Circadian Clock in Cell Culture: II

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Importance of Circadian Timing for Aging and Longevity

REVIEW ARTICLE https://doi.org/10.1038/s41467-021-22922-6 OPEN Importance of circadian timing for aging and longevity Victoria A. Acosta-Rodríguez 1, Filipa Rijo-Ferreira 1,2, Carla B. Green 1 & ✉ Joseph S. Takahashi 1,2 Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by 1234567890():,; adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of which change expression throughout the day, suggesting that the timing of drug administration is critical. Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms. ging is a major risk factor for chronic diseases, including obesity, diabetes, cancer, Acardiovascular disease, and neurodegenerative disorders1. Improvements in healthcare have increased life expectancy worldwide, but as the aged population increases, frailty and morbidity have become a public health burden. Through the Healthy Life Expectancy (HALE) indicator, the World Health Organization estimates that worldwide humans spend >10% of our lives suffering from age-related diseases. Aging research currently focuses on closing the gap between lifespan (living longer) and healthspan (remaining healthier for longer). While lifespan can be easily determined with survival curves, healthspan is more complex to quantify. Several biomarkers of healthspan are used in animal models2,3 and humans4, ranging from levels of metabolites (glucose, cholesterol, fatty acids), biological processes (inflammation, autophagy, senescence, blood pressure) to biological functions (behavior, cognition, cardiovascular perfor- mance, fitness, and frailty).
CURRICULUM VITAE Joseph S. Takahashi Howard Hughes Medical

CURRICULUM VITAE Joseph S. Takahashi Howard Hughes Medical Institute Department of Neuroscience University of Texas Southwestern Medical Center 5323 Harry Hines Blvd., NA4.118 Dallas, Texas 75390-9111 (214) 648-1876, FAX (214) 648-1801 Email: [email protected] DATE OF BIRTH: December 16, 1951 NATIONALITY: U.S. Citizen by birth EDUCATION: 1981-1983 Pharmacology Research Associate Training Program, National Institute of General Medical Sciences, Laboratory of Clinical Sciences and Laboratory of Cell Biology, National Institutes of Health, Bethesda, MD 1979-1981 Ph.D., Institute of Neuroscience, Department of Biology, University of Oregon, Eugene, Oregon, Dr. Michael Menaker, Advisor. Summer 1977 Hopkins Marine Station, Stanford University, Pacific Grove, California 1975-1979 Department of Zoology, University of Texas, Austin, Texas 1970-1974 B.A. in Biology, Swarthmore College, Swarthmore, Pennsylvania PROFESSIONAL EXPERIENCE: 2013-present Principal Investigator, Satellite, International Institute for Integrative Sleep Medicine, World Premier International Research Center Initiative, University of Tsukuba, Japan 2009-present Professor and Chair, Department of Neuroscience, UT Southwestern Medical Center 2009-present Loyd B. Sands Distinguished Chair in Neuroscience, UT Southwestern 2009-present Investigator, Howard Hughes Medical Institute, UT Southwestern 2009-present Professor Emeritus of Neurobiology and Physiology, and Walter and Mary Elizabeth Glass Professor Emeritus in the Life Sciences, Northwestern University
A Calcium Flux Is Required for Circadian Rhythm Generation in Mammalian Pacemaker Neurons

