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PubMed2026

Epigenetic Clocks of Biological Aging and Cognitively Healthy Longevity: The Women's Health Initiative Memory Study.

BACKGROUND: Little is known about whether epigenetic age acceleration (EAA) clocks are capable of predicting exceptional longevity with or without preserved cognitive function. METHODS: We examined 5844 women from the Women's Health Initiative Memory Study. Fifteen epigenetic clocks were measured at baseline (1996-1999). Longevity outcomes were defined as: 1) survival to age 90 with preserved cognition (n = 1726, 29.5%); or 2) survival to age 90 with cognitive impairment (n = 956, 16.4%); vs. 3) death before age 90 (n = 2611, 44.7%). Logistic regression models examined associations between the 15 clocks and survival to age 90 (vs. death before age 90), adjusting for covariates. Multinomial logistic regression models examined associations with survival to age 90 without cognitive impairment and survival to age 90 with cognitive impairment (each vs. death before age 90), also adjusting for covariates. RESULTS: Each standard deviation increase in EAA for the first-generation clocks was associated with 7%-18% reduced odds of survival to age 90 vs. earlier death. Stronger associations were observed for second- and third-generation clocks, including AgeAccelGrim2 (OR = 0.66; 95% CI 0.61-0.71), PCGrimAge (OR = 0.64; 95% CI 0.59-0.69), PCPhenoAge (OR = 0.73; 95% CI 0.68-0.78) and DunedinPACE (OR = 0.77; 95% CI 0.72-0.82). None of the clocks was more strongly associated with survival to age 90 with preserved cognition than with survival to age 90 with cognitive impairment, relative to death before age 90. CONCLUSION: All epigenetic clocks were associated with exceptional longevity, but none were associated with cognitive healthspan. Developing clocks that can differentiate long survival with and without preserved cognitive function is critical.

Healthspan↗
PubMed2001

Molecular mechanisms of morning onset of myocardial infarction.

We recently isolated a novel bHLH/PAS protein, CLIF (cycle like factor), by yeast two-hybrid screening of human umbilical endothelial cell cDNA library. CLIF is preferentially expressed in endothelial and neuronal cells. Because CLIF is expressed in vascular endothelial cells and forms a heterodimer with CLOCK, the key transcription factor controlling the circadian rhythm, we hypothesized that CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. Northern blot analysis of mouse organs showed circadian oscillations of PAI-I mRNA levels. In addition, the clock-related genes also showed circadian oscillation in peripheral tissues. In endothelial cells, the heterodimer of CLIF and CLOCK upregulated the PAI-1 gene expression through E-box sites. Furthermore, Period and Cryptochrome, which are negative regulators in the feedback loop of the biological clock, inhibited PAI-1 promoter activation by the CLOCK:CLIF heterodimer. These results suggest that the peripheral tissues have their own biological clock and CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. This study suggests a novel molecular mechanism of the morning onset of myocardial infarction. Here we review our recent work and literature.

ARNTL Transcription Factors↗
PubMed2003

[Research advances on mammalian circadian clock-related genes].

Circadian rhythms,generated by endogenous biological clocks,regulate physiological activities autonomously. It is one of the focuses in life science in recent years. The researches on the mechanism of mammalian circadian clock have been developed at the molecular level. Some clock-related genes are cloned and identified in succession. The core mechanism for the master circadian clock consists of interaction between the positive and negative transcription and translation feedback loops. The peripheral tissues cultured in vitro exhibit circadian rhythms as well. These give clues to further research.

Animals↗
PubMed2006

PACAP--a multifacetted neuropeptide.

Pituitary adenylate cyclase activating polypeptide (PACAP) was originally isolated from ovine hypothalamus based on its ability to stimulate cAMP production in pituitary cell cultures. The peptide exists in two forms, both of which are derived from the same precursor. PACAP38 and the C-terminal truncated PACAP27 can interact with three subtypes of receptors activating adenylate cyclase and/or phospholipase C. Since its discovery, numerous studies have provided evidence that PACAP is a pleiotropic substance having a broad spectrum of biological functions; the peptide can act as a hormone, neurohormone, autocrine/paracrine substance, neurotransmitter, neuromodulator, neurotrophic factor, and immunomodulator. Two examples of the functional role of PACAP on the biological timing system are presented: 1) the transient expression of PACAP during the periovulatory period in ovarian cells, in which PACAP functions as an autocrine/paracrine inducer of progesterone secretion and subsequent luteinization; and 2) the role of PACAP as a neurotransmitter in the retinohypothalamic tract mediating photic regulation of the brain's biological clock.

