Handbook of the Biology of Aging
von: Matt Kaeberlein, George Martin
Elsevier Reference Monographs, 2015
ISBN: 9780124116207
Sprache: Englisch
576 Seiten, Download: 17837 KB
Format: EPUB, PDF, auch als Online-Lesen
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| Front Cover | 1 | ||
| Handbook of the Biology of Aging | 4 | ||
| Copyright Page | 5 | ||
| Contents | 6 | ||
| Foreword | 10 | ||
| Preface | 12 | ||
| About the Editors | 14 | ||
| List of Contributors | 16 | ||
| I. Basic Mechanisms of Aging: Models and Systems | 18 | ||
| 1 Longevity as a Complex Genetic Trait | 20 | ||
| Introduction | 21 | ||
| Defining the Aging Gene-Space | 21 | ||
| Direct Screens for Genetic Longevity Determinants | 22 | ||
| RNAi Screens in Nematodes | 22 | ||
| Knockout Screens in Budding Yeast | 25 | ||
| Overexpression Screens in Fruit Flies | 26 | ||
| Leveraging Genetic Diversity to Identify Aging Loci | 27 | ||
| Mapping Longevity Genes in Human Populations | 27 | ||
| Mapping Longevity Genes in Mouse Populations | 33 | ||
| Mouse–Human Concordance | 36 | ||
| Age-Associated Gene Expression Studies | 36 | ||
| Non-Genetic Sources of Complexity | 38 | ||
| Tissue-Specific Aging | 38 | ||
| Tissue-Specific Age-Related DNA Methylation | 38 | ||
| Telomere Shortening and Telomerase | 39 | ||
| Tissue-Specific Responses of Aging Pathways | 40 | ||
| Gene–Environment Interaction | 41 | ||
| Genetic Response to DR | 41 | ||
| DR: Quantity, Composition, and Timing | 43 | ||
| Environmental Temperature | 45 | ||
| Environmental Oxygen and the Hypoxic Response | 46 | ||
| Other Environmental Factors That Influence Aging | 47 | ||
| Emerging Tools for Studying Aging as a Complex Genetic Trait | 48 | ||
| High-Throughput Lifespan Assays in Yeast and Worms | 48 | ||
| Genome-Scale Mouse Knockout Collection | 51 | ||
| Collaborative Cross and Diversity Outbred Mice | 51 | ||
| Expression QTLs | 56 | ||
| Aging Biomarkers | 57 | ||
| Conclusions | 59 | ||
| References | 60 | ||
| 2 The mTOR Pathway and Aging | 72 | ||
| Introduction | 72 | ||
| mTOR Signaling Pathway | 73 | ||
| Molecular Composition of mTOR Complex | 73 | ||
| Upstream Regulators of mTOR Complexes | 73 | ||
| Substrates and Actions of mTORC1 | 75 | ||
| Substrates and Actions of mTORC2 | 76 | ||
| Genetic Modulation of Longevity by TOR Signaling in Model Organisms | 76 | ||
| Rapamycin | 79 | ||
| Rapalogs | 80 | ||
| Potential Mechanisms of Life Span Extension by mTOR Inhibition | 83 | ||
| Translation | 83 | ||
| Autophagy | 84 | ||
| Anticancer Effect | 84 | ||
| Stem Cell Maintenance | 84 | ||
| mTOR in Age-Related Diseases | 84 | ||
| Cancer | 84 | ||
| Metabolic Disease | 86 | ||
| Cardiovascular | 87 | ||
| Neurodegeneration and Cognitive Decline | 88 | ||
| Immune Response | 90 | ||
| Conclusion | 90 | ||
| References | 91 | ||
| 3 Sirtuins, Healthspan, and Longevity in Mammals | 100 | ||
| Introduction | 101 | ||
| Sirtuin-Driven Lifespan Extension in Invertebrates | 101 | ||
| Sirtuin Enzymatic Activity | 103 | ||
| Sirtuins and Mammalian Longevity | 107 | ||
| SIRT1 | 107 | ||
| SIRT2 | 109 | ||
| SIRT6 | 109 | ||
| Genetic Variation of Human Sirtuins | 111 | ||
| SIRT1 | 111 | ||
| SIRT3 | 112 | ||
| Sirtuins as Modulators of Responses to CR | 113 | ||
