic nucleus, located in the hypothalamus just above the optic chiasm.1 The current evidence is that melatonin evolved as an especially-po-
This action depends on specific melatonin receptors on the neurons tent antioxidant, a function that has been documented in thousands
of this nuclear group. Exposure to sufficiently bright and appropriate of scientific publications during the last two decades.4 The function
wavelength light at night interrupts pineal melatonin synthesis and of an antioxidant is to neutralize unstable toxic derivatives of oxygen
accordingly disrupts circadian rhythms such as occurs during jet lag referred to as free radicals or reactive oxygen species; the damage these
and in night shift workers. Likewise, in advanced age the melatonin brigands inflict on lipid, proteins, DNA, etc., is referred to as oxidative
rhythms wane, a change that contributes to the circadian destabiliza- stress. Excessive oxidative stress is a feature on most chronic diseases
tion that occurs in the elderly. Well-controlled circadian rhythms are and unequivocally contributes to age-associated organ deterioration, for
an important factor in maintaining optimal health. example, neurodegenerative diseases, visual deterioration, cardiovascular
Since melatonin is a circadian regulator and given its levels are ele- dysfunction, bone loss, hepatorenal failure, auditory loss and others. 5-8
vated during darkness, it was initially presumed to be associated with There is a plethora of antioxidants available to cells, some of which
sleep.2 This idea is strongly ingrained in the mind of the public with humans ingest in the diet (vitamins A, C, E, flavonoids and poly-
dozens of supplemental melatonin products being sold for sleep pro- phenols) and some of which cells produce (glutathione, melatonin,
motion. Melatonin, however, is not a direct soporific and its efficacy as lipoic acid, coenzyme Q10, antioxidative enzymes). Melatonin is both
a sleep aid is variable with its effectiveness in terms of sleep dependent endogenously produced and exogenously acquired in the diet since all
on it being given during a restricted time interval during the 24-hour plants also produce melatonin. Since free radicals damage any mole-
period, an interval that is sometimes difficult to identify and seems to cule in the vicinity of where they are generated within an infinitesi-
vary among individuals. The lack of its direct association with sleep mally short period of time, a scavenging molecule must be within the
is also obvious in nocturnal species that sleep during the day and are immediate neighborhood of where the free radical originated.
active during darkness when their melatonin levels are at their peak. In addition to being an uncommonly multifunctional radical scav-
Within the last two decades it has become apparent that melatonin enger, melatonin acts synergistically with other antioxidants and stimu-
production is not unique to the pineal gland as originally thought. In lates antioxidant enzymes. Like real estate, an essential feature of a potent
fact, it is now estimated that of the total amount of melatonin syn- and reliable antioxidant also is its location because the damage a radical
thesized in the human, that of pineal origin is miniscule (<5%). The inflicts is essentially instantaneous. During oxidative phosphorylation

26 SAN ANTONIO MEDICINE • June 2025