Maintenance Of Circadian Rhythms Research Articles

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells

Crosstalk between metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to disease. Here, we investigated whether maintenance of circadian rhythms depends on specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to signal from a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function across a series of pancreatic adenocarcinoma cell lines. Metabolic profiling of congenic tumor cell clones revealed substantial diversity among these lines that we used to identify clones to generate circadian reporter lines. We observed diverse circadian profiles among these lines that varied with their metabolic phenotype: The most hypometabolic line [exhibiting low levels of oxidative phosphorylation (OxPhos) and glycolysis] had the strongest rhythms, while the most hypermetabolic line had the weakest rhythms. Pharmacological enhancement of OxPhos decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, inhibition of OxPhos enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

Gut microbiota regulates host melatonin production through epithelial cell MyD88

ABSTRACT Melatonin has various physiological effects, such as the maintenance of circadian rhythms, anti-inflammatory functions, and regulation of intestinal barriers. The regulatory functions of melatonin in gut microbiota remodeling have also been well clarified; however, the role of gut microbiota in regulating host melatonin production remains poorly understood. To address this, we studied the contribution of gut microbiota to host melatonin production using gut microbiota-perturbed models. We demonstrated that antibiotic-treated and germ-free mice possessed diminished melatonin levels in the serum and elevated melatonin levels in the colon. The influence of the intestinal microbiota on host melatonin production was further confirmed by fecal microbiota transplantation. Notably, Lactobacillus reuteri (L. R) and Escherichia coli (E. coli) recapitulated the effects of gut microbiota on host melatonin production. Mechanistically, L. R and E. coli activated the TLR2/4/MyD88/NF-κB signaling pathway to promote expression of arylalkylamine N-acetyltransferase (AANAT, a rate-limiting enzyme for melatonin production), and MyD88 deficiency in colonic epithelial cells abolished the influence of intestinal microbiota on colonic melatonin production. Collectively, we revealed a specific underlying mechanism of gut microbiota to modulate host melatonin production, which might provide novel therapeutic ideas for melatonin-related diseases.

The role of astrocyte in the circadian rhythm

The circadian system can be found in nearly all mammalian organs and cells. The maintenance of circadian rhythms is related to the health of human life. Destroying circadian rhythms has a strong correlation with the emergence of many diseases, such as neurological diseases and cardiovascular diseases. Astrocytes are the most common type of cell in the human central nervous system. In recent years, the autonomous regulatory role of astrocytes in the circadian rhythm of the SCN has received increasing attention. This article aims to briefly introduce the role of SCN astrocytes in maintaining circadian rhythm from three aspects: gene expression of astrocytes, regulation of neurotransmitters by astrocytes, and plasticity of astrocytes. At the same time, this article also reviews the relationship between astrocyte activation and circadian rhythm disorders as a neurological disease, and several drugs targeting astrocytes for the treatment of nervous system diseases related to circadian rhythm disorders were proposed to highlight the potential of targeting SCN astrocytes in the treatment of improving circadian rhythm disorders. Finally, this article summarizes current strategies, future challenges, and therapeutic prospects for astrocyte-targeted therapy to improve circadian rhythm disorders. This review aims to highlight SCN astrocytes’ effect on maintaining the circadian rhythm and their related mechanisms and provide a theoretical basis for the future proposal of targeted treatment strategies with astrocytes.

Enhancing circadian rhythms-the circadian MEGA bundle as novel approach to treat critical illness.

Circadian rhythms are essential to physiological homeostasis, but often disrupted in the intensive care unit (ICU) due to the absence of natural zeitgebers and exposure to treatments which affect circadian regulators. This is increasingly recognized as a contributor to morbidity and mortality across a variety of medical conditions including critical illness. Maintenance of circadian rhythms is particularly relevant to critically ill patients, who are restricted not only to the ICU environment but often bed bound. Circadian rhythms have been evaluated in several ICU studies, but effective therapies to maintain, restore, or amplify circadian rhythms have not been fully established yet. Circadian entrainment and circadian amplitude enhancement are integral to patients' overall health and well-being, and likely even more important during response to and recovery from critical illness. In fact, studies have shown that enhancing the amplitude of circadian cycles has significant beneficial effects on health and wellbeing. In this review, we discuss up-to-date literature on novel circadian mechanism that could not only restore but enhance circadian rhythms in critical illness by using a MEGA bundle consisting of intense light therapy each morning, cyclic nutrition support, timed physical therapy, nighttime melatonin administration, morning administration of circadian rhythm amplitude enhancers, cyclic temperature control and a nocturnal sleep hygiene bundle.