| SIRT1 | 114 | ||
| SIRT2 | 114 | ||
| SIRT3 | 115 | ||
| SIRT4 | 115 | ||
| SIRT5 | 115 | ||
| SIRT6 | 116 | ||
| Roles for Sirtuins in Diverse Disease States | 116 | ||
| Cancer | 116 | ||
| SIRT1 | 116 | ||
| SIRT2 | 118 | ||
| SIRT3 | 118 | ||
| SIRT4 | 119 | ||
| SIRT6 | 120 | ||
| SIRT7 | 121 | ||
| Metabolic Syndrome | 121 | ||
| SIRT1 | 121 | ||
| SIRT2 | 123 | ||
| SIRT3 | 123 | ||
| SIRT4 | 124 | ||
| SIRT5 | 124 | ||
| SIRT6 | 125 | ||
| SIRT7 | 126 | ||
| Cardiovascular Dysfunction | 127 | ||
| SIRT1 | 127 | ||
| Other Sirtuins | 128 | ||
| Inflammatory Signaling | 129 | ||
| Neurodegenerative Disease | 130 | ||
| SIRT1 | 130 | ||
| SIRT2 | 131 | ||
| SIRT3 | 132 | ||
| Sirtuin-Activating Compounds | 132 | ||
| Conclusion | 134 | ||
| Acknowledgments | 136 | ||
| References | 137 | ||
| 4 The Hypoxic Response and Aging | 150 | ||
| Introduction | 150 | ||
| The Hypoxic Response | 151 | ||
| Signal Transduction Pathway | 151 | ||
| Hypoxic Signaling in Disease | 155 | ||
| VHL Disease | 155 | ||
| Cancer | 156 | ||
| Environmental Modifiers | 156 | ||
| Physiological Roles for the Hypoxic Response | 159 | ||
| Hypoxia | 159 | ||
| Development/Stem Cell Maintenance | 159 | ||
| Immunity | 159 | ||
| A Direct Role for the Hypoxic Response in Aging | 160 | ||
| The Hypoxic Response in Aging of Other Non-Mammalian Organisms | 162 | ||
| Interactions with Other Longevity Pathways | 163 | ||
| Sirtuins | 163 | ||
| Long-Lived Mitochondrial Mutants | 164 | ||
| Target of Rapamycin | 165 | ||
| HIF in Mammalian Aging | 165 | ||
| Positive Effects of Hypoxia | 167 | ||
| Conclusion | 168 | ||
| Acknowledgments | 168 | ||
| References | 168 | ||
| 5 The Role of Neurosensory Systems in the Modulation of Aging | 178 | ||
| Introduction | 178 | ||
| Peripheral Systems of Sensory Perception | 179 | ||
| Environmental Sensing and the Regulation of Aging | 180 | ||
| Mechanisms of Sensory-Mediated Lifespan Regulation | 182 | ||
| The Next Steps in Mapping Sensory-Mediated Lifespan Circuits | 186 | ||
| Synthesis and Perspectives | 188 | ||
| References | 191 | ||
| 6 The Naked Mole-Rat: A Resilient Rodent Model of Aging, Longevity, and Healthspan | 196 | ||
| What Is a Naked Mole-Rat? | 198 | ||
| Ecophysiology and Tolerance to Hypoxia | 199 | ||
| Eusociality | 201 | ||
| Successful Aging | 202 | ||
| Naked Mole-Rat Aging Biology | 202 | ||
| The Aging Brain | 202 | ||
| The Aging Heart | 203 | ||
| Aging Reproductive Profile | 203 | ||
| End of Life Pathology | 203 | ||
| Resistance to Toxins | 204 | ||
| Cancer Resistance in the Naked-Mole Rat | 206 | ||
| Maintenance of Genomic and Proteomic Integrity | 208 | ||
| Mechanisms in Successful Aging | 208 | ||
| Insulin mTOR Signaling | 209 | ||
| Oxidative Stress | 210 | ||
| Proteolytic Degradation Pathways Include Autophagy and UPS | 213 | ||
| Cytoprotective Signaling—Nrf2 Activity | 214 | ||
| Summary | 215 | ||
| References | 216 | ||
| 7 Contributions of Telomere Biology to Human Age-Related Disease | 222 | ||
| Introduction | 223 | ||
| Telomere Structure and Function | 223 | ||
| Telomerase Structure, Function, and Regulation | 225 | ||
| Cellular Consequences of Telomere Dysfunction | 227 | ||
| Age-Related Changes in Telomere Length | 229 | ||
