Sleep and Clocks in Aging and Longevity

Preface
Contents
Part I Understanding Sleep and Clock Interlink in Health and Longevity
1 Sleep and Circadian Clock: Novel Players in Health Impacts and Aging
	1.1 Introduction
	1.2 Sleep
		1.2.1 What is Sleep?
		1.2.2 Physiological Basis of Sleep
		1.2.3 Types of Sleep/Different Stages of Sleep
		1.2.4 Sleep Duration/Need
		1.2.5 Regulation of Sleep
	1.3 Biological Clock: Circadian Timing System (CTS)
		1.3.1 SCN: Neurotransmitters in Input and Output Pathways
		1.3.2 SCN: Relay Center for Information
		1.3.3 Melatonin: Messenger of Darkness
		1.3.4 Molecular Components of CTS
	1.4 Sleep and Circadian Rhythms: Interplay
		1.4.1 The Two-Process Model: The Interaction of Circadian Forces and Sleep Homeostasis
		1.4.2 Sleep Gate
	1.5 Sleep and Clock Misalignment with Aging
		1.5.1 Alterations in Sleep Structure in Old
		1.5.2 Desynchronization of Circadian Rhythm Patterns in Old
		1.5.3 The Circadian and Sleep Perturbances
	1.6 Interventions to Improve Sleep and Clock Function: A Step Toward Healthy Aging and Longevity
		1.6.1 Sleep Hygiene
		1.6.2 Light Therapy
		1.6.3 Administration of Exogenous Melatonin
		1.6.4 Herbal and Other Interventions
	1.7 Goals and Conclusions
	References
2 Cells and Circuits of the Suprachiasmatic Nucleus and the Control of Circadian Behaviour and Sleep
	2.1 Introduction: Mammalian Circadian System Overview
	2.2 Molecular-Genetic and Cellular Basis of Circadian Timekeeping in Mammals
		2.2.1 The Core Feedback Loop—Genes and Molecules: Discoveries Through Mapping and Mutagenesis Screens
		2.2.2 Additional Feedback Loops Support the TTFL
		2.2.3 Control of the Stability of Clock Proteins and Effect on Behaviour
	2.3 Circadian Properties of SCN Neurons
		2.3.1 Observing Clock Proteins at the Cellular Level
		2.3.2 SCN Neural Activity and Transcriptional Cycles
		2.3.3 The Importance of Coupling Between SCN Neurons
	2.4 Circuit Architecture of the SCN as a Neuronal Network
		2.4.1 Entrainment of the SCN Network: Photic and Non-photic Cues
		2.4.2 SCN Network Synchrony: GABA and Neuropeptides
		2.4.3 VIP Axis: Mediator of SCN Photic Entrainment and Neuronal Synchrony
		2.4.4 GRP Axis: An Accessory Entrainment and Synchronisation Pathway
		2.4.5 AVP Axis: Within-Shell Coupling and Circadian Output
		2.4.6 Prokineticin-2 Axis: More Than an SCN Output?
		2.4.7 An Emerging View of the Functional Topology of the SCN Network
	2.5 The Role of Astrocytes in the SCN
		2.5.1 Astrocytic Control of Circadian Rhythms
		2.5.2 Astrocyte-To-Neuron-To-Astrocyte Communication Within the SCN Network
	2.6 SCN Outputs and Control of Circadian Behaviour and Sleep
		2.6.1 SCN Outputs and Control of Circadian Behaviour
		2.6.2 SCN in the Circadian Regulation of Sleep
	2.7 Conclusion and Future Perspectives
	References
3 Circadian Regulation of Sleep
	3.1 Introduction
	3.2 The Circadian Clock System
	3.3 Regulation of Sleep—Two-Process Model