Circadian rhythm of carbohydrate metabolism in health and disease

The article presents a review of the main circadian mechanisms regulating carbohydrate metabolism and their role in maintenance of energy homeostasis; the molecular genetic structure of the circadian system is also discussed. The role of adipose tissue and other organs and systems in the maintenance of circadian rhythm of carbohydrate metabolism, both in health and in obesity and diabetes, is highlighted. Particular attention is paid to diurnal rhythms of endocrine factors responsible for metabolic patterns of hormones such as cortisol, growth hormone and melatonin. Gender differences in the circadian regulation of energy and carbohydrate metabolism are also discussed, as well as their changes in different age periods. Article provides detailed review of the mechanisms of glucose utilization, reactivity of the pancreatic islets and peripheral insulin sensitivity shifts at different time periods of the day in people with normal body weight, android and gynoid types of obesity, both in women and men. Protective factors of energy metabolism circadian regulation structure preventing the development of diabetes mellitus and cardiovascular disease in individuals with so-called “metabolically healthy” obesity type are discussed. Article provides a review of various pathways of circadian rhythm disturbances, mechanisms of their development, as well as exogenous and endogenous factors leading to carbohydrate metabolic circadian rhythm misalignment, such as shift work, untiming of natural and artificial lighting, jet lags, sleep disorders. Represented data contribute to a new look at the pathogenesis of obesity and carbohydrate metabolism disorders in various types of obesity in men and women, that provides basis for searching for new effective methods of prevention and treatment of these conditions, elaboration of evidence-based diets and physical activity recommendations, as well as approaches to their medical treatment.

Circadian Control of Glial Cell Homeodynamics.

The molecular mechanisms that maintain circadian rhythms in mammalian as well as non-mammalian systems are well documented in neuronal populations but comparatively understudied in glia. Glia are highly dynamic in form and function, and the circadian clock provides broad dynamic ranges for the maintenance of this homeostasis, thus glia are key to understanding the role of circadian biology in brain function. Here, we highlight the implications of the molecular circadian clock on the homeodynamic nature of glia, underscoring the current gap in understanding the role of the circadian system in oligodendroglia lineage cells and subsequent myelination. Through this perspective, we will focus on the intersection of circadian and glial biology and how it interfaces with global circadian rhythm maintenance associated with normative and aberrant brain function.

Pruning deficits of the developing Drosophila mushroom body result in mild impairment in associative odour learning and cause hyperactivity.

The principles of how brain circuits establish themselves during development are largely conserved across animal species. Connections made during embryonic development that are appropriate for an early life stage are frequently remodelled later in ontogeny via pruning and subsequent regrowth to generate adult-specific connectivity. The mushroom body of the fruit fly Drosophila melanogaster is a well-established model circuit for examining the cellular mechanisms underlying neurite remodelling. This central brain circuit integrates sensory information with learned and innate valences to adaptively instruct behavioural decisions. Thereby, the mushroom body organizes adaptive behaviour, such as associative learning. However, little is known about the specific aspects of behaviour that require mushroom body remodelling. Here, we used genetic interventions to prevent the intrinsic neurons of the larval mushroom body (γ-type Kenyon cells) from remodelling. We asked to what degree remodelling deficits resulted in impaired behaviour. We found that deficits caused hyperactivity and mild impairment in differential aversive olfactory learning, but not appetitive learning. Maintenance of circadian rhythm and sleep were not affected. We conclude that neurite pruning and regrowth of γ-type Kenyon cells is not required for the establishment of circuits that mediate associative odour learning per se, but it does improve distinct learning tasks.

