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The interface of aging and the circadian clock

aging alzheimers disease circadian rhythm clock genes metabolism

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#1 Engadin

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Posted 23 April 2019 - 05:01 PM


The circadian clock drives a number of internal processes and relies primarily on external environmental cues to align the master clock in the suprachiasmatic nucleus, responsible for temporal synchronization of peripheral oscillators in various organ systems. This review examines recent evidence for a bidirectional relationship between aging and the circadian system. Recent evidence shows that the aging process can have a direct influence on how the circadian network responds to external stimuli, including altered responsiveness of both central and peripheral oscillators to light stimuli or to changes in the light/dark cycle. Conversely, chronic irregular light/dark exposure can be a detriment to health downstream of the circadian network. Interactions between aging and circadian regulation of cognition, Alzheimer's disease, and metabolism are discussed.



Aging is linked to a myriad of health risks, inclusive of cardiac dysfunction, cognitive impairmentmetabolic disorders, and cancer. Therefore, it may not be surprising that detrimental changes in circadian timekeeping also occur with aging. Recent efforts have focused on elucidating potential mechanisms behind aging-induced circadian dysfunction and understanding how the resulting degradation of the circadian network contribute to the development of age-related health issues. The aim of this review is, then, to garnish an understanding of circadian aging, from the central pacemaker down to circadian oscillators in peripheral tissues and organ systems. In understanding the core biology of circadian aging in terms of progress at present, it becomes plausible to explore the mechanisms that might link the circadian system with age-related pathologies. The following review will attempt to describe the direct relationship between the circadian system and age-related pathologies inclusive of Alzheimer's disease (AD), metabolic disorder, and obesity.


A hierarchical circadian system

The hierarchical manner by which the mammalian circadian system operates has been well characterized. The suprachiasmatic nucleus (SCN) of the basal hypothalamus acts as the master oscillator, receiving photic input via the retinal hypothalamic tract and coordinating peripheral bodily rhythms via multiple output pathways involving neuronal, endocrine, and humoral signaling 12. Bilateral ablation of the SCN eliminates locomotor activity rhythms, whereas implantation of SCN tissue into an ablated animal restores many, but not all, rhythmic processes, indicating that the SCN is crucial for coordinating rhythmic function throughout the organism 34.


The molecular machinery that generates circadian timing in mammals involves a transcriptional–translational feedback loop, as illustrated in Figure 1Transcriptional activators Bmal1 and Clock drive transcription of their own transcriptional repressors Period (Per1 and Per2) and Cryptochrome (Cry1 and Cry2) [5]Post-translational modifications of Per and Cry via casein kinase proteins such as CSNK1E are prerequisite for protein accumulation and heterodimer formation [6]. In addition, Bmal1 can also be inhibited or activated via retinoic acid-related orphan receptor A (Rorα) and Reverbα, respectively, adding in a concurrent feedback loop regulating Bmal1 levels [7]. The core clock machinery drives rhythmicity at the single-cell level and is found across the entire hierarchy of the circadian system, driving oscillatory patterns in the SCN, as well as nearly every peripheral tissue. It is important to note that the circadian system is endogenous and self-sustaining, persisting despite a lack of environmental stimuli. Thus, the core clock machinery as described previously persists in mammals with an approximately 24-h period, even under conditions of constant darkness.




Figure 1Mammalian core clock machinery: The transcriptional–translational feedback loop drives the mammalian clock and is conserved across organ systems. CLOCK and BMAL1 initiate transcription of core clock genes by joining as a heterodimer and binding to the E-box element of the clock gene promoter sequence, driving transcription of circadian-regulated genes including PER and CRY. After translation in the cytoplasm, PER and CRY are either stabilized via post-translational phosphorylationby the casein kinase family of proteins including casein kinase 1 epsilon (CKIE) or marked for degradation. Phosphorylated Per and Cry heterodimerize and cycle back into the nucleus and act on the BMAL1:CLOCK complex as a repressor, thus inhibiting their own transcription and forming the negative limb of the feedback loop. Over time, PER and Cry levels drop because of protein degradation, initiating another turn of the clock through PER and CRY transcription. A secondary feedback loop exists, modulating Bmal1 transcription. RORα and Rev-erbα competitively bind to retinoic acid–related orphan receptor response elements (RORES) in the Bmal1 promoter, either acting as a transcriptional activator or repressor.


