Models, Molecules and Mechanisms in Biogerontology: Cellular Processes, Metabolism and Diseases

Preface
Contents
About the Editor
Part I: Alterations in Cellular Mechanisms During Aging
	1: Protein Structure and Function in Aging and Age-Related Diseases
		Introduction
		Metabolic Pathways and Aging
			TOR-Signaling Network
				mTOR, Protein Synthesis, and Life Span
				Autophagy, mTOR, and Life span
		Posttranslational Modifications of Proteins During Aging
			Phosphorylation
			Methylation
			Deamidation, Racemization, and Isomerization
			Oxidation
			ADP-Ribosylation
		Protein Misfolding, Aggregation, and Associated Diseases
			Neurodegenerative Disorders
				Alzheimer’s Disease
				Parkinson’s Disease
		Protein Turnover During Aging
		Conclusions
		References
	2: DNA, DNA Replication, and Aging
		DNA and Aging
		DNA Replication Stress and Aging
		Telomeres and Aging
		Telomeres, Aging, and Cancer
		DNA Damage and Aging
			Theories of Aging
				Theory of Intrinsic Mutagenesis
				Somatic Mutation Theory of Aging
				The Free Radical Theory of Aging
				DNA Damage Theory of Aging
		Sources and Types of DNA Damage
		DNA Damage and Senescence Pathway
		DNA Repair and Associated Diseases
		DNA Modification and Aging
		DNA Methylation and Aging
		Histone Posttranslational Modification and Aging
		Epigenetics and Age-Related Diseases
		Summary
		References
	3: Transcription and Aging
		Introduction
		A Brief Introduction to Transcription Initiation
		Gene Expression Studies in Yeast
			Replicative Aging
			Chronological Aging
		Aging in Caenorhabditis elegans
		Aging in Drosophila melanogaster
		Aging in Mice
		Aging in Humans
		Transcriptome Heterogeneity During Aging
		Therapeutic Approaches for Aging
		References
	4: Ribosome, Protein Synthesis, and Aging
		Introduction
		Ribosome and the Aging Process
		Age-Related Changes in Protein Synthesis
			Transcriptional Level
			Pre-translational Level
				RNA-Binding Proteins
				Regulation of mRNA Turnover by RNA Granules
				Noncoding RNAs
					Small Noncoding RNAs
					Long Noncoding RNAs
			Translational Level
				Initiation Phase
				Elongation and Termination Phase
		Nonenzymatic Posttranslational Modification of Proteins and Aging
		Signaling Pathways That Regulate Protein Synthesis and Aging
			The TOR Pathway
			The MAPK Pathway
			The Insulin-IGF-1 Pathway
		Aging and Protein Damage
		Hanging in the Balance: Life Span Extension by Regulation of Protein Synthesis
		References
	5: p53 and Aging
		Introduction
		Molecular Mechanisms of Senescence and Aging
			Insulin/IGF-1 Signaling
			TOR Signaling
			AMP Kinase
			Sirtuins
			Inhibition of Respiration
			ROS
			Telomeres
		p53 in Senescence and Aging
			p53 and the IGF-1/mTOR Pathway
			p53 and E2F7
			p53 and Autophagy
			p53 and ROS
			p53 and Mitochondria
			p53 and NF-kB
			p53 and Sirtuins
			p63 and p73
		Conclusion
		References
	6: Paired Box (Pax) Transcription Factors and Aging
		Introduction
		Impact of Pax Family Transcription Factor in Aging
		Conclusion
		References
	7: Telomeres, Telomerase, and Aging
		The Conflict Between Stability and Flexibility
		The End Replication Problem and Replicative Senescence
		Extrinsic Determinants of Lifespan
		Theories of Aging
		Telomeres, Senescence, and Cancer
		The Telomerase Complex
		Telomerase in Stimulated T Cells
		Diseases Resulting from Telomerase Dysfunction
		Telomerase Downregulation May Be a Result of Differentiation Rather than Aging of Myoblasts
		Some Food Supplements and Plant Products Enhance Telomerase Activity
		Multifunctional Complex with Multifunctional Partners
		Anti-apoptotic Proteins and Inhibitor of Apoptosis Protein (IAP) Family
		Telomere Length and Telomerase Activity Measurement
		Telomerase, Telomere, and Redox Homoeostasis
		Stress and Socioeconomic Coordinates of Aging
		Certain Proteins Do Modulate Pluripotency
