Comparative Biology of Aging (eBook)

Contents 5
Contributors 7
Introduction: Lifespans and Pathologies Present at Death in Laboratory Animals 10
Laboratory Strains of Yeast (Saccharomyces cervisiae) Wild Type Only 10
Laboratory Round Worm (Caenorhabditis elegans) 11
Laboratory Fruit Fly (Drosophila melanogaster) 13
Laboratory Mouse (Mus musculus) 13
Laboratory Rat (Ratus norvegicus) 16
Naked Mole-Rat (Heterocephalus glaber) 22
Domestic Dog (Canis familiaris) 24
Rhesus Monkey (Macaca mulata) 25
Baboon (Papio hamadryas) 26
Human (Homo sapiens) 27
Little Brown Bat (Myotis lucifugus) 28
Budgerigar (Melopsittacus undulatus) 29
Quail (Coturnix spp.) 29
Zebra Fish (Danio rerio) 30
Amphibians 30
References 30
Animal Size, Metabolic Rate, and Survival, Among and Within Species 36
Body Size and Interspecific Variation in Mammalian Longevity 37
Body Size and Intraspecific Variation in Mammalian Longevity 43
Conclusions 47
References 47
Hormonal Influences on Aging and Lifespan 51
Introduction 51
C. elegans 52
Drosophila 56
Yeast 58
Mammals 59
Growth Hormone 59
Insulin-Like Growth Factor-1 64
Insulin 65
Insulin Receptor Substrates (IRS) 1 and 2 66
Interactions of Nutrients and Nutritional Status with IIS Signaling 67
Insulin, IGF-1 and Human Aging 68
Conclusion 69
References 69
Exploring Mechanisms of Aging Retardation by Caloric Restriction: Studies in Model Organisms and Mammals 77
Introduction 77
Single-Celled Organism 78
Saccharomyces cerevisiae 78
Methodology 79
Findings and Candidate Mechanisms 79
Invertebrate Animals 82
Caenorhabditis elegans 82
Methodology 82
Findings and Candidate Mechanisms 83
Drosophila melanogaster 85
Methodology 85
Findings and Candidate Mechanisms 86
Mammals 87
Mice and Rats 87
Methodology 87
Findings and Candidate Mechanisms 90
Dogs 91
Non-human Primate Macaca mulatta 91
Methodology 92
Findings and Candidate Mechanisms 93
Humans 93
Methodology 94
Findings and Candidate Mechanisms 94
Outcomes and Conclusion 95
References 95
Cell Replication Rates In Vivo and In Vitro and Wound Healing as Affected by Animal Age, Diet, and Species 105
Introduction 105
Cell Replication and Wound Healing Activity Decrease with Old Age 106
In Vivo Studies of Cell Growth Capacity 106
Cell Division Capacity In Vitro 110
Cell Replication Decline with Aging or Senescence Among Several Species 114
Telomere Shortening with Age 115
DNA Damage in Old Cells That May Result in Senescence 116
Stem Cell Depletion with Aging 117
Wound Healing in Young Versus Old Animals 118
Human Clinical Studies in Age-Related Wound Healing 118
Age-Related Wound Healing in Laboratory Species 119
Metabolic Factors and Cytokine Levels Affect Wound Healing 121
Conclusions on Wound Healing and Age of the Animal 122
Cell Replication and Wound Healing in Non-mammalian Species 123
References 124
Sirtuin Function in Longevity 131
Historical Introduction on Sir2 as a Silencing Factor in Yeast 132
Sir2 as a Longevity Factor in Yeast 133
Catalytic Activity of Sirtuins 134
Calorie Restriction and Sir2 in Yeast Lifespan Extension 136
NAD + Biosynthesis and the Activation of Sir2 137
Sirtuins in the Regulation of C. elegans and Drosophila Lifespan 139
Mammalian Sirtuins in Lifespan Regulation and Age-Related Disease 140
Resveratrol as an Activator of Sirtuins 145
References 146