| Connections Between Human Age-Related Disease and Telomeres | 231 | ||
| Overall Longevity | 233 | ||
| Cardiovascular Diseases | 233 | ||
| Reproductive Aging | 235 | ||
| Type 2 Diabetes Mellitus | 235 | ||
| Osteoporosis | 236 | ||
| Idiopathic Pulmonary Fibrosis | 236 | ||
| Environmental Exposures | 237 | ||
| Cirrhosis | 237 | ||
| Cancer | 238 | ||
| Centenarians | 240 | ||
| Human Progeroid Disorders | 241 | ||
| p16 and Aging | 243 | ||
| Mouse Models | 244 | ||
| Pathologies Associated with Long Telomeres | 245 | ||
| Prospects for Prognostication and Intervention | 246 | ||
| Acknowledgments | 247 | ||
| References | 247 | ||
| 8 Systems Approaches to Understanding Aging | 258 | ||
| Introduction | 259 | ||
| Transcriptomic Approaches Toward Understanding Aging | 260 | ||
| Gene Expression Profiles Related to Aging | 260 | ||
| Inferring Aging Regulators from Gene Expression Profiles | 261 | ||
| Regulatory Networks of Aging | 262 | ||
| MicroRNA, Systems Biology, and Aging | 264 | ||
| Knockdown or Knockout of miRNA Machinery | 264 | ||
| Finding Aging-Related miRNAs by High-Throughput Technologies | 265 | ||
| Searching for miRNA Targets In Silico and In Vivo | 265 | ||
| miRNA as Aging Biomarkers | 267 | ||
| Epigenomics and Aging | 267 | ||
| DNA Methylation and Aging | 267 | ||
| Histone Modification and Aging | 269 | ||
| Approaches to Detecting the Crosstalk of Epigenomic Markers | 271 | ||
| Integrated Microfluidic Systems for Studying Aging | 271 | ||
| Microfluidic Devices for Yeast Aging Study | 272 | ||
| Microfluidic Devices for C. elegans Aging Study | 273 | ||
| Conclusions | 274 | ||
| Acknowledgments | 274 | ||
| References | 274 | ||
| 9 Integrative Genomics of Aging | 280 | ||
| Introduction | 280 | ||
| Post-Genome Technologies and Biogerontology | 281 | ||
| Genome-Wide Approaches and the Genetics of Aging and Longevity | 281 | ||
| Surveying the Aging Phenotype on a Grand Scale | 284 | ||
| Challenges in Data Analysis | 287 | ||
| Data Integration | 288 | ||
| Data and Databases | 288 | ||
| Finding Needles in Haystacks: Network Approaches and Multi-Dimensional Data Integration | 289 | ||
| Construction of Longevity Networks | 290 | ||
| Topological Features | 291 | ||
| Network Modularity | 293 | ||
| Multi-Dimensional Data Integration | 293 | ||
| Predictive Methods and Models | 295 | ||
| Concluding Remarks | 296 | ||
| Acknowledgments | 297 | ||
| References | 297 | ||
| 10 NIA Interventions Testing Program: A Collaborative Approach for Investigating Interventions to Promote Healthy Aging | 304 | ||
| Introduction | 305 | ||
| Features of the ITP Experimental Design | 305 | ||
| Types of Intervention Proposals Sought by the ITP | 308 | ||
| Challenges Encountered Implementing Testing Protocols | 309 | ||
| Summary of ITP Findings | 310 | ||
| Stage II Studies | 314 | ||
| The ITP at 10 Years: Synopsis and Future Goals | 316 | ||
| References | 319 | ||
| 11 Comparative Biology of Aging: Insights from Long-Lived Rodent Species | 322 | ||
| Introduction | 322 | ||
| Rodents as Models for Comparative Research | 324 | ||
| Cross-Species Biological Comparisons | 326 | ||
| Telomerase Maintenance and Replicative Senescence | 327 | ||
| Mechanisms for Controlling Cell Proliferation | 327 | ||
