Bondy / Maiese Aging and Age-Related Disorders

1. Auflage 2010
ISBN: 978-1-60761-602-3
Verlag: Humana Press
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 472 Seiten

Features that characterize the aging process include the gradual accumulation of cell damage after prolonged exposure to oxidative and inflammatory events over a lifetime. In addition to the accretion of lesions, the intrinsic levels of pro-oxidant and aberrant immune responses are elevated with age. These adverse events are often further enhanced by the chronic and slow progressing diseases that characterize the senescent brain and cardiovascular system. The incidence of some disorders such as Alzheimer's disease and vascular diseases are sufficiently prevalent in the extreme elderly that these disorders can arguably be considered "normal". Aging and Aging-Related Disorders examines the interface between normal and pathological aging, and illustrates how this border can sometimes be diffuse. It explores and illustrates the processes underlying the means by which aging becomes increasingly associated with inappropriate levels of free radical activity and how this can serve as a platform for the progression of age-related diseases. The book provides chapters that examine the interactive relationship between systems in the body that can enhance or sometimes even limit cellular longevity. In addition, specific redox mechanisms in cells are discussed. Another important aspect for aging discussed here is the close relationship between the systems of the body and exposure to environmental influences of oxidative stress that can affect both cellular senescence and a cell’s nuclear DNA. What may be even more interesting to note is that these external stressors are not simply confined to illnesses usually associated with aging, but can be evident in maturing and young individuals. A broad range of internationally recognized experts have contributed to this book. Their aim is to successfully highlight emerging knowledge and therapy for the understanding of the basis and development of aging–related disorders.

Autoren/Hrsg.

Bondy, Stephen

Maiese, Kenneth

Inhaltsverzeichnis

1;Preface;5
2;Contents;7
3;Contributors;10
4;Part I General Aspects of Aging;15
4.1;Protein Redox-Regulation Mechanisms in Aging;16
4.1.1;1 Introduction;17
4.1.2;2 Postmitotic Aging and Redox Homeostasis;18
4.1.3;3 Redox-Regulation Pathways and Repair of Proteins;21
4.1.3.1;3.1 General Principles;21
4.1.3.2;3.2 Intracellular Mechanisms;23
4.1.3.2.1;3.2.1 Role of Thiol-Based Repair Systems;23
4.1.3.2.2;3.2.2 The Roles of Proteasome, Ubiquitin, and SUMO;24
4.1.3.2.3;3.2.3 The Roles of Mitochondrial Antioxidant Systems and of ATP-Dependent Proteases;26
4.1.3.3;3.3 Extracellular Mechanisms;27
4.1.4;4 Altered Redox-Regulation Pathways and Age-Related Disorders;28
4.1.4.1;4.1 Role of Thiol-Based Repair Systems;29
4.1.4.1.1;4.1.1 In Alzheimer's Disease;30