7682 • The Journal of Neuroscience, August 17, 2005 • 25(33):7682–7686 Brief Communication A Calcium Flux Is Required for Circadian Rhythm Generation in Mammalian Pacemaker Neurons Gabriella B. Lundkvist,1 Yongho Kwak,1 Erin K. Davis,1 Hajime Tei,2 and Gene D. Block1 1Center for Biological Timing, Department of Biology, University of Virginia, Charlottesville, Virginia 22903, and 2Research Group of Chronogenomics, Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan Generation of mammalian circadian rhythms involves molecular transcriptional and translational feedback loops. It is not clear how membrane events interact with the intracellular molecular clock or whether membrane activities are involved in the actual generation of the circadian rhythm. We examined the role of membrane potential and calcium (Ca 2ϩ) influx in the expression of the circadian rhythm of the clock gene Period 1 (Per1) within the rat suprachiasmatic nucleus (SCN), the master pacemaker controlling circadian rhythmicity. Membrane hyperpolarization, caused by lowering the extracellular concentration of potassium or blocking Ca 2ϩ influx in SCN cultures by lowering [Ca 2ϩ], reversibly abolished the rhythmic expression of Per1. In addition, the amplitude of Per1 expression was markedly decreased by voltage-gated Ca 2ϩ channel antagonists. A similar result was observed for mouse Per1 and PER2. Together, these results strongly suggest that a transmembrane Ca 2ϩ flux is necessary for sustained molecular rhythmicity in the SCN. We propose that periodic Ca 2ϩ influx, resulting from circadian variations in membrane potential, is a critical process for circadian pacemaker function. Key words: circadian rhythm; calcium; potassium; suprachiasmatic nucleus; Period 1; PERIOD 2 Introduction et al., 2002).
A Molecular Perspective of Human Circadian Rhythm Disorders Nicolas Cermakian* , Diane B

Brain Research Reviews 42 (2003) 204–220 www.elsevier.com/locate/brainresrev Review A molecular perspective of human circadian rhythm disorders Nicolas Cermakian* , Diane B. Boivin Douglas Hospital Research Center, McGill University, 6875 LaSalle boulevard, Montreal, Quebec H4H 1R3, Canada Accepted 10 March 2003 Abstract A large number of physiological variables display 24-h or circadian rhythms. Genes dedicated to the generation and regulation of physiological circadian rhythms have now been identiﬁed in several species, including humans. These clock genes are involved in transcriptional regulatory feedback loops. The mutation of these genes in animals leads to abnormal rhythms or even to arrhythmicity in constant conditions. In this view, and given the similarities between the circadian system of humans and rodents, it is expected that mutations of clock genes in humans may give rise to health problems, in particular sleep and mood disorders. Here we ﬁrst review the present knowledge of molecular mechanisms underlying circadian rhythmicity, and we then revisit human circadian rhythm syndromes in light of the molecular data. 2003 Elsevier Science B.V. All rights reserved. Theme: Neural basis of behavior Topic: Biological rhythms and sleep Keywords: Circadian rhythm; Clock gene; Sleep disorder; Suprachiasmatic nucleus Contents 1 . Introduction ............................................................................................................................................................................................ 205
Salt-Inducible Kinase 3 Regulates the Mammalian Circadian Clock By

RESEARCH ARTICLE Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein Naoto Hayasaka1,2,3*, Arisa Hirano4, Yuka Miyoshi3, Isao T Tokuda5, Hikari Yoshitane4, Junichiro Matsuda6, Yoshitaka Fukada4 1Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; 2PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan; 3Department of Anatomy and Neurobiology, Kindai University Faculty of Medicine, Osaka, Japan; 4Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo, Japan; 5Department of Mechanical Engineering, Ritsumeikan University, Kusatsu, Japan; 6Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan Abstract Salt-inducible kinase 3 (SIK3) plays a crucial role in various aspects of metabolism. In -/- the course of investigating metabolic defects in Sik3-deficient mice (Sik3 ), we observed that -/- circadian rhythmicity of the metabolisms was phase-delayed. Sik3 mice also exhibited other circadian abnormalities, including lengthening of the period, impaired entrainment to the light-dark cycle, phase variation in locomotor activities, and aberrant physiological rhythms. Ex vivo -/- suprachiasmatic nucleus slices from Sik3 mice exhibited destabilized and desynchronized molecular rhythms among individual neurons. In cultured cells, Sik3-knockdown resulted in abnormal bioluminescence rhythms. Expression levels of PER2, a clock protein, were elevated in Sik3-knockdown cells but down-regulated in Sik3-overexpressing cells, which could be attributed to a phosphorylation-dependent decrease in PER2 protein stability. This was further confirmed by -/- PER2 accumulation in the Sik3 fibroblasts and liver. Collectively, SIK3 plays key roles in circadian *For correspondence: rhythms by facilitating phosphorylation-dependent PER2 destabilization, either directly or [email protected] indirectly.
Molecular and Cellular Networks in the Suprachiasmatic Nuclei