	3.4 Homeostatic Regulation of Sleep
	3.5 Circadian Regulation of Sleep
		3.5.1 Role of the SCN in Sleep Regulation
		3.5.2 Regulation of Sleep by Canonical Circadian Clock Genes
	3.6 Effects of Circadian Misalignment on Aging
		3.6.1 Attenuation of Circadian Rhythms with Aging
		3.6.2 Acceleration of Aging by Circadian Misalignment/Disruption
	3.7 Effects of Sleep Disorders on Aging
		3.7.1 Age-Related Sleep Changes
		3.7.2 Acceleration of Aging by Sleep Disorders
	3.8 Concluding Remarks
	References
4 Age-Related Decline in the Central Circadian Clock
	4.1 Introduction
	4.2 Effects of Aging on Circadian Rhythms
	4.3 The Central Circadian Clock in the SCN
	4.4 Age-Related Decline in Circadian Rhythms Caused by SCN Disorganization
	4.5 Age-Related Dysfunction of SCN Outputs
	4.6 Mechanisms Underlying SCN Output Dysfunction
	4.7 Conclusion
	References
5 Impact of Cellular Senescence on Cellular Clocks
	5.1 Introduction
	5.2 Evidence that Cellular Senescence Is a Causative Factor for the Different Age-Related Diseases
	5.3 Characteristics of Senescent Cells
	5.4 Permanent Cell Cycle Arrest in Senescent Cells
	5.5 Altered Signaling Pathways in Cellular Senescence
		5.5.1 AMPK Signaling
		5.5.2 P38 MAPK Signaling
		5.5.3 NF-κB Signaling Pathway
		5.5.4 mTOR Signaling Pathway
		5.5.5 Unfolding Protein Response (UPR) Pathway
		5.5.6 Cyto- and Nucleo-Skeletons
	5.6 Metabolic Changes in Cellular Senescence
		5.6.1 Adenosine Triphosphate (ATP)
		5.6.2 Nicotinamide Adenine Dinucleotide (NAD+)
		5.6.3 Polyamines
	5.7 The Circadian Clock
	5.8 Aging of the Circadian Clock
	5.9 Possible Molecular Regulators of Cellular Clocks in Senescent Cells
		5.9.1 P53 Signaling Pathway
		5.9.2 AMPK Signaling
		5.9.3 P38 MAPK Signaling
		5.9.4 NF-κB Signaling Pathway
		5.9.5 mTOR Signaling Pathway
		5.9.6 Unfolding Protein Response Pathway
		5.9.7 Cyto- and Nucleo-Skeletons
		5.9.8 NAD+ and NAD+/NADH Ratio
		5.9.9 Polyamines
	5.10 Conclusions
	References
Part II Sleep, Ageing and Longevity
6 Optimum Sleep for Healthy Ageing
	6.1 Sleep and Wakefulness
	6.2 Cardiovascular and Respiratory Dysfunctions Associated with Sleep Loss
	6.3 Endocrine Dysfunctions Associated with Sleep Loss
	6.4 Metabolic Dysfunctions and Sleep Loss
	6.5 Thermoregulatory Changes in Association with Sleep and Sleep Loss
	6.6 Altered Immune Function in Relation to Sleep Disturbances
	6.7 Cognitive Dysfunction in Association with Sleep Disturbances
	6.8 Sleep Disturbances Associated with Changes in Social Factors
	6.9 Ageing and Sleep Disturbances
	6.10 Sleep Disturbances and Brain Maturity
	6.11 Sleep Disorders in Association with Acute Diseases
	6.12 Sleep Disorders in Association with Chronic Diseases
	6.13 Summary and Conclusion
		6.13.1 Sleep Disruptions as Basis of Many Disorders
		6.13.2 NA, a Common Factor Responsible for Sleep Loss-Associated Pathophysiology
	References
7 Healthy Brain Ageing and Longevity; the Harmony of Natural Products, APOE Polymorphism, and Melatonin