| Body Mass and Lifespan Shape Tumor Suppressor Mechanisms | 328 | ||
| Lifespan and Genome Stability | 328 | ||
| NMRs and BMRs | 329 | ||
| Hyaluronan Mediates Cancer Resistance in the NMR | 330 | ||
| Accurate Protein Synthesis in the NMR | 331 | ||
| Interferon Mediates Cancer Resistance in the BMR | 332 | ||
| Hyaluronan Evolved in Long-Lived Subterranean Rodents | 333 | ||
| Comparative Genomics of Aging and Cancer | 333 | ||
| Strategies for Comparative Genomics | 333 | ||
| Genomics of the NMR | 334 | ||
| Genomics of the BMR | 335 | ||
| Independent Adaptations to Subterranean Life | 335 | ||
| Comparative Genomics of Rodents and Other Mammals | 335 | ||
| Conclusion | 336 | ||
| References | 338 | ||
| II. The Pathobiology of Human Aging | 342 | ||
| 12 Genetics of Human Aging | 344 | ||
| Introduction | 344 | ||
| Genetic Variation in Aging | 345 | ||
| Phenotypes of Human Aging | 346 | ||
| Experimental Models for Studying Human Aging | 348 | ||
| Study Designs for Discovering Genes Related to Human Aging | 350 | ||
| Genetic Linkage Analysis | 352 | ||
| Genetic Association Analysis | 354 | ||
| Genome-Wide Association Studies | 355 | ||
| Rare Variants in Aging | 357 | ||
| Candidate Studies in Aging | 359 | ||
| Functional Analysis | 361 | ||
| In Silico Analysis of Genetic Variants | 362 | ||
| Functional Analysis of Genetic Variants in In Vitro and In Vivo Models | 366 | ||
| Summary and Perspectives | 369 | ||
| References | 370 | ||
| 13 The Aging Arterial Wall | 376 | ||
| Introduction | 377 | ||
| Proinflammatory Molecular Signature of the Aging Arterial Wall | 378 | ||
| Renin–Angiotensin System | 378 | ||
| Aldosterone and Mineralocorticoid Receptor-Mediated Signaling | 378 | ||
| Endothelin-1 Signaling | 378 | ||
| Adrenergic Receptor Signaling | 379 | ||
| Monocyte Chemoattractant Protein-1 | 380 | ||
| Transforming Growth Factor-?1 | 380 | ||
| Bone Morphogenetic Proteins | 380 | ||
| Platelet-Derived Growth Factor | 380 | ||
| Interleukin-6 and Tissue Necrosis Factor-Alpha | 381 | ||
| Matrix Metalloproteinases | 381 | ||
| Calpain-1/Calpastatin | 381 | ||
| Milk Fat Globule EGF-8 and Integrins | 382 | ||
| Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 | 382 | ||
| Reactive Oxygen Species | 382 | ||
| Nitric Oxygen and Bioavailability | 382 | ||
| Cell Cycle Promoter Molecules | 383 | ||
| Intracellular Matrix Messenger Molecules, SMADs | 383 | ||
| Cell Cycle Inhibitory Molecules | 383 | ||
| Proinflammation Transcription Factors Ets-1 and NF-?B | 384 | ||
| Anti-Inflammatory Factors Nrf2, PPAR?, SIRT1, and FOXO3 | 384 | ||
| Proliferation Transcription Factor AP-1 | 384 | ||
| Macroscopic Age-Associated Altered Arterial CELL Phenotypes | 385 | ||
| Arterial Cellular Phenotypes | 385 | ||
| Endothelial Cells | 385 | ||
| EC Morphology and Junctions | 385 | ||
| EC Stiffening | 385 | ||
| EC Apoptosis | 385 | ||
| EC Senescence | 385 | ||
| EC Impairment | 386 | ||
| Vascular Smooth Muscle Cells | 386 | ||
| VSMC Proliferation | 386 | ||
| VSMC Senescence | 387 | ||
| VSMC Migration/Invasion | 387 | ||
| ECM Secretion | 388 | ||
| VSMC Stiffening | 388 | ||
| Fibroblasts | 388 | ||
| Arterial Wall Phenotypes | 388 | ||
| Endothelial Barrier Dysfunction | 388 | ||
| Prothrombosis | 389 | ||
| Fibrosis | 389 | ||