4.1.4.1.2;4.1.2 In Parkinson's Disease;30
4.1.4.1.3;4.1.3 In Cataracts;30
4.1.4.1.4;4.1.4 In Diabetes;31
4.1.4.2;4.2 The Roles of Proteasome, Ubiquitin, and SUMO;31
4.1.4.2.1;4.2.1 In Alzheimer's Disease;32
4.1.4.2.2;4.2.2 In Parkinson's Disease;33
4.1.4.2.3;4.2.3 In Cataracts;33
4.1.4.2.4;4.2.4 In Diabetes;33
4.1.5;5 Concluding Remarks;34
4.1.6;References;34
4.2;Nitrosative Stress in Aging -- Its Importance and Biological Implications in NF-B Signaling;39
4.2.1;1 Introduction;40
4.2.1.1;1.1 The Oxidative Stress Hypothesis of Aging -- Historical Account;40
4.2.1.2;1.2 The Concept of Nitrosative Stress;43
4.2.2;2 Reactive Nitrogen Species and Nitrosative Stress;44
4.2.2.1;2.1 First Come Definitions;44
4.2.2.1.1;2.1.1 “Nitrosation” and “Nitrosylation” – It Obviously Needs SomeClarification;44
4.2.2.2;2.2 Reactive Nitrogen Species -- Chemistry and Availability;45
4.2.2.3;2.3 Nitrosylation and Nitration Are Mediators of Cell Signaling;46
4.2.2.3.1;2.3.1 Nitrosylation;46
4.2.2.3.2;2.3.2 Nitration;47
4.2.3;3 NF-B, Aging, and Nitrosative Stress;48
4.2.3.1;3.1 NF-.B Signaling;48
4.2.3.2;3.2 NF-.B Signaling Increases in Aging;49
4.2.3.3;3.3 Nitration of Proteins Increases with Aging -- Tyrosine Nitration;50
4.2.3.4;3.4 NF-.B Signaling and Skeletal Muscle Atrophy;51
4.2.3.5;3.5 Loss of Skeletal Muscle in Old Age Is Associated with Increased Nitration of Muscle Proteins and NF- B Activation;52
4.2.3.6;3.6 Peroxynitrite-Induced Tyrosine Nitration of I B Causes NF- B Activation;53
4.2.3.7;3.7 Nitration by Peroxynitrite and NF- -- B Activation Is Supported by Proinflammatory Conditions -- Link to Inflamm-aging;54
4.2.3.8;3.8 Thus, Is NF-.B a Signaling Mediator of Aging?;56
4.2.4;4 Summary and Conclusions;57
4.2.5;References;58
4.3;Intervention with Multiple Micronutrients Including Dietaryand Endogenous Antioxidants for Healthy Aging;67
4.3.1;1 Introduction;68
4.3.2;2 Oxidative Stress During Aging;69
4.3.3;3 Oxidative Stress Influencing Mitochondria, Lysosome, and Proteosome Function During Aging;71
4.3.4;4 Oxidative Stress Influencing the Length of Telomere During Aging;72
4.3.5;5 Chronic Inflammation During Aging;73
4.3.6;6 Aging Influencing Immune Function;74
4.3.7;7 Aging Influencing Antioxidant Defense Systems;74
4.3.8;8 Antioxidant Supplementation Influencing Age-Related Functional Deficits;78
4.3.9;9 Rationale for Using Multiple Dietary and Endogenous Antioxidants in Age-Related Functional Deficits;80
4.3.10;10 Changes in Diet and Lifestyle;82
4.3.11;11 Summary and Conclusions;82
4.3.12;References;83
4.4;Advanced Glycation End Products, RAGE, and Aging;91
4.4.1;1 Introduction;91
4.4.2;2 AGEs, Oxidant Stress, and Inflammation;92
4.4.3;3 AGE and AGEing Hypothesis;93
4.4.3.1;3.1 AGEs in Brain;94
4.4.3.2;3.2 AGE--RAGE, Aging, and the Heart;95
4.4.3.3;3.3 Nutritional and Therapeutic Approaches to Limit AGEs;96
4.4.4;4 Conclusions;96
4.4.5;References;97
4.5;Sirtuins and Mammalian Aging;103