International Journal of Molecular Sciences Review Molecular and Cellular Networks in The Suprachiasmatic Nuclei Lama El Cheikh Hussein, Patrice Mollard and Xavier Bonnefont * Institut de Génomique Fonctionnelle (IGF), University Montpellier, CNRS, INSERM, 34094 Montpellier, France; [email protected] (L.E.C.H.); [email protected] (P.M.) * Correspondence: [email protected]; Tel.: +33-4-3435-9306 Received: 1 April 2019; Accepted: 23 April 2019; Published: 25 April 2019 Abstract: Why do we experience the ailments of jetlag when we travel across time zones? Why is working night-shifts so detrimental to our health? In other words, why can’t we readily choose and stick to non-24 h rhythms? Actually, our daily behavior and physiology do not simply result from the passive reaction of our organism to the external cycle of days and nights. Instead, an internal clock drives the variations in our bodily functions with a period close to 24 h, which is supposed to enhance ﬁtness to regular and predictable changes of our natural environment. This so-called circadian clock relies on a molecular mechanism that generates rhythmicity in virtually all of our cells. However, the robustness of the circadian clock and its resilience to phase shifts emerge from the interaction between cell-autonomous oscillators within the suprachiasmatic nuclei (SCN) of the hypothalamus. Thus, managing jetlag and other circadian disorders will undoubtedly require extensive knowledge of the functional organization of SCN cell networks. Here, we review the molecular and cellular principles of circadian timekeeping, and their integration in the multi-cellular complexity of the SCN.
Current Understanding of the Circadian Clock Within Cnidaria 31

Current Understanding of the Circadian Clock Within Cnidaria 31 Kenneth D. Hoadley , Peter D. Vize , and Sonja J. Pyott Abstract Molecularly-based timing systems drive many periodic biological processes in both animals and plants. In cnidarians these periodic processes include daily cycles in metabolism, growth, and tentacle and body wall movements and monthly or yearly reproductive activity. In this chapter we review the current understanding of biological clocks in the cnidaria, with an empha- sis on the molecular underpinnings of these processes. The genes that form this molecular clock and drive biological rhythms in well-characterized genetic systems such as Drosophila and mouse are highly conserved in cnidarians and, like these model systems, display diel cycles in transcription levels. In addition to describing the clock genes, we also review potential entrain- ing systems and discuss the broader implications of biological clocks in cnidarian biology. Keywords Circadian rhythms • Biological clocks • Reproductive timing • Non-visual photodetection • Light perception 31.1 Overview of studies focusing on the molecular basis of the circadian clock . Across species, from bacteria, to fungi, to plants and Entrainment of physiological rhythms to environmental cues animals, this molecular circadian clock involves transcription is ubiquitous among living organisms and allows coordination and translation feedback loops with a self-sustained period of of biology and behavior with daily environmental changes . about 24 h (reviewed in Dunlap 1999 ). Investigation in the This coordination improves survival and reproductive fi tness , model genetic species, mouse and fl y, has identifi ed a core set and, thus, it is not surprising that an endogenous “clock” has of genes that form the central oscillator in animals (reviewed evolved to maintain rhythmicity over a circadian (24 h) period.
Mammalian Circadian Clock and Metabolism – the Epigenetic Link

