Melatonin, the hormone of the pineal gland,
was discovered in 1958 by Aaron Lerner and colleagues (1) who a year later described
also its chemical structure as N
-acetyl-5-methoxytryptamine (2). This
discovery constituted a milestone for further pineal research. Since then the
knowledge of the structure and function of the pineal gland has tremendously
increased, especially during the last three decades. However, it should be stressed
that many functions of the pineal gland and melatonin still remain to be confirmed.
One of the most pronounced consequences of human life is aging. The term 'aging'
(or more correctly 'senescence') refers to post-maturational processes leading
to diminished homeostasis and increased vulnerability of the organism (3). The
worldwide prolongation of the mean life expectancy as well as the drastic reduction
of fertility rate result in a rapid increase of the size of the elderly population
(over the age 65), both in numbers and as a proportion of the whole (4). In
consequence, increasing number of people in advanced age raises many social
and economic problems because these beneficiaries of health and pension funds
are supported by a relatively smaller number of potential contributors (i.e.
those in the economically active age of 18 - 65), and results also in an increase
of the number of people suffering from age-related diseases (such as atherosclerosis,
neoplastic disease, neurodegenerative diseases). Therefore, there is a search
for any therapeutic agent improving quality of life of the elderly. A role for
melatonin as such a compound was recently suggested. Moreover, melatonin which
is currently available in some countries (e.g
. USA, Argentina, and Poland)
as a food supplement or over-the-counter drug, is often advertised as a "rejuvenating"
agent (5, 6).
In this survey, data on the possible role of melatonin in human aging are briefly discussed.
BIOSYNTHESIS OF MELATONIN, AND ITS CIRCADIAN RHYTHM
Although melatonin is synthesized in mammals, including human, mostly in the
pineal gland, it can be produced also in several other organs (e.g
retina, extraorbital lacrimal gland, Harderian gland, gastrointestinal tract,
blood platelets, bone marrow cells) (7). Interestingly, secretion of melatonin
is not restricted to mammalian species but it is also produced in nonmammalian
vertebrates, in some invertebrates, and in many plants (7, 8). It should be
stressed that extraordinariness of melatonin lies in the fact that it is a substance
with the molecular structure unchanged throughout the animal and plant kingdom.
The biosynthesis of melatonin is initiated by the uptake of the amino acid L-tryptophan
from the circulation into the gland. Within the pinealocyte it is catalyzed
to 5-hydroxytryptophan which is then decarboxylated to serotonin. The next step,
., N-acetylation of serotonin to N-acetylserotonin is completed by
-acetyltransferase, the key enzyme in melatonin synthesis.
The final step in the pathway is the O-methylation of N-acetylserotonin to melatonin
Once synthesized, melatonin is not stored in pineal cells but is quickly released into the bloodstream. Beside the blood melatonin is also present in other body fluids, including saliva, cerebrospinal fluid, bile, semen and amniotic fluid (10).
Melatonin is metabolized primarily in the liver by hydroxylation to 6-hydroxymelatonin, followed by sulfate or glucuronide conjugation to 6-hydroxymelatonin sulfate (90%) or 6-hydroxymelatonin glucuronide (10%). About 5% of serum melatonin content is excreted unmetabolized in urine. Melatonin forms also some minor metabolites, such as cyclic 2-hydroxymelatonin, N-gamma-acetyl-N-2-formyl-5-methoxykynurenamine and N-gamma-acetyl-5-methoxykynurenamine (6, 9).
Melatonin has a well-defined circadian rhythm (Fig. 1
) which is generated
by the circadian pacemaker (oscillator, biological clock) situated in the suprachiasmatic
nucleus (SCN) of the hypothalamus, and synchronized to 24 hours primarily by
the light-dark cycle acting via
the SCN. During the day serum melatonin
concentrations are low (10-20 pg/ml), significantly increase at night (80-120
pg/ml) reaching the peak between 24:00 and 03:00 h. The onset of secretion is
usually around 21:00-22:00 h and the offset at 07:00-09:00 h. A very close relationship
to the melatonin rhythm shows its major urinary metabolite - 6-sulfatoxymelatonin
with peak in its production in the pineal gland occurring during the daily dark
period. Melatonin shows this characteristic circadian rhythm in all living organisms
from plants, through animal kingdom to humans (6, 9).
