RESUMEN
Circadian rhythms of approximately 24 h have emerged as important modulators of the immune system. These oscillations are important for mounting short-term, innate immune responses, but surprisingly also long-term, adaptive immune responses. Recent data indicate that they play a central role in antitumor immunity, in both mice and humans. In this review, we discuss the evolving literature on circadian antitumor immune responses and the underlying mechanisms that control them. We further provide an overview of circadian treatment regimens-chrono-immunotherapies-that harness time-of-day differences in immunity for optimal efficacy. Our aim is to provide an overview for researchers and clinicians alike, for a better understanding of the circadian immune system and how to best harness it for chronotherapeutic interventions. This knowledge is important for a better understanding of immune responses per se and could revolutionize the way we approach the treatment of cancer and a range of other diseases, ultimately improving clinical practice.
Asunto(s)
Ritmo Circadiano , Neoplasias , Humanos , Ritmo Circadiano/inmunología , Animales , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Inmunidad Innata , Inmunidad AdaptativaRESUMEN
The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.
Asunto(s)
Linfocitos T CD8-positivos , Inmunoterapia , Linfocitos Infiltrantes de Tumor , Ratones Endogámicos C57BL , Microambiente Tumoral , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Relojes Circadianos , Ritmo Circadiano , Células Endoteliales/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Melanoma/terapia , Melanoma/patología , Microambiente Tumoral/inmunologíaRESUMEN
Terrestrial organisms developed circadian rhythms for adaptation to Earth's quasi-24-h rotation. Achieving precise rhythms requires diurnal oscillation of fundamental biological processes, such as rhythmic shifts in the cellular translational landscape; however, regulatory mechanisms underlying rhythmic translation remain elusive. Here, we identified mammalian ATXN2 and ATXN2L as cooperating master regulators of rhythmic translation, through oscillating phase separation in the suprachiasmatic nucleus along circadian cycles. The spatiotemporal oscillating condensates facilitate sequential initiation of multiple cycling processes, from mRNA processing to protein translation, for selective genes including core clock genes. Depleting ATXN2 or 2L induces opposite alterations to the circadian period, whereas the absence of both disrupts translational activation cycles and weakens circadian rhythmicity in mice. Such cellular defect can be rescued by wild type, but not phase-separation-defective ATXN2. Together, we revealed that oscillating translation is regulated by spatiotemporal condensation of two master regulators to achieve precise circadian rhythm in mammals.
Asunto(s)
Relojes Circadianos , Ratones , Animales , Relojes Circadianos/genética , Ritmo Circadiano/fisiología , Núcleo Supraquiasmático/metabolismo , Procesamiento Proteico-Postraduccional , MamíferosRESUMEN
The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.
Asunto(s)
Antígeno B7-H1 , Relojes Circadianos , Inhibidores de Puntos de Control Inmunológico , Células Supresoras de Origen Mieloide , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Relojes Circadianos/inmunología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Ratones Endogámicos C57BL , Ritmo Circadiano/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/tratamiento farmacológico , Microambiente Tumoral/inmunología , Tolerancia Inmunológica , Humanos , Femenino , Línea Celular Tumoral , Análisis de la Célula Individual , Terapia de Inmunosupresión , Citocinas/metabolismo , MasculinoRESUMEN
Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology. The biological causes or hallmarks of health include features of spatial compartmentalization (integrity of barriers and containment of local perturbations), maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration). Disruption of any of these interlocked features is broadly pathogenic, causing an acute or progressive derailment of the system coupled to the loss of numerous stigmata of health.
Asunto(s)
Salud , Autofagia , Senescencia Celular , Ritmo Circadiano/fisiología , Humanos , Inmunidad , Especificidad de ÓrganosRESUMEN
Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca2+ dynamics and promoted NSC activation. We further discovered a Ca2+ signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca2+ pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca2+ fluxes to mimic quiescent-state-like Ca2+ dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.
Asunto(s)
Células Madre Adultas/metabolismo , Calcio/metabolismo , Ritmo Circadiano , Espacio Intracelular/metabolismo , Células-Madre Neurales/metabolismo , Células Madre Adultas/citología , Células Madre Adultas/efectos de los fármacos , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Conducta Animal/efectos de los fármacos , División Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Citosol/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Melatonina/metabolismo , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Optogenética , Transducción de Señal/efectos de los fármacos , Triptaminas/farmacologíaRESUMEN
Environmental light cycles entrain circadian feeding behaviors in animals that produce rhythms in exposure to foodborne bacteria. Here, we show that the intestinal microbiota generates diurnal rhythms in innate immunity that synchronize with feeding rhythms to anticipate microbial exposure. Rhythmic expression of antimicrobial proteins was driven by daily rhythms in epithelial attachment by segmented filamentous bacteria (SFB), members of the mouse intestinal microbiota. Rhythmic SFB attachment was driven by the circadian clock through control of feeding rhythms. Mechanistically, rhythmic SFB attachment activated an immunological circuit involving group 3 innate lymphoid cells. This circuit triggered oscillations in epithelial STAT3 expression and activation that produced rhythmic antimicrobial protein expression and caused resistance to Salmonella Typhimurium infection to vary across the day-night cycle. Thus, host feeding rhythms synchronize with the microbiota to promote rhythms in intestinal innate immunity that anticipate exogenous microbial exposure.