Animals↗
PubMed2006

Neurotransmitters of the suprachiasmatic nuclei.

There has been extensive research in the recent past looking into the molecular basis and mechanisms of the biological clock, situated in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. Neurotransmitters are a very important component of SCN function. Thorough knowledge of neurotransmitters is not only essential for the understanding of the clock but also for the successful manipulation of the clock with experimental chemicals and therapeutical drugs. This article reviews the current knowledge about neurotransmitters in the SCN, including neurotransmitters that have been identified only recently. An attempt was made to describe the neurotransmitters and hormonal/diffusible signals of the SCN efference, which are necessary for the master clock to exert its overt function. The expression of robust circadian rhythms depends on the integrity of the biological clock and on the integration of thousands of individual cellular clocks found in the clock. Neurotransmitters are required at all levels, at the input, in the clock itself, and in its efferent output for the normal function of the clock. The relationship between neurotransmitter function and gene expression is also discussed because clock gene transcription forms the molecular basis of the clock and its working.

Journal Article↗
PubMed1996

Perinatal development of human circadian rhythms.

The early development of circadian rhythms in primates, including man, was reviewed. Continuous 24-h recordings were carried out for maternal and fetal circadian rhythms during gestation as well as in preterm infants. Several propositions were made based on these new findings: 1. The fetal biological clock is an endogenous clock capable of generating circadian rhythms and responding to maternal entraining signals long before the moment of birth. 2. Through the fetal biological clock, maternal circadian rhythms influence the fetal overt rhythms. 3. Maternal rhythms influence the fetus, and fetal rhythms feed back to the mother (via the placenta). Disruption of this fetal-maternal interaction during gestation leads to: a. disturbances of maternal and fetal circadian rhythms; b. disappearance of circadian rhythms at the time of birth; c. a gestational period which is either too short or too long (see also Honnebier and Swaab, 1973); d. delayed or impaired maturation of the circadian rhythms of the infant.

Body Temperature↗
PubMed2004

Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension.

Patients with essential hypertension have disturbed autonomic cardiovascular regulation and circadian pacemaker function. Recently, the biological clock was shown to be involved in autonomic cardiovascular regulation. Our objective was to determine whether enhancement of the functioning of the biological clock by repeated nighttime melatonin intake might reduce ambulatory blood pressure in patients with essential hypertension. We conducted a randomized, double-blind, placebo-controlled, crossover trial in 16 men with untreated essential hypertension to investigate the influence of acute (single) and repeated (daily for 3 weeks) oral melatonin (2.5 mg) intake 1 hour before sleep on 24-hour ambulatory blood pressure and actigraphic estimates of sleep quality. Repeated melatonin intake reduced systolic and diastolic blood pressure during sleep by 6 and 4 mm Hg, respectively. The treatment did not affect heart rate. The day-night amplitudes of the rhythms in systolic and diastolic blood pressures were increased by 15% and 25%, respectively. A single dose of melatonin had no effect on blood pressure. Repeated (but not acute) melatonin also improved sleep. Improvements in blood pressure and sleep were statistically unrelated. In patients with essential hypertension, repeated bedtime melatonin intake significantly reduced nocturnal blood pressure. Future studies in larger patient group should be performed to define the characteristics of the patients who would benefit most from melatonin intake. The present study suggests that support of circadian pacemaker function may provide a new strategy in the treatment of essential hypertension.

Adult↗
PubMed1994

Light and biological rhythms.

Chronobiology--derived from chronos (time), bios (life), and logos (study of)--is the objective description of biological time structures and plays an important role in medicine. Circadian rhythms regulate the behaviour, physiology and function of living organisms at many biochemical levels. The influence of the rhythmic manifestation of life may be shown in the constructive effects of growth, development and maturation and is named anachronobiology. In contrast catachronobiology denotes deleterious effects of time and rhythm which may lead to a diseased state. This article summarizes some new data about light as a synchronizer of biological rhythms. A time-keeper--biological clock--is used by the body for readjustment of rhythms when this is desirable. More recently, light has been used to adjust the biological clock following changes of circadian rhythms during shift work or jet lag occurring when flying from one time zone to another. Light may be used to treat depression, sleep disorders, menstrual dysregulations and other illnesses with disturbed circadian and seasonal rhythms. Examples of the importance of chronopharmacology (time-dependent changes in drug metabolism and drug effect) are also presented. New findings indicate that circadian oscillators are under genetic control; a light-influenced regulatory role for cellular immediate-early genes in circadian behaviour has been discovered. This suggests that light is of importance in regulation of macromolecular synthesis at all levels of the circadian system.