4.5.1;1 Introduction;104
4.5.1.1;1.1 Aging and Longevity;104
4.5.1.2;1.2 Sirtuin Function and Longevity;105
4.5.2;2 Sirtuins: Localization, Substrates, and Functions;110
4.5.2.1;2.1 Sirt1;110
4.5.2.2;2.2 Sirt2;111
4.5.2.3;2.3 Sirt3;112
4.5.2.4;2.4 Sirt4;112
4.5.2.5;2.5 Sirt5;113
4.5.2.6;2.6 Sirt6;113
4.5.2.7;2.7 Sirt7;114
4.5.3;3 Sirtuins in Aging-Related Processes;115
4.5.3.1;3.1 Immunity, Inflammation, and Aging;115
4.5.3.2;3.2 Autophagy;115
4.5.4;4 Sirtuins in Aging-Associated Degenerative Diseases;116
4.5.4.1;4.1 Type 2 Diabetes and Metabolic Syndrome;116
4.5.4.2;4.2 Alzheimer's Disease;117
4.5.4.3;4.3 Age-Related Macular Degeneration;118
4.5.4.4;4.4 Cardiovascular Disease;118
4.5.4.5;4.5 Stroke;118
4.5.4.6;4.6 Cancer;119
4.5.4.7;4.7 Sarcopenia;120
4.5.5;5 Conclusions;121
4.5.6;Glossary;121
4.5.7;References;122
4.6;Estrogenic Modulation of Longevity by Inductionof Antioxidant Enzymes;130
4.6.1;1 Mitochondria as Sources and Targets of Age-Associated Damage;131
4.6.2;2 Difference in Oxidative Stress in Aging Expressed a Differential Longevity Between Genders;132
4.6.3;3 Telomerase Is a Longevity-Associated Gene Regulated by Estrogens;134
4.6.4;4 Differential Longevity Between Genders: A Methodological Approach;136
4.6.5;5 Concluding Remarks;137
4.6.6;References;138
4.7;Mitochondrial Respiratory Function Decline in Agingand Life-Span Extension by Caloric Restriction;140
4.7.1;1 Introduction;141
4.7.2;2 Mitochondrial Function Decline During the Aging Process;142
4.7.2.1;2.1 Production of ATP and ROS in Human and Animal Cells;142
4.7.2.2;2.2 Accumulation of Mitochondrial DNA Mutation in Aged Tissues;142
4.7.2.3;2.3 Bioenergetic Function Decline of Mitochondria During Aging;144
4.7.2.4;2.4 Mitochondrial Dysfunction in Age-Related Diseases;147
4.7.3;3 Age-Associated Alterations in Gene Expression and Protein Modification;147
4.7.4;4 The Role of Sirt1 in Life-Span Extension by Caloric Restriction;149
4.7.4.1;4.1 Sirtuins in the Life-Span--Extending Effect of Caloric Restriction;149
4.7.4.2;4.2 The Regulation of Mitochondrial Function and Life Span by Sirt1;149
4.7.4.3;4.3 Other Sirtuins in Regulation of Mitochondrial Function;150
4.7.4.4;4.4 Therapeutic Agent Targeting Sirtuins in Age-Related Diseases;151
4.7.5;5 Conclusions;151
4.7.6;References;152
4.8;Methylglyoxal, Oxidative Stress, and Aging;160
4.8.1;1 Introduction;160
4.8.2;2 Methylglyoxal Metabolism;162
4.8.3;3 Free Radical Theory of Aging;163
4.8.4;4 Methylglyoxal and Oxidative Stress;166
4.8.4.1;4.1 Methylglyoxal and Superoxide Anion Formation;166
4.8.4.2;4.2 Methylglyoxal and Hydrogen Peroxide Production;167
4.8.4.3;4.3 Methylglyoxal and Nitric Oxide/Peroxynitrite Production;167
4.8.4.4;4.4 Methylglyoxal and p38 MAPK;167
4.8.4.5;4.5 Methylglyoxal and Activation of NF-B;168
4.8.4.6;4.6 Methylglyoxal, Antioxidant Enzymes, and Reduced Glutathione;168
4.8.5;5 Methylglyoxal, Oxidative Stress, and Aging;169