Dietary Protein Quality Influences Liver Circadian Rhythms in a GCN2‐dependent Manner

Circadian disruption correlates with a wide range of metabolic and neurological disorders. General control non‐derepressible 2 (GCN2) activation, the primary sensory mechanism of amino acid insufficiency, also plays an integral role in maintaining the circadian clock in peripheral tissues such as the liver. The objective of this work is to examine the regulation of the circadian clock via GCN2‐mediated sensing of dietary protein quality. We hypothesized that low protein quality feeding will alter the circadian clock in a GCN2 dependent manner. To test this, wild type (WT) and whole body GCN2 knockout (GCN2KO) mice were housed in total darkness within an environmentally‐controlled indirect calorimetry cabinet and provided a diet either devoid of leucine (LeuD) or amino acid replete (Control) for 8‐days and then killed at 2 circadian time (CT) points 12‐hours apart (CT3, CT15). Following the treatment period, LeuD‐fed GCN2KO mice displayed a 40% reduction in the circadian oscillation of their energy expenditure (p<.001) relative to Controls whereas no such difference was present in their WT counterparts. Measurements of the 12‐hour expression pattern of various circadian oscillatory genes within the liver revealed that GCN2 is necessary for circadian oscillation of Bmal2 mRNA expression independent of diet (p<0.01). Furthermore, LeuD feeding alters the expression pattern of the clock‐controlled genes (CCGs) Ciart, Klf10and Noctby over 5‐, 10‐, and 2‐fold respectively (p<0.05) in a GCN2 dependent manner. Together, these findings demonstrate that dietary protein quality plays a role in the maintenance of circadian rhythms within the liver. Furthermore, GCN2 is required to maintain whole body metabolic rhythms when challenged with a diet of poor protein quality. In observing the alterations in the circadian expression pattern of these CCGs with feeding a low protein quality diet, our findings expand our understanding of the role of dietary amino acid intake and the maintenance of circadian metabolic rhythms within the liver.

Designing the formulations in circadian rhythm activity with chronotherapeutic drug delivery system using ramelteon

Ramelteon is an orally sleep promoting agent that is chemically designated as (S)- N- [2-(1,6,7,8-Tetrahydro-2H-indeno-[5,4b] furan-8-yl) ethyl] propionamide and contains one chiral centre. Ramelteon is a neutral compound with no acid or base functional groups, and as such, its aqueous solubility is independent of pH. The activity of Ramelteon at the MT1and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. These maintenance of circadian rhythm can be well controlled by designing the formulations with chronotherapeutic drug delivery system. This article summarizes to design, develop and evaluate the chronotherapeutic drug delivery system with various approaches using control release polymers like Eudragit RSPO, Hydroxy propyl methyl cellulose (HPMC), Ethyl cellulose etc., the approaches like compression coating technique, pulsatile drug delivery system and coating technique. The main objective of controlling the drug release pattern is to achieve the lag time of 2 hours followed by drug release profile for 4 hours. Also an attempt has been made to conclude on various approaches studied which can be used in the treatment of circadian rhythm using Ramelteon API.

An endogenous basis for synchronisation characteristics of the circadian rhythm in proliferating Lemna minor plants.

The circadian clock is a cell-autonomous system that functions through the coordination of time information in the plant body. Synchronisation of cellular clocks is based on coordination mechanisms; the synchronisation characteristics of proliferating plants remain unclear. The bioluminescence circadian rhythms of fronds (leaf-like plant units) of proliferating Lemna minor plants carrying a circadian bioluminescence reporter, AtCCA1:LUC, were spatiotemporally analysed at a cell-level resolution. We focused on spontaneous circadian organisation under constant light conditions for plants with light:dark treatment (LD grown) or without it (LL grown). Fronds developing even from an LL-grown parental frond showed coherent circadian rhythms among them. This allowed the maintenance of circadian rhythmicity in proliferating plants. Inside a frond, a centrifugal phase/period pattern was observed in LD-grown plants, whereas various phase patterns with travelling waves were formed in LL-grown plants. These patterns were model simulated by local coupling of heterogeneous cellular circadian oscillators with different initial synchronous states in fronds. Spatiotemporal analysis of the circadian rhythms in proliferating plants reveals spontaneous synchronisation manners that are associated with local cell-cell coupling, spatial phase patterns and developmental stages.

Spontaneous Recovery of Circadian Organization in Mice Lacking a Core Component of the Molecular Clockwork.

