Circadian Clock and Aging

This book aims to understand the inherent circadian cycles of biological processes and their role in maintaining health and healing a variety of diseases. The book is divided into eight sections. The first section introduces circadian rhythms and aging. The second section focuses on the detailed mechanistic approach of oscillatory pathways in mammals. The next section summarizes the sensitivity of the biological clock towards light and the circadian response to melatonin in mammals. The fourth section addresses the circadian architecture at the cellular level and introduces an age-dependent experimental model of rodents for subsequent biochemical and molecular investigations. The subsequent section covers the complexity of circadian regulation in mitochondrial dynamics and its impact on aging. The sixth section of the book discusses the findings obtained from different experimental approaches as a critical threat to the functioning of clock regulatory mechanisms and its associated health consequences during aging in humans and animal models. The circadian oscillatory mechanisms that are dysregulated and might play an important role in the development and progression of neurological disorders such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), and Amyotrophic Lateral Sclerosis (ALS), etc are discussed in the next section. Towards the end, the book explores the circadian clock as a possible drug target to restore circadian oscillations. Preface Contents About the Authors 1: Introduction to Circadian Rhythms 1.1 Introduction 1.2 Evolution of Circadian Rhythmicity 1.3 The History of Finding Clock in Rhythms 1.4 Features of the Rhythms 1.5 Ultradian Clocks: Small Steps Toward Circadian Oscillators? 1.6 The Emergence of a Circadian Neurobiology 1.7 Physiological Significance of Circadian Rhythms 1.7.1 The Peripheral Clocks 1.7.2 Effect of Circadian Clock on Physiology 1.8 Health Consequences of Circadian Rhythm Disruption 1.8.1 Neurological Conditions 1.8.2 Metabolic Dysfunction 1.8.3 Cardiovascular Problems 1.8.4 Immune Problems References 2: Mechanisms of Circadian Oscillations 2.1 Introduction 2.2 The Mammalian Circadian Timing System 2.2.1 Input to the Clock: Retina and Non-retinal Origins 2.2.2 The Pacemaker of the Clock: Suprachiasmatic Nuclei 2.2.3 Outputs of the Clock: SCN Outputs 2.3 The Molecular Mechanisms Underlying Circadian Oscillation 2.3.1 Transcription Factors and Cofactors 2.4 Chromatin Remodelling and the Epigenetics of Circadian System 2.5 Post-transcriptional Regulation of the Circadian Clock 2.6 Biochemical Oscillations in the Absence of Transcription 2.7 Mutant Mouse Models of the Clock System 2.8 Conclusion References 3: Light Sensitivity of the Biological Clock 3.1 Introduction 3.2 The Photoperiodic Clock 3.3 CRPP: Phasic Effects 3.4 Induction vs. Entrainment 3.5 Temporal Photosensitivity 3.6 Non-reproductive Circadian Functions 3.7 Non-circadian Functions 3.8 Diversity in the Circadian Response to Melatonin in Mammals 3.8.1 Entrainment to Melatonin 3.8.2 Melatonin Administration Under LD Entrainment 3.8.3 Melatonin Phase Response Curves 3.8.4 Site(s) of Melatonin Action 3.9 Conclusion References 4: Circadian System and Ageing in Rodent Models 4.1 Introduction 4.2 Central and Peripheral Oscillators 4.3 Circadian System in Aged Rodents 4.3.1 Circadian Rhythm Disturbance Related to Ageing 4.3.2 The Ageing SCN 4.3.3 Aging Pineal Gland 4.3.4 Aging Molecular Clock 4.4 Analysis of the Circadian Rhythms in Rodent Models of Accelerated Ageing and Age-Related Pathologies 4.4.1 Clock Genes in Rodent Models of Age-Related Pathologies 4.4.2 Other Rodent Model Systems of Circadian Clock Disruption 4.4.3 Light/Photoperiod 4.5 Effects of Mutations in Circadian Genes on Circadian Rhythms and Age-Related Disorders 4.6 Optimising Circadian Rhythms and Extending Longevity in Rodents Via Interventions 4.7 Conclusion References 5: Circadian Control of Mitochondrial Dynamics and Its Implication in Aging 5.1 Introduction 5.2 Cellular Function Involved in Mitochondrial Dynamics 5.2.1 The Machinery 5.2.2 Mitochondrial Dynamics: Biological Sensor of Bioenergetics and Oxidative Stress 5.2.3 Quality Control and the Mitochondrial Dynamics Involved 5.3 Circadian Rhythms and Regulation of Mitochondrial Activity 5.3.1 Metabolic Rhythms of Metabolism 5.3.2 The Circadian Control 5.3.3 Signaling Pathways Which Integrate Circadian Biology to Mitochondrial Functions 5.4 Circadian Dysregulation and Age-Related Metabolic Diseases: The Role of Mitochondrial Dynamics 5.5 Summary References 6: Health Consequences of Circadian Disruption in Humans and Animal Models During Aging 6.1 Introduction 6.2 Circadian Regulation of Physiology 6.3 Types of Circadian Disruption in Humans and Animal Models 6.4 Measuring Circadian Disruption 6.5 Circadian Disruption in the Real World 6.6 Models of Circadian Disruption in Humans and Animals 6.7 Health Consequences of Circadian Disruption 6.7.1 Longevity and Aging 6.7.2 Cancer and Oxidative Stress 6.7.3 Metabolic Syndrome, Obesity, and Gastrointestinal Problems 6.7.4 Cardiovascular Disorders 6.7.5 Disorders Related to Reproduction 6.7.6 Mood Disorders 6.7.7 Learning and Memory Deficits 6.7.8 Immune Dysfunction 6.8 Future Research Questions 6.9 Conclusion References 7: The Human SCN in Health and Age-Related Neurological Disorders 7.1 Introduction 7.2 The SCN’s Role in Neurodegenerative Diseases 7.2.1 Alzheimer’s Disease (AD) 7.2.2 Huntington’s Disease (HD) 7.2.3 Parkinson’s Disease (HD) 7.2.4 Amyotrophic Lateral Sclerosis (ALS) 7.3 Depression 7.4 Hypertension 7.5 Summary References 8: The Circadian Clock as a Drug Target for Anti-Ageing Strategies 8.1 Introduction 8.2 Targeting Clock for the Development of Therapeutics 8.3 Cellular and Molecular Aspects of Chrono-Pharmacology and Chronotherapy 8.4 Drugs Targeting the Clock 8.4.1 The Clock Gene: PAS/CLOCK: BMAL1 8.4.2 The Clock Gene: Period 8.4.3 The Clock Genes: Cryptochrome 8.4.4 The Clock Genes: Retinoic Acid Receptor-Related Orphan Receptors (Reverb and RoR) 8.4.5 The Kinases 8.5 Effects of Physical Activity on Circadian Rhythms in the Elderly 8.5.1 Physical Activity as a Modulator of Circadian Rhythm 8.5.2 The Effect of Physical Status on Circadian Rhythm of Elderly 8.6 Conclusion References