The synthesis of melatonin is strictly controlled by lighting conditions. Photosensory
information arrives at the pineal via
polyneuronal pathway that begins
in the retina and involves the retinohypothalamic tract, suprachiasmatic nuclei,
paraventricular nuclei, medial forebrain bundle, reticular formation, intermediolateral
cell column of the spinal cord, superior cervical ganglia, internal carotid
nerve, and nervii conarii (6, 9). The crucial role in the control of melatonin
synthesis plays noradrenalin, which is released from postganglionic sympathetic
nerve fibers that ends in the pineal gland, and binds to pinealocyte ß-adrenergic
receptors (and partially alpha
activating adenylate cyclase, and increases cAMP levels leading to stimulation
of the activity of N-acetyltransferase, and subsequently to the synthesis of
MELATONIN AND AGING
Undoubtedly, the aging process is multifactoral, and no single element seems to be of basic importance. Although many theories relating melatonin to aging have been put forward, the role of this compound in the aging processes is not clear. However, there are several reasons to postulate a role for melatonin in aging (5, 6):
- melatonin participates in many vital life processes and its secretion falls gradually over the life-span;
- melatonin is a potent free radical scavenger, and the proposed link between oxidative stress and aging itself as well as age-related diseases suggest a role for melatonin in these processes;
- reduced concentrations of melatonin in the elderly may be related to lowered sleep efficacy very often associated with advanced age;
- reduced concentrations of melatonin may be related to deterioration of many circadian rhythms very often associated with advanced age.
- melatonin exhibits immunomodulatory properties, and a remodeling of immune system function is an integral part of aging.
Changes in melatonin concentrations during the life-span
The nocturnal rise in melatonin concentrations appears in humans in 6th
week of life, and its circadian rhythm seems to be well established in 21st
week of life (12). Amplitude of the nocturnal peak in melatonin secretion reaches
the highest levels between 4th
year of age. There is a drop in melatonin concentrations around maturation,
values remain relatively stable until 35-40 years, and thereafter diminish gradually
reaching around 70's levels similar to daytime concentrations (5, 6, 9). As
a consequence, in advanced age many individuals do not exhibit a day-night differences
in melatonin secretion (Fig. 1
||Fig. 1. Circadian profiles of serum melatonin concentrations in humans at various age; black area = period of darkness.
The amplitude of nocturnal melatonin secretion is believed to be genetically determined and shows great differences among individuals (13). Thus, some individuals produce significantly less melatonin during lifetime than others. However, the circadian profile of melatonin has been found highly reproducible over a six-week period in the same subject (14).
Melatonin and free radicals
Free radicals are reactive molecules which have an unpaired electron and are
continuously produced in cells as byproducts of oxidative phosphorylation and
fatty acid oxidation. It should be stressed that the free radical theory of
aging formulated initially by Harman (15, 16) seems to be recently one of the
most compelling explanations for many degenerative changes associated with aging.
According to the free radical theory of aging the deterioration of functions
in the advanced age is in part related to the damage of subcellular constituents,
cells, and organs sustained as a consequence of their persistent bombardment
by free radicals. This damage is a result of disturbance in the prooxidant-antioxidant
balance in the organism. Moreover, free radicals are believed to be involved
in pathogenesis of large variety of diseases, including age-related diseases
(such as Alzheimer's disease, Parkinson's disease, neoplastic disease, atherosclerosis,
.) (5, 17).
It has been discovered that melatonin is involved in antioxidative defense system
of the organism, designed to protect molecules from damage by toxic oxygen radicals.
Melatonin is a potent free radical scavenger and antioxidant. It scavenges both
hydroxyl radicals and peroxyl radicals, although it is a more efficient direct
scavenger of the highly toxic hydroxyl radicals. Additionally, melatonin stimulates
a number of antioxidative enzymes, e.g
. glutathione peroxidase and glutathione
reductase (18-21). Melatonin is both lipophylic and hydrophilic and diffuses
widely into cellular compartments, thus providing on-site protection against
free radical mediated damage to biomolecules. It may carry out its antioxidant
function with equal efficiency in multiple cellular compartments, i.e
in the nucleus, cytosol, and membranes (20). It should be stressed that melatonin
is the only antioxidant known to decrease substantially after middle age, and
this decrease closely correlates with a decrease in total antioxidant capacity
of human serum with age (22).
Melatonin and sleep in advanced age
It is well known that increased frequency of sleep disorders occurs in the advanced age (23). Sleep disturbances affect 40 to 70% of elderly population, including 10 - 25% of the elderly complaining of persistent insomnia. This may influence the subjective and objective general physical health of the elderly, and may be associated with mental health problems including poor life satisfaction or quality of life as well as poor cognitive, psychological, and social functioning (24).
On the contrary, as indicated above, melatonin concentrations significantly
decrease in the elderly. According to Cajochen et al
. (2003) the soporific
and chronobiotic properties of melatonin make it an optimal candidate for treating
sleep. There are numerous studies in which melatonin was administered in elderly
patients suffering from sleep disorders. Although majority of data show that
melatonin improved sleep parameters in the elderly, in some studies sleep was
unaffected by melatonin (24-30). Melatonin was shown to significantly improve
subjective and/or objective sleep parameters (reduces sleep latency and/or increases
sleep efficacy and total sleep time) in some individuals (27-29).
Lavie et al.