	7.1 Apolipoprotein E (APOE) Polymorphism and Human Longevity
		7.1.1 Population Ageing on Healthy Ageing
		7.1.2 APOE Polymorphism and AD
	7.2 Melatonin in Circadian Rhythms and Healthy Ageing
		7.2.1 Melatonin in AD
		7.2.2 Melatonin Via Plant-Based Diet
	7.3 Antioxidant Properties of Tea
	7.4 Protective Effect of Tea in AD Leading Towards Healthy Ageing
	7.5 Therapeutic Potential of Cinnamon on AD
	7.6 APOE and ACE Polymorphism in Human Longevity and the Protective Effect of Black Tea on AD-Related Neuropathologic Changes: A Proof of Concept
		7.6.1 Sample Collection
		7.6.2 Screening of AD-Related Neuropathologic Changes Using Histopathological and Immunohistochemical Techniques
		7.6.3 Statistical Analysis
		7.6.4 Major Findings
	7.7 Future Perspectives
	References
8 Role of Sleep in Imprinting Healthy Aging
	8.1 Introduction
	8.2 Maternal Sleep Loss During Pregnancy and Poor Health Consequences in F1 Generation
	8.3 Dynamic Role of Sleep and Healthy Aging
	8.4 Conclusion
	References
9 Sleep, Ageing, and Cognitive Decline
	9.1 Introduction
	9.2 Age-Dependent Changes in Sleep Distribution and Oscillations
		9.2.1 Age-Dependent Changes in Sleep
		9.2.2 Age-Dependent Changes in Sleep Oscillations
		9.2.3 Connection to Invertebrates
	9.3 Consequences of Age-Dependent Sleep Loss
		9.3.1 Glymphatic Clearance
		9.3.2 Learning and Memory
	9.4 Conclusions
	References
Part III Clock, Ageing and Longevity
10 How Non-photic Cues for the Circadian Time System Matter in Healthy Aging
	10.1 Introduction
		10.1.1 Central and Peripheral Clocks: Categories of a Hierarchical System Model
		10.1.2 Are Age-Altering Circadian Rhythms Consequences of Impaired Oscillators?
	10.2 Light Versus Non-photic Zeitgebers
		10.2.1 Photoentrainment and Aging
		10.2.2 Feeding Time Entrains the Circadian Time Systems: Impact on Aging
		10.2.3 Social Interactions Entrain the Circadian Time Systems: Impacts on Aging
	10.3 Conclusion
	References
11 Pineal Gland Physiology and Aging-Related Alterations in the Circadian Timing System
	11.1 Introduction
	11.2 Neuroendocrine Perspective of Circadian Rhythm and Aging
	11.3 Changes in Sleep Pattern with Aging
	11.4 The Relationship Between Aging Physiology and Circadian Rhythm
	11.5 Aging and Circadian Rhythms
	11.6 Modifications in Circadian Rhythms with Age
	11.7 Amplitude and Circadian Organization
	11.8 Entrainment and Responsiveness to Zeitgebers: Influence of Aging
	11.9 Age-Associated Changes in Circadian Dysregulation
	11.10 Conclusions
	References
12 Circadian Rhythmicity in Aging and Parkinson’s Disease
	12.1 Basal Ganglia
		12.1.1 Parkinson’s Disease: A Major Basal Ganglia Disorder
		12.1.2 The Neuroanatomical Basis of Parkinson’s Disease
	12.2 Circadian Rhythmicity in Aging and PD
		12.2.1 Role of BG and Clock Genes
		12.2.2 Sleep and PD: The Intriguing Prelude
		12.2.3 Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD)