Asunto(s)
Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Microbioma Gastrointestinal , Inmunidad Innata , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Adhesión Bacteriana , Adhesión Celular , Células Epiteliales/microbiología , Conducta Alimentaria , Intestino Delgado/microbiología , Intestino Delgado/ultraestructura , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Muramidasa/metabolismo , Proteínas Asociadas a Pancreatitis/metabolismo , Factor de Transcripción STAT3/metabolismo , Salmonelosis Animal/microbiología , Transducción de SeñalRESUMEN
The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.
Asunto(s)
COVID-19/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Obesidad/epidemiología , Obesidad/terapia , Pandemias , Medicina de Precisión/métodos , SARS-CoV-2 , COVID-19/virología , Ritmo Circadiano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigénesis Genética , Predisposición Genética a la Enfermedad , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Obesidad/genética , Obesidad/metabolismo , Prevalencia , Factores de Riesgo , TermotoleranciaRESUMEN
Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.
Asunto(s)
Genómica , Mitocondrias/patología , Vuelo Espacial , Estrés Fisiológico , Animales , Ritmo Circadiano , Matriz Extracelular/metabolismo , Humanos , Inmunidad Innata , Metabolismo de los Lípidos , Análisis de Flujos Metabólicos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Músculos/inmunología , Especificidad de Órganos , Olfato/fisiologíaRESUMEN
In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal â¼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.
Asunto(s)
Relojes Circadianos/fisiología , Conducta Alimentaria/fisiología , Proteínas Circadianas Period/metabolismo , Animales , Ritmo Circadiano/fisiología , Femenino , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Mamíferos/metabolismo , Ratones , Ratones Endogámicos C57BL , Receptor IGF Tipo 1/metabolismo , Transducción de SeñalRESUMEN
Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to "remember" time in the absence of external cues.
Asunto(s)
Factores de Transcripción ARNTL/fisiología , Relojes Circadianos/genética , Factores de Transcripción ARNTL/metabolismo , Animales , Proteínas CLOCK/metabolismo , Relojes Circadianos/fisiología , Ritmo Circadiano/genética , Conducta Alimentaria/fisiología , Femenino , Homeostasis , Luz , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Especificidad de Órganos/fisiología , Fotoperiodo , Núcleo Supraquiasmático/metabolismoRESUMEN
Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to â¼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function.
Asunto(s)
Factores de Transcripción ARNTL/fisiología , Relojes Circadianos/genética , Hígado/metabolismo , Factores de Transcripción ARNTL/metabolismo , Animales , Proteínas CLOCK/metabolismo , Relojes Circadianos/fisiología , Ritmo Circadiano/genética , Femenino , Regulación de la Expresión Génica , Homeostasis , Luz , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Especificidad de Órganos/fisiología , Fotoperiodo , Núcleo Supraquiasmático/metabolismoRESUMEN
Thriving in times of resource scarcity requires an incredible flexibility of behavioral, physiological, cellular, and molecular functions that must change within a relatively short time. Hibernation is a collection of physiological strategies that allows animals to inhabit inhospitable environments, where they experience extreme thermal challenges and scarcity of food and water. Many different kinds of animals employ hibernation, and there is a spectrum of hibernation phenotypes. Here, we focus on obligatory mammalian hibernators to identify the unique challenges they face and the adaptations that allow hibernators to overcome them. This includes the cellular and molecular strategies used to combat low environmental and body temperatures and lack of food and water. We discuss metabolic, neuronal, and hormonal cues that regulate hibernation and how they are thought to be coordinated by internal clocks. Last, we touch on questions that are left to be addressed in the field of hibernation research. Studies from the last century and more recent work reveal that hibernation is not simply a passive reduction in body temperature and vital parameters but rather an active process seasonally regulated at the molecular, cellular, and organismal levels.
Asunto(s)
Adaptación Fisiológica , Ambiente , Hibernación/fisiología , Animales , Ritmo Circadiano/fisiología , Humanos , Memoria/fisiología , Sueño/fisiologíaRESUMEN
In Drosophila, well-delineated circuits control circadian rhythms, but the electrophysiological patterns that occur within these circuits are not well understood. In this issue, Tabuchi et al. clarify the temporal coding within a circuit, linking patterns of neural activity to sleep behavior.