Commentary 3837 Mammalian circadian clock and metabolism – the epigenetic link Marina Maria Bellet and Paolo Sassone-Corsi* Department of Pharmacology, Unite 904 Inserm ‘Epigenetics and Neuronal Plasticity’, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA *Author for correspondence ([email protected]) Journal of Cell Science 123, 3837-3848 © 2010. Published by The Company of Biologists Ltd doi:10.1242/jcs.051649 Summary Circadian rhythms regulate a wide variety of physiological and metabolic processes. The clock machinery comprises complex transcriptional–translational feedback loops that, through the action of specific transcription factors, modulate the expression of as many as 10% of cellular transcripts. This marked change in gene expression necessarily implicates a global regulation of chromatin remodeling. Indeed, various descriptive studies have indicated that histone modifications occur at promoters of clock-controlled genes (CCGs) in a circadian manner. The finding that CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyl transferase (HAT) activity has paved the way to unraveling the molecular mechanisms that govern circadian chromatin remodeling. A search for the histone deacetylase (HDAC) that counterbalances CLOCK activity revealed that SIRT1, a nicotinamide adenin dinucleotide (NAD+)-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of aging, inflammation and metabolism. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link between energy balance, chromatin remodeling and circadian physiology. Here we review recent studies that support the existence of this link and discuss their implications for understanding mammalian physiology and pathology.
WCBR Program 04

Welcome to the Thirty-Seventh Annual Winter Conference on Brain Research The Winter Conference on Brain Research (WCBR) was founded in 1968 to promote free exchange of information and ideas within neuroscience. It was the intent of the founders that both formal and informal interactions would occur between clinical and laboratory-based neuroscientists. During the past thirty years neuroscience has grown and expanded to include many new fields and methodologies. This diversity is also reflected by WCBR participants and in our program. A primary goal of the WCBR is to enable participants to learn about the current status of areas of neuroscience other than their own. Another objective is to provide a vehicle for scientists with common interests to discuss current issues in an informal setting. On the other hand, WCBR is not designed for presentations limited to communicating the latest data to a small group of specialists; this is best done at national society meetings. The program includes panels (reviews for an audience not neces- sarily familiar with the area presented), workshops (informal discussions of current issues and data), and a number of posters. The annual conference lecture will be presented at the Sunday breakfast on January 25. Our guest speaker will be The Honorable John Edward Porter, former Congressman from Illinois and Chair of the House Appropriations Committee. The title of his talk will be What’s Going on in Washington: We Need to Talk! On Tuesday, January 27, a town meeting will be held for the Copper Mountain community, at which Dr. Michael Zigmond, Director of the Morris K.
Impact of Circadian Disruption on Glucose Metabolism: Implications for Type 2 Diabetes

Diabetologia (2020) 63:462–472 https://doi.org/10.1007/s00125-019-05059-6 REVIEW Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes Ivy C. Mason1,2 & Jingyi Qian1,2 & Gail K. Adler3 & Frank A. J. L. Scheer1,2 Received: 6 June 2019 /Accepted: 19 August 2019 /Published online: 8 January 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract The circadian system generates endogenous rhythms of approximately 24 h, the synchronisation of which are vital for healthy bodily function. The timing of many physiological processes, including glucose metabolism, are coordinated by the circadian system, and circadian disruptions that desynchronise or misalign these rhythms can result in adverse health outcomes. In this review, we cover the role of the circadian system and its disruption in glucose metabolism in healthy individuals and individuals with type 2 diabetes mellitus. We begin by defining circadian rhythms and circadian disruption and then we provide an overview of circadian regulation of glucose metabolism. We next discuss the impact of circadian disruptions on glucose control and type 2 diabetes. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying the impact of circadian disruption on glucose metabolism may aid in improving glycaemic control. Keywords Beta cell function . Circadian disruption . Circadian misalignment . Circadian rhythm . Diabetes . Glucose control . Glucose metabolism . Glucose tolerance . Insulin sensitivity . Review . Type 2 diabetes mellitus Abbreviation living with type 1 or type 2 diabetes. The prevalence of SCN Suprachiasmatic nucleus type 1 and type 2 diabetes is projected to increase to 693 million adults worldwide by 2045 [2].
Resetting the Biological Clock: Mediation of Nocturnal CREB Phosphorylation Via Light, Glutamate, and Nitric Oxide

