The circadian clock and pathology of the ageing brain

Biological rhythm is one or more biological events or functions that reoccur in time in a repeated order and with a repeated interval between occurrences and allow an organism to harmonize successfully with its environment. Aging leads to a functional deterioration of many physiological systems, including the biological clock – an internal time-keeping system – that generates ∼24-h rhythms in physiology and behavior. Latest data from experiments in model organisms, gene expression studies, and clinical trials imply that dysfunctions of the circadian clock contribute to aging and age-associated pathologies, thereby suggesting a functional link between the circadian clock and age-associated decline of brain functions and various biochemical and physiological processes. With the advancement in understanding the molecular aspects of aging and circadian system, several therapeutic strategies such as antioxidants, feeding regimen, and most advanced small molecule modulators have been extensively studied. In this chapter, we discuss the functional aspects of biological clock, its association with aging and give an insight into the existing therapeutic interventions.

Circadian clock disruption attenuated growth hormone(GH)-mediated signalling

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One of the most indispensable biological functions for all living organisms is the circadian clock, which acts like a multifunctional timer to regulate the homeostatic system including sleep and wakefulness, hormonal secretions, and various other body functions in a 24-hour cycle. Recent molecular dissections of the circadian biological clock system have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of circadian rhythms. Several drugs can affect the expression of clock genes, resulting in alteration of the 24-hour rhythms in physiology and behavior. Here, we report the disruptive effect of interferon (IFN) on the core circadian oscillation mechanism. Treatment of cultured hepatic cells with IFN-alpha caused a significant reduction in Clock and Bmal1 mRNA levels, which are positive regulators of circadian output rhythm, leading to a decrease in their protein levels. The continuous administration of IFN-alpha significantly decreased CLOCK and BMAL1 protein levels in the suprachiasmatic nucleus and liver of mice, thereby preventing oscillations in the expression of clock and clock-controlled output genes. These findings reveal a possible pharmacologic action of IFN-alpha on the core circadian oscillation mechanism and indicate that the disruptive effect of IFN-alpha on circadian output function is the underlying cause of its adverse effects on 24-hour rhythms in physiology and behavior. Furthermore, the alteration of clock function, a new concept of adverse effects, can be avoided by altering the dosage schedule of IFN-alpha to minimize the adverse drug effect on clock gene expression. One approach for increasing the efficacy of pharmacotherapy is administering drugs at the time of day when they are best tolerated. Attention should be paid to the alteration of clock gene expression, and it should be considered an adverse effect when it leads to altered circadian organization of the molecular clockwork which is a serious problem affecting basic function of living organisms.

Neurobiologic Mechanisms of Sleep and Wakefulness

Many behavioral and physiological processes display diurnal (24-h) rhythms controlled by an internal timekeeping system—the circadian clock. In mammals, a circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronizes peripheral oscillators found in most other tissues with the external light-dark (LD) cycle. At the molecular level, circadian clocks are regulated by transcriptional translational feedback loops (TTLs) involving a set of clock genes. The mammalian core TTL includes the transcriptional modulators PER (1–3) and CRY (1/2) that inhibit their own expression by interaction with CLOCK/NPAS2 and BMAL1 (ARNTL). The basic helix-loop-helix transcription factors DEC1 (BHLHE40) and DEC2 (BHLHE41) can interact with this core TTL, forming an accessory feedback mechanism. The authors measured circadian locomotor behavior and clock gene expression in the SCN of Per2/Dec double- and triple-mutant mice to analyze the functional interaction of PER2 and DEC feedback on circadian pacemaker function in the SCN. The data suggest a synergistic interaction of Per2 and Dec1/2 in activity entrainment to a standard LD cycle, correlating with a cumulative deficiency in negative-masking capacities in Per2/Dec double- and triple-mutant mice and suggesting an involvement of Per2-Dec1/2 interactivity in activity-onset regulation and masking under LD, but not under constant conditions. In contrast, under constant darkness (DD) conditions, a deletion of either Dec1 or Dec2 partially rescued the Per2 mutant short-period/arrhythmicity phenotype, accompanied by a restoration of time-of-day effects on clock gene expression in the SCN. Together, these results show an interaction of Per2 and Dec1/2 feedback processes in the SCN with differential modes of interactivity under entrained and free-run conditions. (Author correspondence: henrik.oster@mpibpc.mpg.de)

To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. Emens JS, St Hilaire MA, Klerman EB, etal. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.

The effect of circadian rhythm on prolactin/PRLR-mediated intracellular signaling profiles in vivo and in vitro

Circadian molecular clock disruption in chronic pulmonary diseases.