The Role of TOR Signaling in Aging 155
Introduction and Overview 155
TOR Signaling Modulates Aging in Invertebrate Organisms 158
Role of TOR in Yeast Aging 158
Role of TOR in Nematode Aging 159
Role of TOR in Fly Aging 160
The Relationship Between TOR and Dietary Restriction 160
Downstream Effectors of TOR Signaling and Their Relationship to Aging 160
Autophagy 161
Stress Response 161
Metabolic Effects and Mitochondrial Function 162
mRNA Translation 163
TOR Signaling in Mammalian Aging 164
Conclusion 164
References 165
Mitochondria, Oxidative Damage and Longevity: What Can Comparative Biology Teach Us? 170
Introduction 170
Metabolic Rate and Lifespan 171
Mitochondrial Function and Free Radical Generation 173
Antioxidant Defense Systems 187
Oxidative Damage to Macromolecules 188
Summary 192
References 193
Comparative Genomics of Aging 198
Introduction 198
Somatic Mutations and Epimutations in Aging 200
Somatic Mutation Accumulation in Mice and Flies 202
Summary and Future Prospects 205
References 206
Changes in Lysosomes and Their Autophagic Function in Aging: The Comparative Biology of Lysosomal Function 208
Introduction 208
Lysosomes: Concept and Properties 210
Lysosomal Pathways for Protein Degradation 211
Heterophagy 214
Autophagy 215
Macroautophagy 216
Microautophagy 218
Chaperone-Mediated Autophagy (CMA) 218
Vacuole Import and Degradation (vid) 219
The Cytosol to Vacuole Targeting Pathway (cvt) 219
Functions of the Autophagic Pathways 220
Lysosomes and Aging 221
Protein Degradation and Aging 221
Primary Changes in Lysosomes with Age 222
Changes in Autophagy with Age 223
Autophagy and Longevity 224
Lysosomal Dysfunction in Age-Related Pathologies 225
Concluding Remarks 227
References 227
Telomeres and Telomerase 234
Introduction 234
Evolution of Telomeres 237
Unicellular Organisms 237
Plants 241
Metazoa 242
Invertebrates 242
Vertebrates 246
Animal Cloning 256
Conclusion 256
References 257
Cardiac Aging 266
Introduction 266
Cardiac Aging in Humans 267
Murine Model of Cardiac Aging 270
Molecular Mechanisms of Cardiac Aging (Data from Mice and Humans) 272
Mechanism of Age-Dependent LV Hypertrophy and Diastolic Dysfunction 272
Decreased Cardiac Functional Reserve in Aging Mice and Humans 273
Aging of Cardiac Stem/Progenitor Cells 273
Role of Mitochondria and mt ROS in Cardiac Aging 274
Neurohormonal Regulation: The Role of Insulin/IGF1, the Renin Angiotensin System (RAS) and Adrenergic Signaling in Cardiac Aging 275
Renin Angiotensin Aldosterone System 275
Adrenergic Signaling 276
Insulin/IGF1 Signaling 276
Mechanisms of Progression from Cardiac Hypertrophy to Heart Failure in the Old Age 277
Increased Cardiomyocyte Death 277
Extracellular Matrix Remodeling 278
Alteration of Calcium Handling Proteins 278
Hypoxic Response and Angiogenesis 278
Mitochondrial Dysfunction and Abnormalities in Energetics 279
Beneficial Effects of DR on Cardiac Function in Aging 279
Drosophila : An Invertebrate Model of Cardiac Senescence 280
Normal Aging of the Drosophila Heart 280
Heart Rate 280
Rhythmicity 280
Fiber Structure 281
Stress Resistance 281
Genetic Regulation 282
Ion Channels 282
Contractile Proteins 282
ROS-Scavenging Proteins 283
Nutrient-Sensing Signaling Pathways 283
Exercise 284
Cardiac Aging in Dogs 284
Cardiac Aging in Non-Human Primates 285
Summary 285
References 285