		GHRH Antagonists Reflect on Association with Telomerase in Younger Mice
		Telomerase RNA Component Variants Influence Telomere Length
		Exposure to Environmental Pollutants Can Retard Telomerase Activity and Reduce Telomere Length
		The Dream Therapeutic Strategy
		Telomerase Has Pleiotropic Regulatory Interaction with Other Cellular Molecules
		References
	8: The Epigenome of Aging
		Introduction
		The DNA Damage Theory of Aging
		The Basis of Epigenetics
			Histone Modifications
			Histone Variants
			ATP-Dependent Chromatin Remodeling Proteins
			DNA Methylation
			Non-Coding RNA
		Disease Models for Aging
			Werner’s Syndrome (WS)
			Hutchinson–Gilford Progeria Syndrome (HGPS)
			Cockayne Syndrome (CS)
			Ataxia-Talengiectsia (A-T)
			Xeroderma Pigmentosum (XP)
			Trichothiodystrophy (TTD)
		The Role of Histone Modifications in Aging
			Loss of Histones and Heterochromatin During Aging
			Histone Acetyltransferases in DNA Damage Repair
			Histone Deacetylases: The Role of Sirtuins in Ageing
			Histone Methylation in Aging
			Histone Variants in Aging
			ATP-Dependent Chromatin Remodeling Proteins and Aging
		DNA Methylation and Aging
		Non-Coding RNA in Aging
			miRNA in Aging
			Role of Long Non-Coding RNA in Aging
		Conclusion
		References
	9: Attaining Epigenetic Rejuvenation: Challenges Ahead
		Epigenetics and Aging
		DNA Methylation and Aging
		Post-Translational Modifications of Histones and Aging
		Histone Acetylation and Aging
		Histone Methylation and Aging
		Other Histone Modifications and Aging
		Generation of Heterochromatin Foci
		Intertwining of DNA Methylation and Histone Modification
		Chromatin Remodelling and Aging
		Histone Variants, Histone Exchange and Aging
		Non-coding RNA and Aging
		Linking Metabolic Reprogramming to Aging Epigenetics
		Caloric Restriction and Metabolic Reprogramming
		Delaying Aging
		Reversal of Aging: Aging Clock Resetting
		Rejuvenation Without Differentiation
		Epigenetic Reprogramming Is the Basis of Epigenetic Rejuvenation
		Epigenetic Signatures of the Aged and Rejuvenated Cells
		Are Aging Signs Reversed by Reprogramming?
		Attaining Epigenetic Rejuvenation: Challenges Ahead
		References
	10: Mitochondria as a Key Player in Aging
		Introduction
		Mitochondrial Cause of Aging
			ROS Generation
			Mitochondrial DNA Damage
			Altered Gene Expression
				Maintenance of Mitochondrial Protein Homeostasis
				Mitochondrial Unfolded Protein Response (UPRmt)
				Mitochondrial Quality Control
			Fission and Fusion
				Mitophagy-Damaged components
		Manifestation of Age-Related Diseases
			Neurodegeneration
			Myopathy
			Cancer
		Conclusion
		References
	11: Aging, Free Radicals, and Reactive Oxygen Species: An Evolving Concept
		Aging: An Overview
		The “Free Radical Theory of Aging”: An Historical Perspective
		Emergence of the “Oxidative Stress Theory of Aging”
		Questioning the “Oxidative Stress Theory of Aging”
		Signaling by Reactive Oxygen Species: A Paradigm Shift
		Role of Signaling by ROS in Aging Process
		Concluding Remarks
		References
	12: Stem Cells and Aging
		Introduction
		Hallmarks of Stem Cell and Organismal Aging
			Stem Cell Pool, Self-Renewal, Quiescence, Terminal Differentiation, and Aging
			Metabolic Stress, ROS Generation, Oxygen Sensitivity, and Mitochondrial Dysfunction
			Telomere Dysfunction
			Epigenetic Alteration
			Age-Dependent Enhancement in Replication Stress in Stem Cells
			Age-Induced Shift in Proteostasis Equilibrium Drives Stem Cell Aging
			Nutrient Sensing and Changes in Nutrition Affect Stem Cell Functions
		Ex Vivo Stem Cell Aging
		Exercise Induces Stem Cell Functions and Slows Down Aging Process
		Role of p53 in Aging of Stem Cells
		Discussion and Conclusions
		References
	13: Can Autophagy Stop the Clock: Unravelling the Mystery in Dictyostelium discoideum
		What Is Aging and Longevity?