Chronobiology Phenomena↗
PubMed1998

[Advanced sleep phase syndrome (ASPS) and delayed sleep phase syndrome (DSPS)].

Circadian rhythm sleep disorders which may result from dysfunction of biological clock have recently been noticed and the number of patients suffering from these types of sleep disorders have been increased. In this article, clinical features, pathophysiological aspects, diagnoses and treatments for advanced sleep phase syndrome (ASPS) and delayed sleep phase syndrome (DSPS) are described. Although the pathophysiology or the etiology of ASPS and DSPS have not definitely been elucidated, the evidence that the chronobiological treatments sometimes improve patients with these disorders confirms the possibility that circadian rhythm sleep disorders are caused by dysfunction of biological clock. Further studies based on chronobiology or molecular biology are necessary to clarify the pathophysiology or the etiology of ASPS and DSPS and to develop the treatments against these circadian rhythm sleep disorders.

Animals↗
PubMed1988

Social zeitgebers and biological rhythms. A unified approach to understanding the etiology of depression.

Results of biological and psychosocial studies of depression completed in the last decade have stimulated the need for new hypotheses that synthesize these findings in a unified etiologic theory. The importance of disruption of biological rhythms on the one hand, and psychosocial losses on the other, in the causation of depressive episodes suggest one possible unifying hypothesis. The concept of loss of "social zeitgebers," ie, persons, social demands, or tasks that set the biological clock, may provide the link between biological and psychosocial theories of etiology. We suggest that a disruption of social rhythms, which may result in instability in biological rhythms, could be responsible for triggering the onset of a major depressive episode in vulnerable individuals.

Biological Clocks↗
PubMed2006

Roles of PACAP-containing retinal ganglion cells in circadian timing.

The brain's biological clock located in the suprachiasmatic nucleus (SCN) generates circadian rhythms in physiology and behavior. The clock-driven rhythms need daily adjustment (entrainment) to be synchronized with the astronomical day of 24 h. The most important stimulus for entrainment of the clock is the light-dark (LD) cycle. In this review functional elements of the light entrainment pathway will be considered with special focus on the neurotransmitter pituitary adenylate cyclase-activating polypeptide (PACAP), which is found exclusively in the monosynaptic neuronal pathway mediating light information to the SCN, the retinohypothalamic tract (RHT). The retinal ganglion cells of the RHT are intrinsically photosensitive due to the expression of melanopsin and seem to constitute a non-image forming photosensitive system in the mammalian eye regulating circadian timing, masking behavior, light-regulated melatonin secretion, and the pupillary light reflex. Evidence from in vitro and in vivo studies and studies of mice lacking PACAP and the specific PACAP receptor (PAC1) indicate that PACAP and glutamate are neurotransmitters in the RHT which in a clock and concentration-dependent manner interact during light entrainment of the clock.

Animals↗
PubMed1976

Characteristics of a neural clock regulating perception and psychomotor performance in man.

A biological clock regulating some psychomotor aspects of perception has been adduced from the results of the repetitive administration of a maximal speed tapping test of 15 sec per hand per min for a total of 20 min. 412 longitudinal timed tests from 8 healthy control subjects, 4 physically healthy and 6 brain damaged psychiatric patients formed the basis for the investigation of the properties of this clock. It was found that this perceptual clock is endogenous, self-sustaining and innate. Its free-running oscillations are independent of psychic state, emotions and affect. They are, however, dependent upon the subject's neural integrity and their phase may be influenced by an orientating reflex. Timing is precise but the preceding phase may influence a succeeding one. Despite the muscular activity of the task the clock is relatively independent of body temperature. It is also immune to most psychoactive drugs.

Adult↗
PubMedDate not supplied

Cyclic esotropia with minimal brain dysfunction.

An eight year old with a long history of hyperkinesis and learning difficulties compatible with the diagnosis of minimal brain dysfunction developed alternate day squint known as Cyclic Esotropia. No other abnormal cyclic phenomena such as alterations in sleep structure, diurnal variations in hemoglobin, hematocrit, electrolytes, body temperature, blood pressure or pulse rate was found. In view of the fact that cyclic esotropia may represent an impairment of the "biological clock" thought to be located in the hypothalamus, detailed studies of the hypothalamic hypophyseal axis were performed and found to be normal. It is suggested that if such a biological clock is present, its location is remote from the neural circuits involved in hypothalamic-hypophyseal hormonal release.

Attention Deficit Disorder with Hyperactivity↗
PubMed2001

Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations.