4.8.6;6 Prevention of Methylglyoxal-Induced Aging;170
4.8.7;7 Conclusions;171
4.8.8;References;172
5;Part II The Cardiovascular System;179
5.1;Novel Strategies for Neurovascular Longevity During Aging;180
5.1.1;1 Introduction;181
5.1.1.1;1.1 Aging and Oxidative Stress;181
5.1.2;2 FoxOs;183
5.1.2.1;2.1 Background, Expression, and Regulation of FoxOs;183
5.1.3;3 Erythropoietin;187
5.1.3.1;3.1 Background, Structure, and Expression for EPO;187
5.1.3.2;3.2 Cellular Signaling for EPO and the EPO Receptor;188
5.1.4;4 FoxOs, EPO, and the Control of Cell Injury;189
5.1.5;5 FoxOs, EPO, and the Immune System;190
5.1.6;6 FoxOs, EPO, Stems Cells, and Tissue Development;192
5.1.7;7 FoxOs, EPO, Diabetes, and Metabolic Pathways;194
5.1.8;8 Clinical Strategies and Future Perspectives;197
5.1.9;References;201
5.2;Oxidative Stress in Vascular Disease;219
5.2.1;1 Introduction;220
5.2.2;2 Lipoprotein Oxidation in Atherosclerosis;222
5.2.3;3 Oxidants in the Vascular Wall;223
5.2.4;4 Role of Redox Enzymes in Vascular Disease;224
5.2.4.1;4.1 NADPH Oxidase;224
5.2.4.2;4.2 Xanthine Oxidase;225
5.2.4.3;4.3 Endothelial Nitric Oxide Synthase;226
5.2.4.4;4.4 Myeloperoxidase;226
5.2.4.5;4.5 Lipoxygenases;226
5.2.4.6;4.6 Antioxidants;227
5.2.5;5 Role of Reactive Species in Mechanical and Shear Stress;227
5.2.6;6 Role of Mitochondria in Vascular Disease;228
5.2.7;7 Oxidative Stress, Telomere Length, and Senescence;229
5.2.8;8 DNA Damage in Vascular Disease;231
5.2.9;9 Antioxidants and Cardiovascular Diseases;233
5.2.10;10 Conclusions;234
5.2.11;References;235
5.3;The Role of Mitochondrial Reactive Oxygen Species Formation for Age-Induced Vascular Dysfunction;244
5.3.1;1 Introduction;244
5.3.2;2 The Cardiovascular System;245
5.3.2.1;2.1 Vascular Function and Oxidative Stress;246
5.3.2.2;2.2 The Nitric Oxide/Superoxide System;248
5.3.2.3;2.3 Cross-Talk Between Mitochondrial and NADPH Oxidase--Generated Reactive Nitrogen and Oxygen Species;249
5.3.3;3 Clinical Background;251
5.3.4;4 Aging;253
5.3.4.1;4.1 Aging and Oxidative Stress;253
5.3.4.2;4.2 Aging and Mitochondrial DNA;253
5.3.4.3;4.3 Aging, Mitochondrial Oxidative Stress, and Endothelial Dysfunction;254
5.3.4.4;4.4 Futile Counterregulation by Enhanced Gene Expression of Oxidant Defense Mechanisms;255
5.3.5;5 Recent Developments in Aging Concepts;258
5.3.6;6 Perspective;259
5.3.7;References;259
5.4;Aging, Oxidative Stress, and Cardiovascular Disorders;265
5.4.1;1 Background;265
5.4.2;2 Free Radical Theory of Aging;266
5.4.3;3 Imbalance Between Oxygen-Derived Free Radicals and Antioxidative Defense in Aging;267
5.4.4;4 Age-Induced Oxidative Stress and Vascular Dysfunction;267
5.4.5;5 Aging-Related Genes: p66Shc;268
5.4.6;6 p66Shc: Role in Aging and Age-Related CardiovascularDiseases;269
5.4.7;7 Aging-Related Gene: Sirt1;272
5.4.8;8 Sirt1: Role in Aging and Age-Related Cardiovascular Diseases;273
5.4.9;9 Environmental Factors Affecting Life Span;274