		Longevity in Different Model Systems
		Autophagy and Longevity
		Increased Autophagy Delays Aging and Increases Lifespan
		How Longevity Is Studied in Different Model Systems
		Drugs That Influence Longevity
		How D. discoideum as a Model Organism Overcomes These Limitations
		Life Cycle of D. discoideum
		Autophagy in D. discoideum
		Signaling Pathways Involved in Autophagy in D. discoideum
		D. discoideum to Study Longevity
		Monitoring Autophagic Flux in D. discoideum
		Other Molecules Involved in Autophagy-Mediated Longevity in D. discoideum
		Conclusions
		References
	14: Aging: Reading, Reasoning, and Resolving Using Drosophila as a Model System
		Introduction
		Drosophila melanogaster as a Model Organism for Aging Research
			Drosophila in Aging Research: An Overview
			Evaluating Aging in Drosophila
				Environmental and Physiological Approaches
					Analyzing Demographics
					Dietary Restriction
					Stress Resistance
					Reproductive Output
				Behavioral Approaches
					Rapid Iterative Negative Geotaxis (RING) Assay
					Drosophila Activity Monitoring (DAM) System
				Genetic Approaches
				Cellular, Molecular, Biochemical, and Other Approaches
		Cellular Pathways Affecting Aging in Drosophila
			Genomic Instability
			Defects in Nuclear Architecture
			Telomere Abrasion
			Nuclear–Mitochondrial (NM) Signaling in Aging
			Oxidative Stress
				What Does Oxidative Stress Do?
				Effect of Oxidative Stress on Cellular Components
				Signaling Cascades Activated by ROS
			Proteostasis Loss During Aging
			Molecular Chaperones Facilitated Protein Folding
			Impact of Epigenetic Changes on Aging
				DNA Methylation
				Histone Modification with Aging
				Noncoding RNAs
			Dietary Restriction
			Insulin Signaling/mTOR Network
		Aging-Associated Diseases
		Antiaging Drugs and Natural Products
		Concluding Remarks
		References
	15: Nothobranchius furzeri as a New Model System for Ageing Studies
		Model Organisms in Ageing Research
		Nothobranchius furzeri as an Experimental Model
		Nothobranchius furzeri as Experimental Ageing Model
		Nothobranchius furzeri as a Model for Evolutionary Genetics of Ageing
		Nothobranchius furzeri and Longitudinal Analysis
		Nothobranchius furzeri and Quantitative Genetics of Ageing
		References
Part II: Alterations in Metabolism During Aging and Diseases
	16: Aging in Muscle
		Introduction
		Changes in Skeletal Muscle during Aging
			Morphological Changes
			Fiber-Type Distribution
			Neuromuscular Junction
			Adipocyte Accumulation
			Vascularization
		Changes in Cardiac Muscle during Aging
			Morphological Changes
			Vascularization
			Contractile Capacity
		Sex-Specific Differences in Muscle Aging
		Aging and Insulin Resistance
			Insulin Signaling and Glucose Uptake
			Diabetes and Skeletal Muscle Insulin Resistance
			Lipid Accumulation and Muscle Insulin Resistance
		Role of Mitochondria in Muscle Aging
			Mitochondrial Content, Morphology, and Metabolism
			Mitochondrial Plasticity in Aging Skeletal Muscle
		Inflammatory Processes and Cytokines in Muscle Aging
		Fibroblast in Muscle Aging
		Muscle Plasticity and Regeneration
		Role of Satellite Cells and Aging
		Using Exercise and NEAT to Counter Muscle Aging
		Targeting Noncontractile Metabolism to Counter Muscle Aging
		Suggested Reading
			Books and book chapters
			Research Article
	17: Metabolic Diseases and Aging
		Introduction
		Metabolic Syndrome and Aging
		Metabolism and Cell Aging
		Tissue-Specific Metabolic Disorder and Aging
			CNS/Brain and Aging
			Cardiovascular Complications and Aging
			Peripheral Vascular Disease
			Respiratory Complications and Aging
		Metabolic Process Linked to Diseases and Aging
			Alteration of Body Composition and Aging
			Abnormal Endocrine Function
			Decline in Cellular Antioxidant Capacity and Aging
			Decline in Mitochondrial Function and Aging
			Increase in Advanced Glycation End Products (AGEs) and Aging
			AGEs and Organ/Tissue Complications
			AGEs and Skeletal Tissues
			AGEs and Lens
			AGEs and Cornea/Vitreous
			Retina
		Proteasome and Aging
		Metabolic Signaling Networks and Aging
		Hormonal Signaling
			Insulin/Insulin-Like Signaling and Metabolic Diseases
			Insulin Signaling and Action
			Insulin Receptor