Circadian rhythms are generated by interlocked transcriptional-translational feedback loops of circadian clock genes and their protein products. Mice homozygous for a functional deletion in the Period-2 gene (Per2m/m mice) exhibit short free-running circadian periods and eventually lose behavioral circadian rhythmicity in constant darkness (DD). We investigated Per2m/m mice in DD for several months and identified a categorical sex difference in the dependence on Per2 for maintenance of circadian rhythms. Nearly all female Per2m/m mice became circadian arrhythmic in DD, whereas free-running rhythms persisted in 37% of males. Remarkably, with extended testing, Per2m/m mice did not remain arrhythmic in DD, but after varying intervals spontaneously recovered robust, free-running circadian rhythms, with periods shorter than those expressed prior to arrhythmia. Spontaneous recovery was strikingly sex-biased, occurring in 95% of females and 33% of males. Castration in adulthood resulted in male Per2m/m mice exhibiting female-like levels of arrhythmia in DD, but did not affect spontaneous recovery. The circadian pacemaker of many gonad-intact males, but not females, can persist in DD for long intervals without a functional PER2 protein; their circadian clocks may be in an unstable equilibrium, incapable of sustaining persistent coherent circadian organization, resulting in transient cycles of circadian organization and arrhythmia.

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models.

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is, therefore, critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive HSD11B1 activity and amplification of local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and ageing-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated mechanisms by which glucocorticoids exert their metabolic effects and have guided us towards more targeted future treatments for metabolic diseases.

Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia.

BackgroundCircadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia.Methods and ResultsA jet‐lag model was established in C57BL/6J mice using a light‐controlled isolation box. Control mice were kept at a light/dark 12:12 (12‐hour light and 12‐hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet‐lag model (P<0.05). The jet‐lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet‐lag condition. Next, Cry1 and Cry2 double‐knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double‐knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis.ConclusionsOur data suggest that circadian rhythm disorder deteriorates reparative ischemia‐induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

Managing Bilateral Oro-Sino-Orbital Fistulae in the Setting of Bilateral Tessier IV Clefts.

The number IV orofacial cleft is extremely rare, and reports on long-term outcomes are limited. Here we present the management of a child born with bilateral Tessier number IV clefts and microphthalmia, who developed bilateral oro-sino-orbital fistulae. He presented 8 years after his index procedure with persistent ocular drainage and radiographic evidence of bilateral oro-sino-orbital fistulae. His globes maintained light perception, and in order to protect them from chemical reflux he underwent fistula obliteration with demineralized bone matrix and acellular dermal matrix. His orbits were reconstructed by Imre and conjunctival flaps. In the presence of marginally functioning globes, the importance of timely intervention is critical in order to preserve residual ocular function. Light perception vision assists in the maintenance of circadian rhythm and physiologic functions that are critical to the developing pediatric patient. This case also emphasizes the importance of a multi-disciplinary team in the correction of complex craniofacial deformities.

Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene.

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep-phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian-relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2-related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.

A quantitative analysis of the retinofugal projections in congenital and late-onset blindness

Vision loss early in life has dramatic consequences on the organization of the visual system and hence on structural plasticity of its remnant components. Most of the studies on the anatomical changes in the brain following visual deprivation have focused on the re-organization of the visual cortex and its afferent and efferent projections. In this study, we performed a quantitative analysis of the volume and size of the optic chiasm, optic nerve, optic tract and the lateral geniculate nucleus (LGN), the retino recipient thalamic nucleus. Analysis was carried out on structural T1-weighted MRIs from 22 congenitally blind (CB), 14 late blind (LB) and 29 age -and sex-matched sighted control (SC) subjects. We manually segmented the optic nerve, optic chiasm and optic tract, while LGN volumes were extracted using in-house software. We also measured voxel intensity of optic nerve, optic chiasm and optic tract. Mean volumes of the optic nerve, optic tract and optic chiasm were reduced by 50 to 60% in both CB and LB participants. No significant differences were found between the congenitally and late-onset blind participants for any of the measures. Our data further revealed reduced white matter voxel intensities in optic nerve, optic chiasm and optic tract in blind compared to sighted participants, suggesting decreased myelin content in the atrophied white matter. The LGN was reduced by 50% and 44% in CB and LB, respectively. In LB, optic nerve volume correlated negatively with the blindness duration index; no such correlation was found for optic chiasm, optic tract and LGN. The observation that despite the absence of visual input about half of the subcortical retinofugal projections are structurally preserved raises the question of their functional role. One possibility is that the surviving fibers play a role in the maintenance of circadian rhythms in the blind through the intrinsically photosensitive melanopsin-containing retinal ganglion cells.

