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The human organism is characterized by an
intricate time structure consisting of rhythms of multiple frequencies
superimposed upon trends like child development and aging (Haus and
Touitou 1992). Rhythmicity
in certain frequencies is genetically fixed with oscillator genes and
gene products for e.g., the prominent about 24-hour (circadian) rhythms
identified in the central nervous system and in peripheral tissues (Reppert
and Weaver 2001). Rhythms
can be modulated and adjusted in their timing (synchronized or
entrained) by environmental factors.
Some circadian rhythms, although genetically determined, become
manifest only after exposure of the organism to a 24-hour periodic
environment. The
genetic-environment interaction in the establishment and maintenance of
rhythms begins early in intrauterine life and continues throughout
infancy and childhood with the establishment of the mature time
structure similar to that seen in the adult during the first 12 to 24
months of extrauterine life (Rivkees and Hao 2000).
Circadian variations
develop during intrauterine
life in numerous variables apparently induced and/or
synchronized from the mother through humoral messengers passing through
the placenta and/or through changes in placental hemodynamics.
Circadian and ultradian
patterns in fetal movement can be recognized beginning between
24 and 30 weeks of gestation with increasingly prominent peaks
during the night hours, especially during REM sleep of the mother.
A rhythm in the “breathing” movements of the fetus is present
after 30 weeks of gestation with a peak between 02:00 and 07:00 during
maternal sleep and with a superimposed ultradian rhythm component with a
cycle length of 100-500 minutes. The human fetal heart rate shows a
trough between 02:00 and 06:00 similar to the maternal rhythm in heart
rate with, in some instances, a drop in heart rate deep enough to raise
clinical concern. A
circadian rhythm in fetal bladder volume with a trough between 00:00 and
06:00 indicates circadian rhythmicity in fetal cardiovascular, renal
and/or adrenal function (Haus and Smolensky 2004)
The endogenous and/or maternally induced rhythms of the fetus
give rise to circadian differences in the susceptibility to toxic agents
and most likely therapeutic interventions.
In animal experiments, the circadian periodicity encountered in
the fetus is linked to circadian variations in the susceptibility to fetotoxic (teratogenic)
agents. The type
and severity of embryopathies due to fetal toxicity is in experimental
models determined by the interaction of both the circadian time and the
developmental stage of exposure (Sauerbier 1992).
Circadian rhythms in fetal toxicity have been shown for cortisol,
dexamethasone, hydroxyurea, cyclophosphamide, 5-fluorouracil, cytosine
arabinoside and ethanol.
At
the time of birth, the newborn
is suddenly separated from its intra-uterine environment in which
synchronizing signals are provided from the mother via the placenta.
The ambient environment presents a different and foreign set of
time cues resulting in an initial disruption or even loss of circadian
synchronization. The
circadian oscillator system is not yet mature in normal-term newborns,
and it is even less mature in pre-term newborns.
At birth, high-frequency ultradian rhythms predominate over
circadian rhythms. After
birth, two processes together determine the establishment of the
circadian time organization. One
is the ongoing maturation process of the oscillatory system, and the
other is time structure synchronization provided by the 24-hour cycle of
light and dark, feeding, and handling, among other periodic aspects of
the infant’s environment and care regimen.
The development of the circadian time organization seems to be
dependent on the strength of the 24-hour periodic inputs by the
nurturing environment; the strong the inputs, the faster the development
of the circadian time structure. The
functional importance of the establishment of an environmentally
synchronized circadian periodicity has been documented in several
studies. Pre-term infants
kept under ambient-like light-dark cycles wean earlier from ventilator
support, feed by mouth sooner, gain weight faster and develop quicker
physically, behaviorally, and are healthier than infants kept under
constant illumination (Miller et al. 1995).
Accordingly, it is widely recommended that hospital nurseries be
outfitted with a day-night alternating light-dark schedule like that of
the natural environment and that care patterns be redesigned to mimic
the diurnal activity-nocturnal sleep routine characteristic of the human
species.
In sleep-wakefulness, a circadian rhythm becomes more prominent
in a matter of weeks to months (as every mother can tell).
In other variables, the adult
pattern of circadian rhythmicity is not reached before 12-24
months of age. The
circadian periodic input provides a circadian experience and entrains
the developing neuroendocrine system of the infant, which establishes
the circadian time organization of the infant and child parallel to its
maturation.
The circadian time organization in all age groups determines the
times of maximal and minimal performance in physical as well as
cognitive functions and the times of maximal and minimal response and
resistance to environmental agents, including many drugs used in
clinical medicine. The time
dependent differences in the pharmacokinetics and pharmacodynamics allow
in many instances to improve the therapeutic effects and/or minimize the
undesirable side effects of numerous drugs, including chemotherapeutic
agents used in cancer therapy.