| Calcification | 389 | ||
| Elastin Fragmentation | 389 | ||
| Amyloidosis | 390 | ||
| Glycoxidization | 390 | ||
| Arterial Tissue Senescence | 390 | ||
| Clinical Signs of Arterial Wall Aging | 391 | ||
| Blood Pressure | 391 | ||
| Intimal-Medial Thickness | 391 | ||
| Pulse Wave Velocity | 392 | ||
| Endothelial Dysfunction | 393 | ||
| Interaction of Aging, Hypertension, and Atherosclerosis | 393 | ||
| Hypertension and Aging | 393 | ||
| Atherosclerosis and Aging | 393 | ||
| Interventions on Arterial Wall Aging | 396 | ||
| Blockade of Ang II Signaling, Adverse Remodeling, and Proinflammation | 396 | ||
| MMP Inhibition, Elastin Fragmentation, and ECM Deposition | 396 | ||
| Breakers of AGEs, RAGE and arterial stiffening | 397 | ||
| Caloric Restriction, Resveratrol, and Adverse Remodeling | 397 | ||
| Physical Conditioning and Proinflammation | 397 | ||
| Concluding Remarks and Future Perspectives | 397 | ||
| Acknowledgments | 398 | ||
| References | 398 | ||
| 14 Age-Related Alterations in Neural Plasticity | 408 | ||
| Introduction | 408 | ||
| Short (Milliseconds) Timeframe: Paired-Pulse Facilitation and Paired-Pulse Depression | 410 | ||
| Intermediate (Seconds) Timeframe: Frequency Facilitation (FF) and the Post-Burst Afterhyperpolarization | 412 | ||
| Frequency Facilitation | 412 | ||
| Post-Burst Afterhyperpolarization | 413 | ||
| Long (Minutes to Days) Timeframe: Long-Term Potentiation and Long-Term Depression | 415 | ||
| Neural Plasticity and the Calcium Dysregulation Hypothesis of Aging | 418 | ||
| References | 419 | ||
| 15 The Aging Immune System: Dysregulation, Compensatory Mechanisms, and Prospects for Intervention | 424 | ||
| Introduction | 425 | ||
| Innate and Adaptive Immunity | 425 | ||
| Age and Immunity | 427 | ||
| Effect of Age on Hematopoiesis | 428 | ||
| Effect of Age on Innate Immunity | 431 | ||
| NK Cells | 431 | ||
| Dendritic Cells | 432 | ||
| Effect of Age on Adaptive Immunity | 432 | ||
| Impact of Thymic Involution and Thymectomy on T Cells | 433 | ||
| Immune Cell Function | 436 | ||
| T-Cell Function | 436 | ||
| B-Cell Function | 437 | ||
| Clinical Consequences of Immunosenescence | 437 | ||
| Effect of Age on Vaccination | 438 | ||
| Immune Senescence and All-Cause Mortality | 440 | ||
| Interventions to Restore Appropriate Immunity | 441 | ||
| Perspectives | 443 | ||
| References | 444 | ||
| 16 Vascular Disease in Hutchinson Gilford Progeria Syndrome and Aging: Common Phenotypes and Potential Mechanisms | 450 | ||
| Introduction | 451 | ||
| Progeria as a Model for Studying Vascular Disease | 451 | ||
| Vascular Pathology in Progeria and Aging | 451 | ||
| Hypertension | 452 | ||
| Adventitial Fibrosis | 452 | ||
| Medial Cell Death | 454 | ||
| Atherosclerosis in Progeria and Aging | 455 | ||
| ECM Changes in Progeria and Aging and Their Potential Contribution to Atherosclerosis | 457 | ||
| Potential Molecular Mechanisms Driving Vascular Disease in Progeria | 460 | ||
| A-Type Lamin Mutation and Progerin Processing | 460 | ||
| Progerin Expression in Normal Aging Vasculature | 461 | ||
| Chromatin Reorganization | 462 | ||
| Altered Transcription Factor Regulation | 462 | ||
| DNA Damage and Dysfunctional Telomeres | 463 | ||
| Mechanosensitivity | 463 | ||