			Paradox of Insulin Resistance and Aging
			Insulin Resistance and Metabolic Diseases
			IRS1 and IRS2 in Metabolic Diseases
			IRS1/IRS2 in PI3K/Akt/MAP Kinase-Regulated Metabolic Diseases
			PI3K/Akt/Foxo1 in Metabolic Diseases
			Insulin Resistance by Hyperinsulinemia
			Insulin Resistance and Foxo1 Activation
		Insulin Resistance and Metabolic Diseases
			Insulin Resistance in CNS and Obesity
			Insulin Resistance in Adipose Tissue and Inflammation
			Insulin Resistance in Liver and Hyperglycemia
			Insulin Resistance in Cardiac Tissues and Heart Failure
			Insulin Resistance in Pancreas and β-Cell Regeneration
			Insulin Resistance in Skeletal Muscle Tissue and Shortened Lifespan
			Insulin Resistance in Vascular Endothelium and Glucose Homeostasis
			Insulin Resistance in Bone and Glucose Homeostasis
		Neurohormonal Regulation
			Renin-Angiotensin-Aldosterone System (RAAS)
			Adrenergic Signaling
			Growth Hormone Signaling
			Klotho Signaling
			Steroid Signaling
		Akt/mTOR Signaling and Metabolic Diseases
			Mitochondria and ROS Signaling
		Genome Surveillance Pathways
			DNA Repair and Telomere Pathways
			Telomere Length in Metabolic Disease
			Telomere Length in Diabetes
			Telomere Length in Cardiovascular Disease and Diabetes
		Metabolic Strategies to Delay Aging
			Regular Exercise
			Caloric Restriction
			Restoration of Cellular Antioxidants and Attenuated Oxidative Stress
			Pharmacological Intervention
			Reduced Somatotropic Signaling
			Attenuation of mTOR Signaling
			Anti-AGEs Therapeutic Strategies
			Stem Cells and the Promise of Pancreas Regeneration
		Future Direction and Conclusion
		References
	18: Interplay Between Nutrient-Sensing Molecules During Aging and Longevity
		Introduction
		Amino Acid Sensing
			GCN2 Senses Amino Acid Starvation
			mTOR Senses Amino Acid Abundance
		Lipid Sensing
		Glucose Sensing
		Energy Sensing
			AMPK Senses AMP/ATP
			Sirtuins Sense NAD+/NADH Level
		Nutrient-Sensing Molecules, Aging, and Dietary Restriction
		Conclusion
		References
	19: Protein Aggregation, Related Pathologies, and Aging
		Protein Aggregation and Related Diseases
		Neurodegenerative Diseases
			Alzheimer’s Disease
			Prion Diseases
			Polyglutamine Diseases
			Parkinson’s Disease
		Nonneurodegenerative Amyloid Diseases
			Type II Diabetes
			Cataract
			Nonneuropathic Systemic Amyloidosis
		Does Coaggregation of Proteins Exist in Biology?
		Mechanism of Protein Aggregation
		Strategies to Target Protein Aggregation Process
		The Relationship Between Aging and Protein Aggregation
		Conclusions
		References
	20: Biological Rhythms and Aging
		Biological Rhythms
		Circadian Rhythms
		Circadian Time-Keeping System (CTS)
			Input Pathways to the SCN
			Output Pathways from the SCN
			Molecular Mechanisms
		Aging and Theories of Aging
		Age-Associated Circadian Dysfunction
			Influence of Aging on Central and Peripheral Clocks
			Influence of Aging on Clock Genes and Proteins
		Therapeutic Interventions
		Effect of Antioxidants on Aging and CTS
		Effect of Calorie Restriction (CR) on Aging and CTS
		Effect of Small Molecules as Modulators in Aging and CTS
		Conclusion
		References
	21: The Biology of Aging and Cancer: A Complex Association
		Introduction
		Aging and Its Hallmarks
		Causes of Aging
		Aging and Senescence
		Potential Animal Models for Investigating Connections Between Aging and Cancer
		Cancer and Its Incidences with Aging
		Common Biology of Cancer and Aging
			Telomere Shortening
			Genomic Instability
			Senescence
			Senescence in Cancer and Aging
			Epigenetic Modifications
			Metabolism
			Autophagy and Apoptosis
		Interplay Between Cancer and Aging
		Factors Influencing Cancer Incidence with Age
			Accumulation of Damaged Macromolecules
			Carcinogen Exposure
			Senescence
			Immune Senescence
			Hormones
			Activation of INK4 Locus
			Angiogenesis
		Molecular Events Involved in Aging and Cancer
			Signaling Pathways Involved in Aging and Cancer
			Role of Oxidative Stress in Cancer and Aging
			Deterioration of Immune System with Aging
			Role of p53 in Aging and Cancer
			Insulin/IGF1 Signaling Is Intricate to Aging and Cancer
			Nutrient Signaling
		Role of Stem Cells in Aging and Cancer
		Conclusions
		References