The effects of melatonin on glucose metabolism are far from understood. In rats, the biological clock generates a 24-h rhythm in plasma glucose concentrations, with declining concentrations in the dark period. We hypothesized that, in the rat, melatonin enhances the dark signal of the biological clock, decreasing glucose concentrations in the dark period. We measured 24-h rhythms of plasma concentrations of glucose and insulin in pinealectomized rats fed ad libitum and subjected to a scheduled feeding regimen with six meals equally distributed over the light/dark cycle and compared them with previous data of intact rats. Pinealectomy dampened the amplitude of the 24-h rhythm in plasma glucose concentrations in rats fed ad libitum, and abolished it completely in rats subjected to the scheduled feeding regimen, while plasma insulin concentrations did not change under both conditions. Pinealectomy abolished the nocturnal decline in plasma glucose concentrations irrespective of whether rats were fed ad libitum or subjected to the scheduled feeding regimen. Melatonin replacement restored 24-h mean plasma glucose concentrations in pinealectomized rats that were subjected to the scheduled feeding regimen but, interestingly, it did not restore the 24-h rhythm. Melatonin treatment also resulted in higher meal-induced insulin responses, probably mediated via an increased sensitivity of the beta-cells. Taken together, our data demonstrate that the pineal hormone, melatonin, influences both glucose metabolism and insulin secretion from the pancreatic beta-cell. The present study also demonstrates that removal of the pineal gland cannot be compensated by mimicking plasma melatonin concentrations only.

Animals↗
PubMed2001

Mechanisms and clinical significance of circadian rhythms in children.

Circadian rhythms are endogenously generated rhythms with a period length of about 24 hours. A biologic clock in the hypothalamic suprachiasmatic nuclei is responsible for the generation of circadian rhythms. Notable examples of the circadian rhythms include the sleep-wake cycle and rhythms in hormone production. Abnormalities of the circadian system include biologic clock lesions that result in arrhythmic behavior and irregular sleep patterns. Abnormalities of the circadian system also occur when there is desynchronization of clock phase with that of the outside world, resulting in conditions such as "jet-lag." Numerous aspects of human physiology are greatly influenced by the time of day, as is the pathogenesis of illness. During development, the circadian system becomes functional at early stages and is regulated by photic information. With the continued elucidation of circadian system influences on human physiology and illness, it is anticipated that circadian biology will have an increasingly important impact on the clinical care of children.

Adolescent↗
PubMed2002

Circadian patterns of breathing.

In the rat, a mostly nocturnal animal, activity, body temperature and metabolic rate increase during the dark hours of the day. Since all these variables are known to influence breathing, it is expected that also pulmonary ventilation (VE) will present a circadian pattern. In rats chronically instrumented for measurements of body temperature and activity by telemetry, carbon dioxide production and oxygen consumption (V(O(2))) were measured continuously for several days by an open-circuit method, while VE was monitored by a modification of the barometric technique. Tidal volume, frequency, and VE increased in the dark (D) compared to the light (L) hours, with minor L-D differences in VE/V(O(2)). L-D differences in activity were not responsible for the circadian pattern of VE. Both in hypoxia and in hypercapnia the degree of hyperventilation (percent increase in VE/V(O(2))) was essentially independent of the time of the day, despite the fact that in hypoxia, differently from hypercapnia, the amplitude of the circadian pattern of all variables decreased, activity being the least affected, and body temperature the most. These effects of hypoxia, which occurred before and after sino-aortic denervation and did not compromise the period of the biological clock, may be mediated by the hypothalamic thermoregulatory centers. The data of these experiments and of others reviewed in this article indicate that (1) breathing and its control mechanisms accompany the daily oscillations of numerous physiological variables, and (2) the advantages of a biological clock do not compromise the adequacy of the hyperventilatory responses to chemical challenges.

Animals↗
PubMed1977

Seasonal variation in the active transporting ability and in the membrane ATPase activity of the frog intestinal epithelium.

The active sugar and amino acid transport in the small intestine of the American leopard frog (Rana pipiens) and a species of European frog (Rana esculenta) decreases during the winter months. Parallel with this the (Na+, K+)-stimulated ("pump") ATPase activity is markedly depressed. No seasonal changes are observed in the intestine of the tropical bullfrog (Rana catesbeiana). It is assumed that the low pump-ATPase activity is caused by the hibernation of the frogs living in moderate or subtropical areas and is connected to a biological clock. The decreased active transport of non-electrolytes appears to be a consequence of the change of the ATPase activity.

Adenosine Triphosphatases↗