The different types of adipose tissues fulfill a wide range of biological functions—from energy storage to hormone secretion and thermogenesis—many of which show pronounced variations over the course of the day. Such 24‐h rhythms in physiology and behavior are coordinated by endogenous circadian clocks found in all tissues and cells, including adipocytes. At the molecular level, these clocks are based on interlocked transcriptional‐translational feedback loops comprised of a set of clock genes/proteins. Tissue‐specific clock‐controlled transcriptional programs translate time‐of‐day information into physiologically relevant signals. In adipose tissues, clock gene control has been documented for adipocyte proliferation and differentiation, lipid metabolism as well as endocrine function and other adipose oscillations are under control of systemic signals tied to endocrine, neuronal, or behavioral rhythms. Circadian rhythm disruption, for example, by night shift work or through genetic alterations, is associated with changes in adipocyte metabolism and hormone secretion. At the same time, adipose metabolic state feeds back to central and peripheral clocks, adjusting behavioral and physiological rhythms. In this overview article, we summarize our current knowledge about the crosstalk between circadian clocks and energy metabolism with a focus on adipose physiology. © 2017 American Physiological Society. Compr Physiol 7:383‐427, 2017.

The different types of adipose tissues fulfill a wide range of biological functions-from energy storage to hormone secretion and thermogenesis-many of which show pronounced variations over the course of the day. Such 24-h rhythms in physiology and behavior are coordinated by endogenous circadian clocks found in all tissues and cells, including adipocytes. At the molecular level, these clocks are based on interlocked transcriptional-translational feedback loops comprised of a set of clock genes/proteins. Tissue-specific clock-controlled transcriptional programs translate time-of-day information into physiologically relevant signals. In adipose tissues, clock gene control has been documented for adipocyte proliferation and differentiation, lipid metabolism as well as endocrine function and other adipose oscillations are under control of systemic signals tied to endocrine, neuronal, or behavioral rhythms. Circadian rhythm disruption, for example, by night shift work or through genetic alterations, is associated with changes in adipocyte metabolism and hormone secretion. At the same time, adipose metabolic state feeds back to central and peripheral clocks, adjusting behavioral and physiological rhythms. In this overview article, we summarize our current knowledge about the crosstalk between circadian clocks and energy metabolism with a focus on adipose physiology. © 2017 American Physiological Society. Compr Physiol 7:383-427, 2017.

The Circadian Timekeeping System of Drosophila

All organisms have various circadian, behavioral, and physiological 24-h periodic rhythms, which are controlled by the circadian clock. The circadian clock controls various behavioral and physiological rhythms. In mammals, the primary circadian clock is present in the suprachiasmatic nucleus of the hypothalamus. The rhythm of the circadian clock is controlled by the interaction between negative and positive feedback loops, consisting of crucial clock regulators (including Bmal1 and Clock), three cycles (mPer1, mPer2, and mPer3), and two cryptochromes (Cry1 and Cry2). The development of early mammalian embryos is an ordered and complex biological process that includes stages from fertilized eggs to blastocysts and undergoes important morphological changes, such as blastocyst formation, cell multiplication, and compaction. The circadian clock affects the onset and timing of embryonic development. The circadian clock affects many biological processes, including eating time, immune function, sleep, energy metabolism, and endocrinology, therefore, it is also crucial for overall health, growth and development after birth. This review summarized the effects of the circadian clock in the body's physiological activities. A new strategy is proposed for the prevention of malformations or diseases by regulating the circadian clock or changing circadian rhythms.

The role of the suprachiasmatic nuclei (SCN) in generating circadian rhythms in physiology and behavior is well established. Recent evidence based on clock gene expression indicates that the rodent SCN are composed of at least two functional subdivisions. In Syrian hamsters (Mesocricetus auratus), cells in a subregion of the caudal SCN marked by calbindin-D(28K) (CalB) express light-induced, but not rhythmic, clock genes (Per1, Per2, and Per3). In the SCN region marked by vasopressinergic cells and fibers, clock gene expression is rhythmic. Importantly, lesions of the CalB subregion that spare a significant portion of the SCN abolish rhythms in locomotor behavior. One possibility is that the CalB subregion is required to maintain SCN function necessary to support all behavioral and physiological rhythms. Alternatively, this subregion may control circadian rhythms in locomotor behavior, whereas other circadian responses in physiology and behavior are sustained by different SCN compartments. The present study sought to distinguish between these possibilities by examining the role of the CalB subregion in a battery of rhythms within an individual animal. The results indicate that lesions of the CalB subregion of the SCN abolish circadian rhythms in behavior (locomotion, drinking, gnawing), physiology (body temperature, heart rate), and hormone secretion (melatonin, cortisol), even when other SCN compartments are spared. Together, these findings suggest a novel fundamental property of SCN organization, with a subset of cells being critical for the maintenance of SCN function manifest in circadian rhythms in physiology and behavior.

Daily fluctuation (circadian and ultradian) in biogenic amines of the rat brain.