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American Association for Medical Chronobiology and Chronotherapeutics (AAMCC)

The Development of the Human Time Structure from Childhood to Senescence

China, December, 2004

Erhard Haus, M.D., Ph.D., Professor, Department of Laboratory Medicine & Pathology, University of Minnesota; HealthPartners Medical Group, Regions Hospital, St. Paul, Minnesota, 55101

 

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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.

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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.

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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).

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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).

References

Haus E., Nicolau G., Lakatua D.J., Sackett-Lundeen L.: Reference values for chronopharmacology. Ann. Rev. Chronopharm. 4:333-342, 1988.

Haus E., Nicolau G., Lakatua D.J., Sackett-Lundeen L., Petrescu E.: Circadian rhythm parameters of endocrine functions in elderly subjects during the seventh to the ninth decade of life. Chronobiologia 16:331-352, 1989.

Haus E. and Smolensky M.: Development of circadian time structure and blood pressure rhythms. In: Portman R.J., Sorof J.M., Inglefinger J.R. (eds). Clinical Hypertension and Vascular Disease: Pediatric Hypertension. Humana Press Inc., NJ, pp 45-73, 2004.

Haus E. and Touitou Y.: Chronobiology of development and aging. In: Handbook of Experimental Pharmacology: Physiology and Pharmacology of Biologic Rhythms. Redfern P. and Lemmer B. (eds). Springer-Verlag, Heidelberg, pp 9-134, 1997.

Haus E. and Touitou Y.: Biological rhythms and aging. In: Touitou Y., Haus E. (eds). Biologic Rhythms in Clinical and Laboratory Medicine. New York, Springer-Verlag, pp 188-207, 1992.

Miller C.L., White R., Whitman T.L., O’Callaghan M.F., Maxwell S.E.: The effects of cycled versus non-cycled lighting on growth and development of preterm infants. Infant Behavior and Development 18:87-95, 1995.

Mormont M-C., Waterhouse J., Bleuzen P., Giacchetti S., Jami A., Bogdan A., LeMonch J., Misset J.-L., Touitou Y., Levi F.: Marked 24-hour rest-activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clinical Cancer Research 6:3038-3045, 2000.

Reinberg A., Gervais P., Halberg F., Gaultier M., Poynette N., Abulker C., Dupont J. Mortalite des adultes: rythmes circadiens et circannuels. Nouv. Presse Med. 2:289-294, 1973.

Reppert S.M. and Weaver D.R.: Molecular analysis of mammalian circadian rhythms. Ann. Rev. Physiol. 63:647-676, 2001.

Rivkees S.A. and Hao H.: Developing circadian rhythmicity. Seminar in Perinatology 24(4):232-242, 2000.

Sauerbier I.: Rhythms in drug-induced teratogenesis. In: Touitou Y., Haus E. (eds). Biologic Rhythms in Clinical and Laboratory Medicine. New York, Springer-Verlag, pp 151-157, 1992.

Schernhammer E.S., Laden F., Speizer F.E., Willett, W.C., Hunter D.J., Kawachi I., Fuchs C.S., Colditz G.A.: Night shift work and risk of colorectal cancer in the Nurses Health Study. J. Natl. Cancer Inst. 95(11):825-828, 2003.

Touitou Y. and Haus E.: Aging and the endocrine circadian systems. In: The Neuroendocrine Immune Network in Aging. Straub R.H., Mocchegiani E. (guest eds). Neuroimmune Biology 4:165-193, 2004.

Touitou Y. and Haus E.: Alterations with aging of the endocrine and neuroendocrine system in humans. Chronobiology International 17(3):369-390, 2000.

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