		12.2.4 Stress
	12.3 Factors Ascribing Longevity and Symptom Alleviation in PD
		12.3.1 Relevance of Social Enrichment
		12.3.2 Yoga
		12.3.3 Healthy Living and Exercise
		12.3.4 External Stimuli and the Imaginary World
		12.3.5 Intermittent Fasting
	12.4 Conclusion
	References
Part IV Melatonin, Sleep and Clock
13 Sleep Hormone Melatonin, Inflammation and Aging
	13.1 Introduction
	13.2 Aging and Inflammation
	13.3 Melatonin and Aging
	13.4 Regulatory Effects of Melatonin on Aging
		13.4.1 Melatonin Slows Aging Through Antioxidant Function
		13.4.2 Melatonin Delays Aging by Repairing DNA Damage
		13.4.3 Melatonin Promotes Autophagy and Reduces the Accumulation of Harmful Substances During Aging
		13.4.4 Melatonin May Rescue Aging by Inhibiting Hyperactive Sympathetic Nerve Activity
		13.4.5 Melatonin Regulates Infection and Delays Aging by Modulating Gut Microbiota
	13.5 Conclusion
	References
14 Melatonin as a Chronobiotic and Cytoprotector in Healthy Aging
	14.1 Introduction
	14.2 Inflammaging
	14.3 The Circadian Apparatus
	14.4 Melatonin as a Chronobiotic
	14.5 Use of Melatonin in Aged Sleep
	14.6 Melatonin and Inflammaging
	14.7 Melatonin, Sirtuins, and the Anti-inflammatory Network
	14.8 Therapeutic Value of Melatonin in Animal and Clinical Models of Age-Related NCDs
	14.9 Concluding Remarks
	References
15 Melatonin: A Saga of Health and Longevity
	15.1 Introduction
	15.2 Stress and Melatonin
	15.3 Oxidative Stress and Melatonin
	15.4 Melatonin in Immunomodulation
		15.4.1 Melatonin and Immune Cells
		15.4.2 Immunocompetent Cells and Melatonin Receptors
		15.4.3 Anti-inflammatory Potential of Melatonin
	15.5 Melatonin and Metabolic Health
		15.5.1 Melatonin in the Protection of Cardiovascular Health
		15.5.2 Melatonin and Diabetic Nephropathy
	15.6 Bone Health (Osteoporosis and Osteoarthritis) and Melatonin
		15.6.1 Osteoporosis and Melatonin
		15.6.2 Melatonin and Osteoarthritis
	15.7 Life Span Extending Benefits of Melatonin
		15.7.1 Melatonin and Mitochondrial Health
		15.7.2 Melatonin, Circadian Rhythm and Health
	15.8 Phytomelatonin: A Natural Nutraceutical for Health
	References
Part V Genetic Regulation of Sleep and Clock
16 Circadian Rhythm Manipulations: Implications on Behavioral Restoration in Central Nervous System Insults
	16.1 Introduction
	16.2 Circadian Rhythm Manipulation in Human Neurodegenerative Conditions
	16.3 Evidence of Circadian Rhythm Manipulation to Restore Behavior and Cognition in Animal Models
	16.4 Possible Underlying Mechanisms for the Potential Role of Circadian Manipulation on Behavior and Cognition
	16.5 Conclusion
	References
17 Epigenetics of Altered Circadian and Sleep Cycle Induced Effects on Aging and Longevity
	17.1 Introduction
	17.2 Circadian Rhythm: Regulation and Implications in Aging
	17.3 Circadian Control of Sleep
		17.3.1 Sleep Physiology
		17.3.2 Sleep Architecture
		17.3.3 Sleep Cycle Regulation
	17.4 Sleep Dysregulation: Aging and Epigenetics
	17.5 Epigentic Clock Theory and DNA Methylation
	17.6 Heterochromatin Loss Model of Aging
	17.7 Role of Non-coding RNA (NcRNA) in Aging
	17.8 Histone Modifications in Aging Process
		17.8.1 Histone Methylation in Aging
		17.8.2 Histone Acetylation
		17.8.3 Histone Deacetylation: Role of Sirtuins
	17.9 Calorie Restriction: Rhythms and Implications in Aging
	17.10 Sex Differences in Aging Epigenetics
	17.11 Epigenetic Therapeutics
	17.12 Concluding Remarks
	References
18 Chronotype and Its Relation to Healthy Aging
	18.1 Introduction
	18.2 Chronotype and its Distribution among Population
	18.3 Assessing the Chronotype
	18.4 Chronotype and Variability in Biological Variables
	18.5 Determinants of Chronotype
		18.5.1 Endogenous Nature
		18.5.2 Genetic Basis