The circadian timing system provides an endogenous self-perpetuated near 24 oscillations in physiological function, gene expression, and behavior. At the top of the hierarchy, the SCN is uniquely positioned to respond to environmental stimuli. Although a variety of environmental and physiological input is received by the SCN, environmental light is perhaps the strongest external cue in terms of setting the internal clock. Light impacts the SCN through a direct monosynaptic connectioncarried by a subset of melanopsin-containing retinal ganglion cells. The SCN integrates light information with other feedback and generates output via the endocrine and autonomic nervous systems to coordinate and synchronize clocks located within the peripheral oscillators 18. Alterations to the ambient light/dark cycle can have a strong impact on circadian health, as is seen in models of jet lag or phase advancement/delay of the light/dark schedule. Circadian disruption models experimentally mimic conditions of repeated jet lag similar to those experienced by a transcontinental flight attendant or people working shift work schedules. Monitoring responsiveness to these changes in timing of light/dark cycles can provide insight into the integrity of the circadian system, which can be systematically dissected using various genetic models, analysis of clock gene expression, or other clock outputs across organ systems 9101112.


Aging impacts the internal clock

Sleep quality is directly correlated to overall human health. Furthermore, a decline in sleep quality has been associated with deterioration in physical and mental health, which occurs as a result of aging. The circadian system interacts with the homeostatic drive for sleep to impact sleep onset. Therefore, irregularities in the circadian system are potent contributors to age-dependent reduction in sleep quality. Multiunit neural activity recording demonstrated that the amplitude of rhythmic SCN firing is suppressed in aged animals [9]. Although rhythmic activity in individual SCN neurons is maintained in aged animals, Per2:luciferase reporter mice demonstrate reduced synchrony between SCN neurons, which is likely responsible for diminished SCN output in aging, particularly at the behavioral level [13]. Subregional oscillators within the SCN also become decoupled with age, particularly when challenged with unnatural lighting conditions such as constant light exposure or simulated jet lag ∗∗14151617. Deterioration of rhythmic output from the SCN, locomotor activity patterns, and production of neuropeptidesresponsible for mediating rhythmicity and internal synchrony within the SCN contribute to a destabilized circadian system in aging 91819.


Changes in rhythmic patterns in response to light and darkness can assess the integrity of the circadian system in experimental model systems. A strict light/dark cycle (12 h lights on/12 h lights off) constrains SCN transcriptional activity and output to produce precise 24-h rhythmicity. Under constant conditions, however, the endogenous rhythm, which is often slightly different than 24 h, is expressed. In mice, activity onset occurs approximately 15 min earlier each subsequent day [20]. Nocturnal light exposure alters activity onset; early night light exposure delays activity onset, whereas late night light advances activity onset 2122 (Figure 2). Similar changes in clock gene expression occur within the central and peripheral oscillators.



Figure 2Behavioral activity patterns under alternative light/dark cycles. A typical actogram is shown illustrating home cage activity of a single mouse under a regular light/dark (L/D) cycle (days 1–15), exposure to a single 8-h phase advance of the light/dark cycle (days 16–30) and under conditions of constant darkness (days 31–41). Activity counts are double-plotted along the x-axis (h = hour) for continuity. Under a normal L/D schedule of 12 h on/12 h off, activity onset runs parallel with time of lights off (h = 19). After an 8-h advance of the light schedule (lights on, h = 23 and lights off, h = 11), animals are shown to gradually adjust to the advance over multiple days, as can be seen by the negative slope of activity onset from day 16 through day 25. Under conditions of constant darkness, an animal's endogenous circadian period is expressed, typically slightly less than 24 h. The endogenous period can be seen by the slightly negative slope through activity onset under constant darkness.


Light responsiveness is altered in aged mice [22]. Locomotor activity and clock gene rhythms in peripheral oscillators in aged animals adjusted more slowly to a 6-h advance of the light/dark cycle. Paradoxically, Per2 rhythms in the ventral SCN of old animals adjusted faster than young animals because of strong retinal innervation [22]. However, the overall synchrony of the SCN was less organized in aged animals, suggesting problems with cell-to-cell communication with the nucleus in aging 1022. Considering that the aged SCN has overall reduced responsiveness to light stimuli, the counterintuitive fast response of the ventral SCN may reflect diminished pacemaker amplitude resulting from intra-SCN desynchrony, as weak oscillators have been shown to have a finer tuned response to external stimuli 2324. Aging also reduces expression of the N-methyl-d-aspartate receptor subunit 2B (NR2B) subunit of the n-methyl-d-aspartate (NMDA) receptor in the SCN, resulting in a diminished receptiveness to glutamate-driven photic input [25].