The Journal of Neuroscience, January 15, 1997, 17(2):667–675 Resetting the Biological Clock: Mediation of Nocturnal CREB Phosphorylation via Light, Glutamate, and Nitric Oxide Jian M. Ding,1,3 Lia E. Faiman,1 William J. Hurst,1 Liana R. Kuriashkina,2 and Martha U. Gillette1,2,3 1Department of Cell and Structural Biology, 2Molecular and Integrative Physiology, and 3The Neuroscience Program, University of Illinois, Urbana, Illinois 61801 Synchronization between the environmental lighting cycle and neurons in which P-CREB-lir was induced by light were the biological clock in the suprachiasmatic nucleus (SCN) is NADPH-diaphorase-positive neurons of the SCN’s retinorecipi- correlated with phosphorylation of the Ca21/cAMP response ent area. Glu treatment increased the intensity of a 43 kDa band element binding protein (CREB) at the transcriptional activating recognized by anti-P-CREB antibodies in subjective night but site Ser133. Mechanisms mediating the formation of phospho- not day, whereas anti-aCREB-lir of this band remained con- CREB (P-CREB) and their relation to clock resetting are un- stant between night and day. Inhibition of NOS during Glu known. To address these issues, we probed the signaling stimulation diminished the anti-P-CREB-lir of this 43 kDa band. pathway between light and P-CREB. Nocturnal light rapidly and Together, these data couple nocturnal light, Glu, NMDA recep- transiently induced P-CREB-like immunoreactivity (P-CREB-lir) tor activation and NO signaling to CREB phosphorylation in the in the rat SCN. Glutamate (Glu) or nitric oxide (NO) donor transduction of brief environmental light stimulation of the ret- administration in vitro also induced P-CREB-lir in SCN neurons ina into molecular changes in the SCN resulting in phase re- only during subjective night.
UTR and Microrna-24 Regulate Circadian Rhythms By

Period2 3′-UTR and microRNA-24 regulate circadian PNAS PLUS rhythms by repressing PERIOD2 protein accumulation Seung-Hee Yooa,b,1, Shihoko Kojimab,2, Kazuhiro Shimomurac,3, Nobuya Koikeb,d, Ethan D. Buhrc,4, Tadashi Furukawac,5, Caroline H. Koc,6, Gabrielle Glostona, Christopher Ayouba, Kazunari Noharaa, Bryan A. Reyese, Yoshiki Tsuchiyad, Ook-Joon Yoof, Kazuhiro Yagitad, Choogon Leeg, Zheng Chena, Shin Yamazaki (山崎晋)e,7, Carla B. Greenb, and Joseph S. Takahashib,h,1 aDepartment of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX 77030; bDepartment of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390; cDepartment of Neurobiology, Northwestern University, Evanston, IL 60208; dDepartment of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; eDepartment of Biological Sciences, Vanderbilt University, Nashville, TN 37235-1634; fGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; gProgram in Neuroscience, Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306; and hHoward Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390 Contributed by Joseph S. Takahashi, September 7, 2017 (sent for review April 21, 2017; reviewed by Paul E. Hardin, Satchin Panda, and Hiroki R. Ueda) We previously created two PER2::LUCIFERASE (PER2::LUC) circadian for binding to the shared element RORE and thus play important reporter knockin mice that differ only in the Per2 3′-UTR region: Per2:: roles in circadian amplitude regulation (17). More recent studies Luc, which retains the endogenous Per2 3′-UTR and Per2::LucSV,where have also shown amplitude regulatory mechanisms distinct from the endogenous Per2 3′-UTR was replaced by an SV40 late poly(A) the competitive binding model (18, 19), suggesting an integrated signal.