	18.6 Moderators of Chronotype
		18.6.1 Age and Gender
		18.6.2 Entrainment to Environmental Light/Geographical Region
		18.6.3 Culture/Ethnicity/Work Schedule
	18.7 Chronotype as Determinant of
		18.7.1 Chronotype, Physical Activity and Sleep Health
		18.7.2 Chronotype, Disease and Health Outcomes
		18.7.3 Chronotype and Mental/cognitive Performances
		18.7.4 Chronotype and Social Jetlag (Chronotypes and Circadian Desynchrony)
		18.7.5 Chronotype with Reference to COVID-19 Pandemic
	18.8 Summary and Recommendations
	References
Part VI Therapeutic Interventions in Sleep Disorders and Clock Misalignment
19 Physical Exercise and Circadian Rhythm in Humans
	19.1 Basic Characteristics of the Circadian System in Humans
	19.2 Effects of Single-Bout Exercise on Circadian Rhythm in Humans
	19.3 Effects of Repeated Exercise on the Circadian Rhythm in Humans
	References
20 Circadian Rhythms and Time-Restricted Eating in Healthy Aging and Longevity
	20.1 Introduction
	20.2 Circadian Clock and Its Disruption with Aging
	20.3 Time-Restricted Eating as a Novel Dietary Intervention
		20.3.1 Circadian Rhythms, TRE, and Energy Metabolism
		20.3.2 Time-Restricted Eating to Align with Circadian Rhythms for Healthy Aging
	20.4 Conclusion
	References
21 Achieving Healthy Aging in the Light-Polluted World
	21.1 Introduction
	21.2 Light Pollution—What Does It Mean?
	21.3 Effects of Light Pollution on Human Circadian Organization
		21.3.1 Desynchronization of the Circadian Rhythm by ALAN
		21.3.2 ALAN Affects Pineal Gland Function
		21.3.3 Misalignment of the Circadian System by Light Pollution
	21.4 Light Pollution and Aging
		21.4.1 Examples of Studies Involving Humans
		21.4.2 Examples of Model Studies on Animals
	21.5 Summary and Conclusion
	References
22 Disruptions of Circadian Rhythms and Sleep/Wake Cycles in Neurologic Disorders
	22.1 Introduction
	22.2 Alzheimer’s Disease
	22.3 Parkinson’s Disease
	22.4 Huntington’s Disease
	22.5 Stroke
	22.6 Conclusion
	References
23 Insomnia in the Elderly and Its Treatment
	23.1 Definitions
	23.2 Setting the Scene
		23.2.1 Historical
		23.2.2 Demographics
		23.2.3 Socioeconomic Impact of Insomnia
	23.3 Clinical Parameters
		23.3.1 Diagnostic Tools
		23.3.2 Comorbidities
		23.3.3 Neurobiophysical and Cognitive Background of Insomnia
		23.3.4 Nutrition and Insomnia
		23.3.5 Thermoregulation and Insomnia
		23.3.6 Behavioral and Physiological Conditions at Crosshairs
		23.3.7 COVID-19 Pandemic and Insomnia
	23.4 Therapy: A Broadband of Different Disciplines
		23.4.1 The Light Therapy for Insomnia
		23.4.2 Insomnia Pharmacology
	23.5 Final Note
	References
Part VII Experimental Models to Study Sleep and Clocks in Aging and Longevity
24 Invertebrate and Vertebrate Models in Sleep and Circadian Aging
	24.1 Introduction
	24.2 Changes in Sleep Quality and Circadian Rhythms Across Aging
	24.3 Mice as a Model for Probing Sleep and Circadian Behaviors Across Aging
	24.4 Non-mammalian Models of Sleep
	24.5 Studying Sleep and Circadian Rhythms Across Aging in Zebrafish
	24.6 Invertebrate Models for Sleep and Circadian Research Across Aging
	24.7 Concluding Remarks
	References
25 Melatonin, Circadian Rhythms, and Sleep: An Opportunity to Understand Mechanisms for Protecting Against Neurodegenerative Disease in Drosophila
	25.1 Brief Introduction to Melatonin
	25.2 Melatonin: Phase Marker and Chronobiotic
	25.3 Melatonin’s Role in Sleep
	25.4 A Primer on Reactive Oxygen Species
	25.5 Melatonin: Innerworkings of a Powerful Antioxidant System
	25.6 Melatonin: A Functionally Relevant Antioxidant
	25.7 Melatonin: A Functionally Relevant Antioxidant, Part II
	25.8 Do Discoveries Await in Drosophila?
	25.9 Conclusion
	References