Abstract 13133: Impact of Circadian Rhythm Disorders on Reparative Angiogenesis

Introduction: Circadian rhythm disorder seen in shift-worker or jet-lag is major social health concerns in advanced industrialized countries. The aim of this study was to examine if circadian rhythm disorders would influence on angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia (HLI). Methods and Results: First, we established a jet-lag model in C57BL/6J (wild type; WT) mice (8-10 weeks old, N=10 for each) using a light controlled isolation box. Mice were exposed to advanced 8-hr light phase once every 4 days in a jet-lag group as previously described. Conversely, control mice were kept a regular condition of LD 12:12 (12-hr light and 12-hr dark). Then, we surgically induced HLI in each group. The results showed that the condition jet-lag deteriorated capillary formation detected by CD31-immunohistochemistry at post-operative day (POD) 28 and tissue blood perfusion recovery demonstrated by laser Doppler perfusion imaging (LDPI) in HLI. The expression of clock genes (i.e. Clock, Bmal1, Per2, Cry1 and 2 ) in ischemic muscles were regulated by jet-lag condition at POD7.Next, we examined whether inhibition of clock gene had any effects on angiogenesis. For this study, we focused on Cryptochrome ( Cry ), which is well known as one of the core-loop forming clock genes producing circadian rhythm in mammals. Our loss-of-function study revealed that the abilities of proliferation, migration and tube formation were significantly inhibited by CRY1 and CRY2 double knockdown in HUVECs. Interestingly, although the knockdown of CRY1 and CRY2 changed the mRNA expression of PERIOD2 , it did not affect those of BMAL1 and CLOCK in HUVECs. Finally, we tested if Cry1 and Cry2 double knockout ( Cry1/2 -DKO) mice of HLI models displayed worse blood perfusion recoveries with deterioration of angiogenesis. Cry1/2 -DKO mice were reported to display circadian rhythm disorder in previous reports. As results, compared with control WT mice, Cry1/2 -DKO mice revealed suppressed capillary density and tissue blood perfusion recovery in HLI model. Conclusion: Our data suggest that a maintenance of circadian rhythm plays an important role in reparative angiogenesis of the tissue ischemia model.

The Role of the Molecular Clock in Promoting Skeletal Muscle Growth and Protecting against Sarcopenia.

The circadian clock has a critical role in many physiological functions of skeletal muscle and is essential to fully understand the precise underlying mechanisms involved in these complex interactions. The importance of circadian expression for structure, function and metabolism of skeletal muscle is clear when observing the muscle phenotype in models of molecular clock disruption. Presently, the maintenance of circadian rhythms is emerging as an important new factor in human health, with disruptions linked to ageing, as well as to the development of many chronic diseases, including sarcopenia. Therefore, the aim of this review is to present the latest findings demonstrating how circadian rhythms in skeletal muscle are important for maintenance of the cellular physiology, metabolism and function of skeletal muscle. Moreover, we will present the current knowledge about the tissue-specific functions of the molecular clock in skeletal muscle.

Nutrition and Inflammation: Are Centenarians Similar to Individuals on Calorie-Restricted Diets?

Individuals capable of reaching the extreme limit of human life such as centenarians are characterized by an exceptionally healthy phenotype-that is, a low number of diseases, low blood pressure, optimal metabolic and endocrine parameters, and increased diversity in the gut microbiota-and they are epigenetically younger than their chronological age. We present data suggesting that such a remarkable phenotype is largely similar to that found in adults following a calorie-restricted diet. Interviews with centenarians and historical data on the nutritional and lifestyle habits of Italians during the twentieth century suggest that as children and into adulthood, centenarians lived in an environment that was nonobesogenic, but at the same time the environment did not produce malnutrition. Centenarians appear to be creatures of habit, and we argue that their habit of eating meals at the same time each day favored the maintenance of circadian rhythms, including their sleep cycle. Finally, we argue that centenarians' chronic inflammatory status, which we dubbed inflammaging, is peculiar, likely adaptive, and less detrimental than in younger people.

Chapter 13 - Sleep disorders and concussion

Sleep disorders are a common sequel of sports-related concussion. Sleep-wake dysfunction can vary among patients, independent of cause or severity of concussive injury. The pathogenesis of postconcussive sleep disorder is unclear, but may be related to impaired signaling in neurons involved in normal sleep-wake control and circadian rhythm maintenance. Standardized methods of assessment for sleep disorders following concussion are important for diagnosis and management. Appropriate management is key because sleep dysfunction can have deleterious effects on concussion recovery. Management is patient-specific, based on sleep pathology and comorbid postconcussive symptomatology.