(31) suggest that from the accumulated data it is evident
that melatonin characteristics are not those of a typical hypnotic or sedative.
Melatonin affects sleep in much more subtle way. The authors propose that the
role of melatonin in the induction of sleep does not involve the active induction
of sleep, but rather is mediated by an inhibition of a wakefulness-producing
Although melatonin can not be considered as universally effective drug for treatment of sleep disorders, it may be helpful in elderly patients suffering from insomnia. It should be stressed that melatonin seems to be superior to some other hypnotics because it does not influence psychomotor performance (32).
Melatonin and circadian rhythms in the elderly
Deterioration of many circadian rhythms which play an important role in homeostasis
. sleep/wake cycle, the core body temperature, performance, alertness,
and secretion of many hormones) is characteristic of advanced age (24), and
most probably related to changes in neurons of SCN (33). It is manifested by
reduced amplitude of many rhythms, earlier timing of endogenous circadian rhythmicity,
disorganization of temporal order, loss of entrainment stability and responsiveness
to Zeitgebers (24).
A significant role in timing of the circadian system is attributed to melatonin. In 1989 Armstrong (34) proposed that melatonin is an internal Zeitgeber, and the function of the pineal gland is to adjust the phase and synchronize internal rhythms by the periodic nocturnal release of melatonin. Two years later Armstrong and Redman (35) suggested that melatonin might have beneficial effects in terms of aging just because of its association with circadian timing system. The loss of melatonin in advanced age leads to disturbances in the circadian pacemaker, which causes internal temporal desynchronization inducing a variety of chronopathologies and leads to generalized deterioration of health.
The importance of melatonin in regulation of circadian rhythms is also suggested by studies on its beneficial effects for amelioration of jet-lag symptoms as well as in phase shifting of the circadian clock for phase resetting in blind people (9, 29, 36, 37).
Melatonin and immune system in the elderly
Many alterations in the immune system are observed in the individuals in advanced age, generally viewed as a deterioration of immunity, and termed 'immunosenescence' (38) which have clear clinical consequences, leading to increased incidence of infections, cancers, autoimmune disorders, and chronic inflammatory diseases (39). The age-associated decline in the immune system refers to both humoral and cellular responses, although an overwhelming decrease in T cell functions with aging seems to play the main role (39, 40). Recent reports indicate "remodeling" of structure and function of the immune system rather than its deterioration in aging (40, 41). This remodeling involves several modifications at the level of hematopoiesis, in the compartments of lymphoid organs, and in the peripheral cell populations number and function. As a result, immune parameters measured in old individuals exhibit different values, in comparison with those observed in young counterparts.
Numerous experimental data show that melatonin exerts immunoenhancing action (42-44). Moreover, there are several indications that diurnal changes in the immune system function are controlled by or correlated with the pineal melatonin synthesis and secretion (45). For example, a circadian rhythm of the thymic hormones thymosin a1 and thymulin was demonstrated to be strictly parallel with that of melatonin content in the pineal gland and in blood (46). It seems that melatonin may exert a direct effect on the immune system because melatonin receptors have been discovered in immune cells (42). Moreover, it was recently reported that cultured human lymphocytes synthesize and release large amount of melatonin which could act, in addition to its endocrine effect, as an intracrine, autocrine, and/or paracrine substance for the local coordination of the immune response (47). Our recent data suggest that endogenous melatonin is an essential part for an accurate response of human lymphocytes through the modulation on interleukin-2/interleukin-2 receptor system (48).
IS THERE A RATIONALE FOR MELATONIN SUPPLEMENTATION IN THE ELDERLY?
It has been proposed that melatonin may be of some therapeutic significance,
and in some countries it is available as OTC drug or even food supplement. In
Poland melatonin is registered since 2000 as OTC drug for sleep and circadian
rhythm disorders. Beside widely accepted indications for therapeutic use of
., sleep disorders and such circadian clock disturbances
as jet-lag and phase-shifting of the circadian clock in blind people), there
are also perspectives for its broader use, although other possibilities for
therapeutic usefulness of melatonin are not definitively proved (49).
Melatonin is often advertised as an antiaging agent ("fountain of youth"). However, presently available data do not allow us to conclude that melatonin may have a role in extending normal longevity. Although melatonin can not be recognized as a "rejuvenating" agent, some of its actions may be beneficial for the process of aging. Administration of melatonin may improve temporal organization in advanced age. Moreover, it has beneficial effects on sleep as well as on age-related diseases. Although recommendations of melatonin supplementation in elderly should be considered, there is a need for extensive studies on the use of melatonin in order to improve the quality of life in advanced age.
It should be stressed that melatonin treatment seems to be safe because of its remarkable low toxicity and absence of any significant side effects (49). Additionally, melatonin has been shown to reduce the toxicity and increase the efficacy of a large number of drugs whose side effects are well documented (50).
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