Rhythm disturbances by night and shift work or transmeridian
flights over several time zones lead to functional impairment (e.g.,
jet-lag) and if prolonged have been shown to be associated with a higher
incidence of cardiovascular diseases and according to some recent
reports with colonic and breast cancer (Schernhammer et al. 2003).
Rhythm alterations by disease lead to impaired well being and to poorer
prognosis, e.g. in patients with malignancies (Mormont et al. 2000).
It appears that in all age groups, maintenance of a strong
circadian time organization favors a good performance status and
physical and mental well-being.
In the course of the aging
process, changes in the human time structure occur (Haus et al.
1988, 1989; Haus and Touitou 1997; Touitou and Haus 2000, 2004), which
accompany physiologic senescence and may be instrumental in producing
some of the performance decrements occurring in old age.
These changes may be exaggerated in pathologic aging leading to
senility.
Age
related changes affect differently the rhythms of various physiologic
variables, of different frequencies and within a given frequency of
different rhythm parameters. Characteristic
changes of the human circadian time structure, which are related to
aging are summarized in Table 1. These
changes are listed in the order of frequency and consistency with which
they have been observed.
Age-related
changes in circadian rhythm parameters observed in different variables
are summarized in Tables 2-5, and age-related changes in circadian time
adaptation in Table 6
.
Among the most prominent
changes found in the course of aging is the reduction of the circadian
amplitude of many circadian rhythms, which appears to be an important part
of the aging process. The
measurement of the amplitude of certain circadian periodic variables is
regarded by some as a sensitive index of aging and to provide a measurable
endpoint to determine the stage and progression of the aging process.
A decrease in amplitude of a physiologic variable during aging may
be the expression of a functional decline.
Of special interest is, in this context, the decrease in the
circadian amplitude (and especially the decrease in the nocturnal rise) of
melatonin. The decrease in the nightly surge of melatonin may be a
factor favoring circadian (external and internal) desynchronization and
may lead to a defect in time adaptation, e.g., after transmeridian
flights.
In
studies of groups of subjects, the absence of a rhythm as a group
phenomenon, as reported occasionally in the elderly, does not necessarily
mean absence of a rhythm in single individuals, but rather may be due to a
lack of synchronization of the subjects within the group. Rhythms free running from environmental synchronizers and/or
among the subjects of a group have been observed in the aged both in the
circadian and the circannual frequency range.
In contrast to the majority of
circadian rhythms showing a decrease in amplitude, a number of rhythms
show an increase in amplitude and/or in circadian mean which may be
interpreted as an adaptive response to some of the changes developing
during senescence. The
increase in amplitude does not necessarily accompany an increase in
circadian mean.
The
question has been raised if a decrease in the circadian amplitude of some
variables may play a primary causative role in aging, and if attempts to
counteract the decrease of amplitude could delay the aging process. Healthy elderly subjects may show a well-maintained circadian
time organization until very old age.
However, internal desynchronization of circadian rhythms has
frequently been documented in older individuals and may lead to
disturbances in the sleep-wakefulness pattern, and may be responsible for
problems in adaptation and resistance to environmental stimuli.
In senile dementia of vascular origin and in Alzheimer’s disease,
circadian rhythm disturbances occur as a consequence of the disease rather
than its cause. Attempts of
maintenance of an environmentally synchronized circadian time organization
by bright light exposure in the morning alone or reinforced by melatonin
in the evening have led to symptomatic improvement in general well-being,
and as suggested by some preliminary results in certain patients, also to
some improvement of cognitive functions.
Changes related to age have
been observed not only in the circadian frequency range but also in
ultradian and infradian rhythms including circannual rhythms.
Circannual rhythms of some variables like e.g., thyroid hormones or
catecholamine excretion were not found in groups of elderly subjects,
which may represent a lack of adaptation to the season dependent
environmental stimuli or a lack of synchronization of circannual rhythms
within groups of subjects by those stimuli.
In some longitudinally studied subjects, free running circannual
rhythms with periods significantly different from one year were found in
some variables like, e.g., blood pressure (Table 7).
The circadian, circaseptan, and seasonal or circannual variations
in human mortality of many causes indicate transient risk states for many
potentially fatal events. Some
of these may be related to changes in rhythmic functions (chronopathology),
and/or lack of adaptive capability in the aged leading to the high
mortality noticed during the winter months in human subjects (e.g.
Reinberg et al. 1973).
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