Comparative Skeletal Muscle Aging 294
Introduction 294
Sarcopenia 296
Muscle Atrophy in Humans 296
Atrophy in Animal Models 297
Fiber Loss 297
Apoptosis 297
Preferential Loss of Type II Fibers 298
Force Production 298
Changes in Contractile Apparatus 299
Changes in Muscle Innervation 300
Muscle Oxidative Metabolism 300
Mitochondrial Content vs. Dysfunction 301
Reduced Mitochondrial Content 301
Mitochondrial Dysfunction 303
Mechanisms of Dysfunction 303
Reduced Coupling with Age 303
Uncoupling Paradox 304
Focal Electron Transport Chain Defects 305
mtDNA Mutations in Focal ETC Defect 305
Shared mtDNA Mutation Characteristics 306
Biological Impact of Focal ETC Defects 306
Abundance of Focal ETC Defects and Sarcopenia 307
Interventions that Alter ETC Defect Abundance 308
Future Directions in Study of ETC Defects 308
Muscle Injury 308
Muscle Satellite Cells and Injury Repair 309
Exercise and Muscle Aging 310
Slowing Muscle Degeneration 310
Reversal of Dysfunction 310
Reduced Response to Cellular Stress 312
Summary 312
References 313
Aging of the Nervous System 325
Introduction and Overview 325
Nervous System Intrinsic Changes Associated with Aging 327
Elevated Oxidative Stress oxidative stress 328
Reactive Oxygen Species: Sources and Sinks 329
Molecular Damage Caused by ROS 329
Consequences of Oxidative Damage for Nervous System Function During Aging 330
Energy Metabolism 331
Protein Homeostasis and Aging 333
The Ubiquitin/Proteasome Pathway in Brain Aging 333
Autophagic Processes and Aging 333
Protein Translation Rates as a Factor in Aging 334
Pathways for Cell Replacement 335
Aging's Effects on Regeneration and Repair 335
Intrinsic Changes in the Nervous System Associated with Aging 336
Sensory Loss 336
Cognitive Decline 336
Regulating Lifespan by the Nervous System -- Insights from Genetics 337
Alzheimers Disease 338
Clinical, Histological and Molecular Pathology of Alzheimer's Disease 339
Genetic and Environmental Factors 339
Animal Models of Alzheimer's Disease 340
Parkinson Parkinsons Disease (PD) 341
Symptoms of PD 341
Risk Factors for PD 341
Genetics of PD 342
Model Systems for Mechanistic Studies of PD 342
Huntingtons Disease 343
The Role of Polyglutamine Repeat Expansions in Huntington's Disease 343
Animal Models Establishing the Role of Polyglutamine Repeat Expansion in HD 343
ALS 343
Clinical and Pathological Features of ALS 344
Genetic Mutations Cause Some Cases of ALS 344
Sporadic ALS 345
Environmental Factors and Their Effect on the Aging Nervous System 345
Energy Intake 345
Exercise 346
Stress 346
Social Interaction 346
References 347
Aging of the Immune System Across Different Species 359
Introduction 360
Pathogen-Associated Molecular Patterns and Innate Immunity in Vertebrates and Invertebrates 361
Pathogen Recognizing Receptors 362
Toll Like Receptors 362
NOD Like Receptors 363
Antigen Specific Receptors 363
LRR-Based ASR 364
Immunoglobulin (Ig)-Like Antigen Specific Receptors 364
Adaptive Immunity as a Requirement for Increased Life Span 366
Immune Senescence 367
Aging of Innate Immunity in Different model Systems 368
Similarities and Differences in Aging of the Adaptive Immunity in Mice and Humans 370
Aging of Adaptive Immune Systems in Other Species 372
Birds 372
Rats 372
Dogs 373
Monkeys 374
Concluding Comments 374
References 375
Index 383