Circadian dysfunction and cognitive impairment

In normal aging, the SCN is comparatively resistant to neurodegenerationcompared with other brain regions. SCN volume and neuronal number are maintained in aging 2627. Human studies demonstrate that SCN cell loss occurs at ages 80–100 years, which is usually beyond the onset of circadian disturbances, indicating that dysfunction likely stems from other physiological factors 162829. In terms of cognition changes during normal aging, strong evidence, using a Siberian hamster model of circadian disruption, has shown that an intact circadian system is vital for memory formation 3031. In this model, a single light-induced phase change induced a permanently arrhythmic SCN and impaired performance on a novel object recognition task and spontaneous alternation in T-maze task; however, performance could be restored via administration of the gamma amino butyric acid (GABAA) antagonist pentylenetetrazole. Interestingly, SCN-lesioned animals performed similar to perfectly rhythmic animals on a hippocampal-dependent novel object recognition task. Taken together, these data prompt the hypothesis that an arrhythmic SCN produces constant firing across a 24-h cycle as opposed to the normal oscillatory firing pattern. This constant firing produces a continuous GABAergic input to the septum, inhibiting septal cholinergic excitationof hippocampal regions responsible for learned memory 323334 (Figure 3).



Figure 3An arrhythmic SCN impacts memory formation via increased inhibitory output. In normal SCN function, rhythmic firing with peak firing during the middle of the light cycle and diminished firing at night result in rhythmic GABAergic output. The medial septum (MS) serves as an intermediate structure between SCN projections to the hippocampus. Thus, in an arrhythmic animal or after exposure to lighting conditions that might act as a stressor to the circadian system, tonic firing of the SCN could produce an increase in GABAergic inhibition to the MS, resulting in decreased glutamatergic and/or cholinergic excitatory input to the hippocampus, resulting in attenuated memory formation. SCN, suprachiasmatic nucleus.


Core clock genes may be important in learning and memory independent from their role in driving circadian oscillations. Aging-induced epigenetic alterations in hippocampal Per1 impair long-term memory and synaptic plasticity. Specifically, histone deacetylase 3 (HDAC3) deletion in the dorsal hippocampus of mice ameliorated age-dependent Per1 reduction in the dorsal hippocampus and preserved memory functions ∗3536. Interestingly, HDAC3-induced reduction in hippocampal Per1 levels had no effect on behavioral activity patterns, indicating an extracircadian function of Per1 ∗3537. It remains possible, however, that alterations in clock gene expression outside the SCN could impact other genes without producing altered circadian behavior. Deletion of the canonical clock gene, Bmal1, generates differential phenotypes depending on whether the deletion occurs in the germ line or is conditional, demonstrating a role for Bmal1 in development. In both models, clock function was abolished, and certain aging markers were accelerated, including brain astrogliosis and ocular abnormalities. However, other aging markers such as shortened life span, impaired glucose metabolism, and bone calcification were only observed in conventional knockout, indicating a potential role of Bmal1 in aging independent of its involvement of circadian timekeeping ∗∗383940. Furthermore, point mutations in core clock genes have been linked to cognitive aging, reinforcing the role of the clock in cognitive function ∗4142.


Circadian disruption in AD

Although patients with dementia exhibit well-recognized circadian dysfunction, the relationship between circadian physiology and AD is complex, and a mechanistic understanding remains elusive. Growing evidence signifies a role for sleep and the circadian system in AD pathophysiology before cognitive decline 4344. Sleep deprivation increases average interstitial fluid amyloid β (Aβ), suggesting that sleep regulates Aβ metabolism and clearance [45]. Human cerebral spinal fluid Aβ levels are rhythmic, and daily orexin fluctuations mirror the interstitial fluid Aβ levels, which are suppressed by the orexin receptor antagonistalmorexant 4546. Similarly, in an amyloid precursor protein (APP)-transgenic mouse model of AD, chronic sleep deprivation increases plaque formation, which is mitigated by concurrent orexin receptor blockade [45].


The importance of orexin-mediated hippocampal clock function in regulating AD-associated genes is emerging [47]. The hippocampal clock controls rhythmic expression of beta-secretase and presenilin-1. The APP/PS1dE9 AD mouse model exhibits elevated levels of orexin precursor protein and a shortened oscillatory period in the hippocampus [47]. As high orexin levels promote Aβ plaque formation and regulate circadian oscillations, disrupted orexin signaling could impact hippocampal rhythms, leading to dysregulation of circadian-controlled AD risk genes ∗∗474849.


A relationship between tau pathology and rhythms is also emerging. In a Drosophilamodel of AD with tau accumulation, nocturnal light exposure disrupts circadian rhythms, alters sleep–wake cycles, and increases tau phosphorylation and neurodegeneration, indicating that circadian disruption promotes progressive AD pathology ∗∗5051. These studies suggest that nocturnal light exposure, through light pollution, shift work, or even screen time may negatively impact circadian health and promote cognitive decline or other circadian-influenced pathologies 5253.