| Dysfunctional Stem Cell Niche | 464 | ||
| Mouse Models of Progeria | 465 | ||
| Current Status of Clinical Intervention Trials for Progeria | 465 | ||
| Concluding Remarks | 467 | ||
| References | 468 | ||
| 17 Cardiac Aging | 476 | ||
| Introduction | 477 | ||
| Cardiac Aging in Humans | 477 | ||
| Murine Model of Cardiac Aging | 480 | ||
| Molecular Mechanisms of Cardiac Aging | 482 | ||
| Role of Mitochondria and ROS in Cardiac Aging | 482 | ||
| Nutrient Signaling in Cardiac Aging | 483 | ||
| Neurohormonal Regulation of Cardiac Aging | 485 | ||
| Renin–Angiotensin–Aldosterone System (RAAS) | 485 | ||
| Adrenergic Signaling | 485 | ||
| Insulin/IGF-1 Signaling | 486 | ||
| Aging of Cardiac Stem/Progenitor Cells | 486 | ||
| Decreased Cardiac Functional Reserve in Aging | 487 | ||
| Mechanisms of Progression to Heart Failure in Old Age | 488 | ||
| Mitochondrial Dysfunction and Abnormalities in Energetics | 488 | ||
| Increased Cardiomyocyte Death and ECM Remodeling | 490 | ||
| Alteration of Calcium Handling Proteins | 491 | ||
| Hypoxic Response and Angiogenesis | 492 | ||
| Other Models of Cardiac Aging | 492 | ||
| Drosophila: An Invertebrate Model of Cardiac Senescence | 492 | ||
| Normal Aging of the Drosophila Heart | 492 | ||
| Heart Rate | 492 | ||
| Rhythmicity | 493 | ||
| Fiber Structure | 493 | ||
| Stress Resistance | 493 | ||
| Genetic Regulation | 493 | ||
| Ion Channels | 494 | ||
| Contractile Proteins | 494 | ||
| ROS-Scavenging Proteins | 495 | ||
| Nutrient-Sensing Signaling Pathways | 495 | ||
| Exercise | 496 | ||
| Large Animal Models of Cardiac Aging | 496 | ||
| Interventions to Delay or Reverse Vertebrate Cardiac Aging | 497 | ||
| Calorie Restriction and Its Mimetics | 497 | ||
| Mitochondrial Intervention | 498 | ||
| Antioxidants | 498 | ||
| SS-31 | 499 | ||
| Inhibition of Renin–Angiotensin–Aldosterone signaling | 500 | ||
| Other Novel Agents | 500 | ||
| References | 501 | ||
| 18 Current Status of Research on Trends in Morbidity, Healthy Life Expectancy, and the Compression of Morbidity | 512 | ||
| Introduction | 512 | ||
| Dimensions of Morbidity | 513 | ||
| The Length of Life Cycles and Population Health | 514 | ||
| Trends in Population Prevalence of Physiological Dysregulation, Diseases and Conditions, Functioning Loss and Disability, a ... | 514 | ||
| Length of Life and Length of Healthy Life | 517 | ||
| Conclusions | 521 | ||
| References | 521 | ||
| 19 On the Compression of Morbidity: From 1980 to 2015 and Beyond | 524 | ||
| Introduction | 524 | ||
| Compression of Morbidity | 524 | ||
| The Science of Postponement of Disability | 526 | ||
| Synonyms and Antonyms | 526 | ||
| Human Aging | 528 | ||
| Themes and Paradigms | 528 | ||
| Longitudinal Study of Human Aging | 528 | ||
| Long-Distance Runners Versus Community Controls | 531 | ||
| Two or More Risk Factors (Smoking, Inactivity, or Obesity) Versus None of These | 533 | ||
| Morbidity is Best Compressed by Regular, Vigorous, and Sustained Exercise | 535 | ||
| Disease, Diagnosis, Morbidities, and Trajectories | 536 | ||
| Delayed Aging | 537 | ||
| Concluding Remarks | 538 | ||
| State of the Evidence | 538 | ||
| Possibilities and Uncertainties | 539 | ||
| References | 539 | ||
| Author Index | 542 | ||
| Subject Index | 560 |