Asunto(s)
Proteínas de Drosophila , Animales , Ritmo Circadiano , Drosophila , Plasticidad Neuronal , SueñoRESUMEN
Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity in mouse liver, triggering synchronous high-amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced by DIO, leading to circadian FA synthesis and, surprisingly, FA oxidation (FAO). DIO similarly caused a high-amplitude circadian rhythm of PPARα, which was also required for FAO. Provision of a pharmacological activator of PPARα abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPARα ligands. The high-amplitude rhythm of PPARα imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPARα and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders.
Asunto(s)
Ritmo Circadiano , Dieta/efectos adversos , Hígado/metabolismo , Obesidad/metabolismo , PPAR alfa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Animales , Regulación de la Expresión Génica , Metabolismo de los Lípidos , Lipogénesis , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/patología , PPAR alfa/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.
Asunto(s)
Afecto/efectos de la radiación , Aprendizaje/efectos de la radiación , Luz , Afecto/fisiología , Animales , Encéfalo/fisiología , Ritmo Circadiano , Aprendizaje/fisiología , Ratones , Ratones Endogámicos C57BL , Fototerapia/métodos , Retina/metabolismo , Retina/fisiología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/fisiología , Células Ganglionares de la Retina/efectos de la radiación , Transducción de Señal/fisiología , Núcleo Supraquiasmático/metabolismo , Visión Ocular/fisiología , Vías Visuales/metabolismo , Percepción Visual/fisiologíaRESUMEN
Peroxiredoxins (Prxs) constitute a major family of peroxidases, with mammalian cells expressing six Prx isoforms (PrxI to PrxVI). Cells produce hydrogen peroxide (H2O2) at various intracellular locations where it can serve as a signaling molecule. Given that Prxs are abundant and possess a structure that renders the cysteine (Cys) residue at the active site highly sensitive to oxidation by H2O2, the signaling function of this oxidant requires extensive and highly localized regulation. Recent findings on the reversible regulation of PrxI through phosphorylation at the centrosome and on the hyperoxidation of the Cys at the active site of PrxIII in mitochondria are described in this review as examples of such local regulation of H2O2 signaling. Moreover, their high affinity for and sensitivity to oxidation by H2O2 confer on Prxs the ability to serve as sensors and transducers of H2O2 signaling through transfer of their oxidation state to bound effector proteins.
Asunto(s)
Ritmo Circadiano/genética , Regulación de la Expresión Génica , Peróxido de Hidrógeno/metabolismo , Mitocondrias/metabolismo , Peroxirredoxinas/metabolismo , Animales , Dominio Catalítico , Centrosoma/metabolismo , Centrosoma/ultraestructura , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Mitocondrias/ultraestructura , Mitosis , Oxidación-Reducción , Peroxirredoxinas/genética , Fosforilación , Transducción de SeñalRESUMEN
The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a 'disarming' strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.
Asunto(s)
Ritmo Circadiano/inmunología , Inflamación/metabolismo , Neutrófilos/metabolismo , Neumonía/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Animales , Degranulación de la Célula/inmunología , Gránulos Citoplasmáticos/inmunología , Gránulos Citoplasmáticos/metabolismo , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Humanos , Inflamación/inmunología , Ratones , Neutrófilos/inmunología , Neumonía/complicaciones , Neumonía/inmunología , Proteoma/inmunología , Proteoma/metabolismo , Síndrome de Dificultad Respiratoria/inmunologíaRESUMEN
To accommodate daily recurring environmental changes, animals show cyclic variations in behaviour and physiology, which include prominent behavioural states such as sleep-wake cycles but also a host of less conspicuous oscillations in neurological, metabolic, endocrine, cardiovascular and immune functions. Circadian rhythmicity is created endogenously by genetically encoded molecular clocks, whose components cooperate to generate cyclic changes in their own abundance and activity, with a periodicity of about a day. Throughout the body, such molecular clocks convey temporal control to the function of organs and tissues by regulating pertinent downstream programmes. Synchrony between the different circadian oscillators and resonance with the solar day is largely enabled by a neural pacemaker, which is directly responsive to certain environmental cues and able to transmit internal time-of-day representations to the entire body. In this Review, we discuss aspects of the circadian clock in Drosophila melanogaster and mammals, including the components of these molecular oscillators, the function and mechanisms of action of central and peripheral clocks, their synchronization and their relevance to human health.
Asunto(s)
Relojes Circadianos/genética , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Animales , Relojes Circadianos/fisiología , Drosophila melanogaster/fisiología , Humanos , Mamíferos/fisiologíaRESUMEN
Aging and circadian rhythms have been linked for decades, but their molecular interplay has remained obscure. Sato et al. and Solanas et al. now reveal that, while core clock components remain nearly unaltered, aging is associated with tissue-specific rewiring, which can be prevented by calorie restriction.