The impact of aging on circadian regulation of metabolism

The circadian system imposes strong regulation on cellular and systemic metabolism [54]. Circadian disruption via jet lag or shift work promotes metabolic disease. Similarly, circadian dysfunction resulting from aging has also been implicated in metabolic pathology. Core clock gene expression is highly dysregulated in most peripheral tissues of aged mice with impaired glucose homeostasis. However, the clock was relatively spared in the pancreas, with pancreatic tissue showing slight upregulation of Bmal1 and downregulation of Clockexpression. Impaired glucose homeostasis in these animals despite quasi-regular expression of pancreatic clock genes implies a potential noncircadian effect of elevated Bmal1 on pancreatic beta-cell deterioration [55]. Exposure to a regular light/dark cycle could not compensate for clock dysfunction in these animals, indicating that dysfunction occurs via an uncoupling of the SCN-driven rhythmicity and peripheral clocks. Although the aging pancreatic clock was resilient to circadian dysregulation under regular lighting conditions, chronic exposure to constant light induced permanent lengthening of the pancreatic circadian period and diminished pacemaker amplitude, supporting the hypothesis that chronic exposure to irregular lighting conditions could produce negative impacts on glucose homeostasis [55].


Mechanisms by which aging impacts circadian control of metabolism may relate to redox state and oxidative stress. Aging alters rhythmic expression of liver mitochondrial genes and disrupts circadian control of oxidative stress, resulting in general increases in reactive oxygen species generation [56]. Temporal control of a number of metabolic processes occurs in anticipation of environmental changes. For example, mitochondrial fatty acid oxidation is likely mediated through circadian influences on mitochondrial nicotinamide adenine dinucleotide (NAD+) levels and NAD-dependent deacetylase sirtuin-3 (SIRT3) activity 5758. Although lacking, current efforts are focused on elucidating the significance of rhythmic mitochondrial gene expressions and their age-dependent changes.


Circadian rhythms and cellular senescence

Recent evidence demonstrates that genetic or environmental disruption of circadian rhythms severely affects cellular senescence. In the cardiovascular system, circadian disruptions that promote cardiovascular disease increase vascular senescence. The core clock gene, Per2, is an important mediator of vascular senescence, angiogenesis, and function of epithelial progenitor cells [59]. Increased vascular senescence in Per2 mutant mice is correlated directly with chronic elevation of Akt phosphorylation, which may induce oxidative stress 5960. Akt-dependent senescence, together with decreased mobilization of endothelial progenitor cells in response to ischemia, demonstrates the importance of Per2 function in vascular function and mediating an angiogenic response [59]. Similarly, TIMELESS, a protein associated with normal circadian function and interactions with Per, may regulate cellular senescence. Hypoexpression of TIMELESS facilitates a senescent fate and exacerbates genomic instability 6162. TIMELESS is downregulated in oncogene-induced senescence of human diploid fibroblast; the transcription factor, E2F1, commonly associated with regulation of cell cycle and tumor suppressor genes, binds to the TIMELESS promoter to suppress its expression [61]. Finally, overexpression of TIMELESS delays cellular senescence [61]. In contrast, Cry1/Cry2 double-knockout mice, although demonstrating similar circadian dysfunction as Per2 mutants, do not exhibit a phenotype of increased vascular senescence, suggesting that the involvement of Per2 in senescence is peripheral to its core clock function or mediated through potential interactions with TIMELESS [59].


Simulated jet lag provides an environmental approach to examine the effects of circadian disruption on cellular senescence. Telomere length and oxidative state were assessed as outputs of cellular aging after chronic jet lag protocol in young and old grass rats [63]. Although oxidative balance was not affected, circadian disruption led to premature telomere shortening [63]. The telomere erosion could be attributed to a number of biological factors; however, evidence from the literature has shown that chronic stress (increased corticosterone) and decreased NAD-dependent deacetylase sirtuin-1 (SIRT1) expression could produce such an effect, both of which were observed in jet-lagged grass rats 636465. Collectively, these studies indicate that circadian clock integrity may be important for preventing premature cellular senescence.



Clearly, the natural aging process significantly impacts the circadian system and a number of other age-related pathologies. Although clear pathways relating the circadian network to pathogenesis of age-related diseases, such as AD and metabolic syndrome, remain to be completely understood, the reciprocal relationship between the circadian system and aging is undeniable. Understanding the coupling and decoupling of the central pacemaker to peripheral oscillators, particularly under conditions of circadian stress, will provide invaluable insight and identify promising therapeutic targets for people exposed to chronic irregularities in daily light exposure. It is vital for organ systems to operate in internal synchrony with one another, just as an orchestra cannot play in harmony without a conductor. Research into aging-induced changes in the internal structure, coordination of subregional oscillators within the SCN, and identification of changes to rhythmic output to peripheral oscillators will promote progress toward therapeutic interventions for age-related circadian dysfunction and its involvement in relevant pathologies.


Source: https://www.scienced...451965018300322

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