5.4.9.1;9.1 Caloric Restriction;274
5.4.9.2;9.2 Physical Exercise;274
5.4.9.3;9.3 Antioxidant Treatment;275
5.4.9.4;9.4 Resveratrol;275
5.4.10;10 Summary and Conclusions;275
5.4.11;References;276
5.5;Oxidative Stress, Aging, and Cardiovascular Disease;282
5.5.1;1 Introduction;282
5.5.2;2 Oxidative Stress;283
5.5.3;3 Free Radicals;284
5.5.3.1;3.1 Production;287
5.5.3.2;3.2 Damaging Reactions;288
5.5.3.3;3.3 Defense: Antioxidants;290
5.5.4;4 Free Radicals and Aging;292
5.5.5;5 Oxidative Stress and Cardiovascular Diseases;293
5.5.6;6 Atherosclerosis;294
5.5.7;7 Conclusions;297
5.5.8;References;298
5.6;Antioxidation in Prevention of CardiovascularDiseases -- An Effect of Polyphenols;302
5.6.1;1 Introduction;302
5.6.2;2 Catechins Suppress Oxidative Stress in Myocardial Ischemia;304
5.6.3;3 Catechins Suppress Oxidative Stress in Myocarditis;305
5.6.4;4 Catechins Suppress Oxidative Stress in Transplant Rejection;306
5.6.5;5 Summary and Future Direction;307
5.6.6;References;308
5.7;Vascular Aging and Oxidative Stress: HormesisINTbreak; and Adaptive Cellular Pathways;313
5.7.1;1 Introduction;314
5.7.1.1;1.1 Aging: Different Theories of Aging;314
5.7.1.2;1.2 Cellular Aging or Cellular Senescence;315
5.7.1.3;1.3 Vascular Endothelial Aging;317
5.7.1.4;1.4 Hormesis in Aging;319
5.7.2;2 Summary and Conclusions;320
5.7.3;References;321
5.8;Role of Oxidative Stress in Mediating Elevated Blood Pressure with Aging;326
5.8.1;1 Introduction;326
5.8.2;2 The Role of Oxidative Stress in Control of Blood Pressure;327
5.8.2.1;2.1 Blood Pressure, Oxidative Stress, and the Kidney;327
5.8.2.2;2.2 Sex Differences in Oxidative Stress;329
5.8.2.3;2.3 Postmenopausal Hypertension;331
5.8.3;3 Studies in Aging Animals Linking Oxidative Stress and Blood Pressure;331
5.8.3.1;3.1 Studies in Spontaneously Hypertensive Rats;331
5.8.3.2;3.2 Measurement of Oxidative Stress;332
5.8.3.3;3.3 Measurement of Antioxidant Enzyme Expression;332
5.8.3.4;3.4 Functional Studies to Evaluate the Role of Oxidative Stress on Blood Pressure in SHR;333
5.8.3.5;3.5 Studies to Mimic Endothelial Dysfunction in Aging;335
5.8.3.6;3.6 Lack of Tools to Study ROS and Blood Pressure Regulation;335
5.8.4;4 Summary and Conclusions;336
5.8.5;References;336
6;Part III The Nervous System;340
6.1;Melatonin, Oxidative Stress, and the Aging Brain;341
6.1.1;1 Introduction;341
6.1.1.1;1.1 Oxidative Stress and Brain Aging;342
6.1.1.2;1.2 Inflammation and the Aged Brain;342
6.1.1.3;1.3 Mitochondrial Dysfunction and Brain Aging;343
6.1.2;2 The Treatment of Chronic Neurodegenerative Disorders;344
6.1.2.1;2.1 The Potential Retardation of Brain Aging by Melatonin;345
6.1.2.1.1;2.1.1 Melatonin and Overall Phenotypic Aging;346
6.1.2.1.2;2.1.2 Specific Effects of Melatonin on Events Relating to Brain Aging;346
6.1.2.1.3;2.1.3 The Potential for Melatonin Treatment of Specific Neurologic Disease;346
6.1.3;3 Processes That May Underlie the Ability of Melatonin to Modulate the Aging Process;347
6.1.3.1;3.1 Melatonin as an Antioxidant;347
6.1.3.2;3.2 The Role of Melatonin in the Regulation of Immune Function;348
6.1.3.3;3.3 Melatonin Receptors and Enzyme Induction;348
6.1.3.4;3.4 The Link Between Aging and Circadian Events;349
6.1.3.5;3.5 Melatonin and Mitochondria;350
6.1.3.6;3.6 Summary of Mechanisms of Melatonin Action and Suggestions for Future Work;350
6.1.4;4 Conclusions;351
6.1.5;References;352
6.2;The SAM Strain of Mice, a Higher Oxidative Stress,Age-Dependent Degenerative Disease, and SenescenceAcceleration Model;360
6.2.1;1 The SAM Strain of Mice Is a Unique Model for Senescence Acceleration;361
6.2.1.1;1.1 A Brief History of the Development of SAM Strains of Mice -- A Mechanism to Generate Mice;361
6.2.1.2;1.2 Accelerated Senescence and SAM Mice;362
6.2.2;2 The SAM Strain of Mice Is a Unique Model for Several Age-Dependent Disorders;363
6.2.2.1;2.1 The SAM Strain of Mice Is a Model for Age-Associated Disorders;364
6.2.2.2;2.2 Age-Dependent Degenerative Change of Tissues in SAMP Mice;365
6.2.3;3 SAMP Strains of Mice Show a Higher Oxidative Stress Status as a Unique Biological Characteristic;366
6.2.3.1;3.1 A Higher Oxidative Stress Status is a Primary Characteristic of SAMP Strains of Mice;366
6.2.3.2;3.2 Mitochondrial Dysfunction Is Observed in SAMP Mice;367
6.2.3.3;3.3 A Higher Oxidative Stress Status Is a Possible Cause of Senescence Acceleration and Degeneration of Cells in SAMP Mice;369
6.2.4;4 Interventions of Mitochondrial Dysfunction, Senescence Acceleration, and Age-Dependent Disorders;371
6.2.4.1;4.1 Interventions of Senescence Acceleration and Age-Dependent Disorders;371
6.2.4.2;4.2 Improvements in Mitochondrial Dysfunction;372
6.2.5;5 Conclusions;373
6.2.6;References;373
6.3;Antioxidants Combined with Behavioral Enrichment Can Slow Brain Aging;381
6.3.1;1 Introduction;382
6.3.2;2 Antioxidants and Healthy Brain Aging;382
6.3.3;3 Behavioral Enrichment and Healthy Brain Aging;384
6.3.4;4 Antioxidants and Behavioral Enrichment in the Canine Model of Human Aging;385
6.3.4.1;4.1 Neurobiological and Cognitive Features of the Aged Dog;385
6.3.4.2;4.2 Cognitive Benefits of Antioxidants and Behavioral Enrichment in Aged Dogs;386
6.3.4.3;4.3 Neurobiological Changes in Response to Antioxidants and Behavioral Enrichment;387
6.3.5;5 Summary and Conclusions;388
6.3.6;References;388
6.4;Role of Nitric Oxide in Neurodegeneration and Vulnerabilityof Neuronal Cells to Nitric Oxide Metabolites and ReactiveOxygen Species;398
6.4.1;1 Introduction;399
6.4.1.1;1.1 Neuronal Death and Survival Under Oxidative Stress in AD and PD;399
6.4.1.2;1.2 Superoxide and NO in Senescence and Aging;400
6.4.1.3;1.3 Role of Reactive Oxygen Species and Reactive Nitrogen Species in Oxidative and Nitrosative Stress and in Aging;400
6.4.1.4;1.4 Role of NO in Aging, AD, Obesity, and Heart Disease;400
6.4.1.5;1.5 Role of NO and Cellular Stress Response in Brain Aging and Neurodegenerative Disorders;401
6.4.1.6;1.6 Interplay Between Superoxide and NO in Aging and Diseases via Many Physiologic Functions;401
6.4.2;2 NO and Its Physiologic Role;401
6.4.2.1;2.1 Aß, NO, and Synaptic Plasticity;402
6.4.2.2;2.2 Aß Fragment Impairs Memory and IncreasesNO in the Temporal Cortex of Rats;403
6.4.3;3 The Vulnerability of Different Cell Types to ROS and RNS Insults;403
6.4.4;4 Use of SNP to Study the Susceptibility of Different Cell Types Toward Free Radicals;404
6.4.5;5 Different Cell Types Generate NOx Differently When Treated with SNP;404
6.4.5.1;5.1 Increased Levels of NOx Release in SNP-Treated Astrocytic and Epithelial Cell Lines;404
6.4.5.2;5.2 Reduced Levels of NOx Release in SNP-Treated Neuronal Cell Lines;405
6.4.6;6 SNP-Induced Cell Death;406
6.4.7;7 NOS in Different Cell Types;406
6.4.7.1;7.1 Lack of NOS Activity in U-138, C6, and HeLa Cells;406
6.4.7.2;7.2 Presence of NOS Activity in N1E-115 Cells;406
6.4.7.3;7.3 Inhibition of NOS Activity by SNP;407
6.4.8;8 Effects of Different Agents on NOx Production and LDH Release in Astrocytic Cells;407
6.4.8.1;8.1 High Dose of IL-1ß Decreased Nitrite Production in C6 CellsWhen Stimulated with SNP;407
6.4.8.2;8.2 Inhibition of NOx Release with Carboxyl-PTIO Treatment;407
6.4.8.3;8.3 Inhibition of NOx Release with SOD-1 Treatment;408
6.4.8.4;8.4 L-NAME Treatment Did Not Change the Release of NOx Release;408
6.4.9;9 Pathway of NOx Production in Various Cell Types;408
6.4.10;10 Mechanism of NOx Production from SNP;409
6.4.11;11 Levels of NOx and Cellular Viability;410
6.4.12;12 Protective Cellular Mechanism to Reduce the SNP-Induced Toxicity;410
6.4.13;13 Relationship Between the Enzymatic and Nonenzymatic Pathways of NO Release;411
6.4.14;14 Cellular Participation for the Generation of NOx;411
6.4.15;15 Role of Melatonin in the Inhibition of NOx Release;411
6.4.16;16 Relationship Between NO Metabolites, Antioxidants, and AD;412
6.4.17;References;412
6.5;Free RadicalMediated Damage to Brain in Alzheimers Disease: Role of Acrolein and Preclinical Promise of Antioxidant Polyphenols;415
6.5.1;1 Introduction;415
6.5.1.1;1.1 Free Radical'Mediated Damage to Brain During Aging and in Alzheimer's Disease;415
6.5.2;2 Markers of Free RadicalMediated Damage in Transgenic Mouse Models;419
6.5.3;3 Acrolein as a Potential Inducer of Oxidative Stress and Its Role in AD;421
6.5.4;4 Dietary Antioxidants and Risk of AD: Mechanisms of Action;424
6.5.5;5 Conclusions;428
6.5.6;References;429
6.6;An Epigenetic Model for Susceptibility to Oxidative DNAINTbreak; Damage in the Aging Brain and Alzheimer's Disease;436
6.6.1;1 Introduction;436
6.6.2;2 Epigenetics and AD;437
6.6.3;3 Oxidative Stress and AD;438
6.6.4;4 Exposure to Lead and the Developmental Basis of AD;439
6.6.5;5 Epigenetics, the Environment, and Load;440
6.6.6;6 DNA Methylation and DNA Oxidation;442
6.6.7;7 Summary and Conclusions;444
6.6.8;References;445
6.7;Index;451