Musi / Hornsby Handbook of the Biology of Aging

8. Auflage 2015
ISBN: 978-0-12-411620-7
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 576 Seiten

Reihe: Handbooks of Aging

Handbook of the Biology of Aging, Eighth Edition, provides readers with an update on the rapid progress in the research of aging. It is a comprehensive synthesis and review of the latest and most important advances and themes in modern biogerontology, and focuses on the trend of 'big data' approaches in the biological sciences, presenting new strategies to analyze, interpret, and understand the enormous amounts of information being generated through DNA sequencing, transcriptomic, proteomic, and the metabolomics methodologies applied to aging related problems. The book includes discussions on longevity pathways and interventions that modulate aging, innovative new tools that facilitate systems-level approaches to aging research, the mTOR pathway and its importance in age-related phenotypes, new strategies to pharmacologically modulate the mTOR pathway to delay aging, the importance of sirtuins and the hypoxic response in aging, and how various pathways interact within the context of aging as a complex genetic trait, amongst others. - Covers the key areas in biological gerontology research in one volume, with an 80% update from the previous edition - Edited by Matt Kaeberlein and George Martin, highly respected voices and researchers within the biology of aging discipline - Assists basic researchers in keeping abreast of research and clinical findings outside their subdiscipline - Presents information that will help medical, behavioral, and social gerontologists in understanding what basic scientists and clinicians are discovering - New chapters on genetics, evolutionary biology, bone aging, and epigenetic control - Provides a close examination of the diverse research being conducted today in the study of the biology of aging, detailing recent breakthroughs and potential new directions

Autoren/Hrsg.

Musi, Nicolas

Hornsby, Peter

Inhaltsverzeichnis

1;Front Cover;1
2;Handbook of the Biology of Aging;4
3;Copyright Page;5
4;Contents;6
5;Foreword;10
6;Preface;12
7;About the Editors;14
8;List of Contributors;16
9;I. Basic Mechanisms of Aging: Models and Systems;18
9.1;1 Longevity as a Complex Genetic Trait;20
9.1.1;Introduction;21
9.1.2;Defining the Aging Gene-Space;21
9.1.2.1;Direct Screens for Genetic Longevity Determinants;22
9.1.2.1.1;RNAi Screens in Nematodes;22
9.1.2.1.2;Knockout Screens in Budding Yeast;25
9.1.2.1.3;Overexpression Screens in Fruit Flies;26
9.1.2.2;Leveraging Genetic Diversity to Identify Aging Loci;27
9.1.2.2.1;Mapping Longevity Genes in Human Populations;27
9.1.2.2.2;Mapping Longevity Genes in Mouse Populations;33
9.1.2.2.3;Mouse–Human Concordance;36
9.1.2.2.4;Age-Associated Gene Expression Studies;36
9.1.3;Non-Genetic Sources of Complexity;38
9.1.3.1;Tissue-Specific Aging;38
9.1.3.1.1;Tissue-Specific Age-Related DNA Methylation;38
9.1.3.1.2;Telomere Shortening and Telomerase;39
9.1.3.1.3;Tissue-Specific Responses of Aging Pathways;40
9.1.3.2;Gene–Environment Interaction;41
9.1.3.2.1;Genetic Response to DR;41
9.1.3.2.2;DR: Quantity, Composition, and Timing;43
9.1.3.2.3;Environmental Temperature;45
9.1.3.2.4;Environmental Oxygen and the Hypoxic Response;46
9.1.3.2.5;Other Environmental Factors That Influence Aging;47
9.1.4;Emerging Tools for Studying Aging as a Complex Genetic Trait;48
9.1.4.1;High-Throughput Lifespan Assays in Yeast and Worms;48
9.1.4.2;Genome-Scale Mouse Knockout Collection;51
9.1.4.3;Collaborative Cross and Diversity Outbred Mice;51
9.1.4.4;Expression QTLs;56
9.1.4.5;Aging Biomarkers;57
9.1.5;Conclusions;59
9.1.6;References;60
9.2;2 The mTOR Pathway and Aging;72
9.2.1;Introduction;72
9.2.2;mTOR Signaling Pathway;73
9.2.2.1;Molecular Composition of mTOR Complex;73
9.2.2.2;Upstream Regulators of mTOR Complexes;73
9.2.2.3;Substrates and Actions of mTORC1;75
9.2.2.4;Substrates and Actions of mTORC2;76
9.2.3;Genetic Modulation of Longevity by TOR Signaling in Model Organisms;76
9.2.4;Rapamycin;79
9.2.5;Rapalogs;80
9.2.6;Potential Mechanisms of Life Span Extension by mTOR Inhibition;83
9.2.6.1;Translation;83
9.2.6.2;Autophagy;84
9.2.6.3;Anticancer Effect;84
9.2.6.4;Stem Cell Maintenance;84
9.2.7;mTOR in Age-Related Diseases;84
9.2.7.1;Cancer;84
9.2.7.2;Metabolic Disease;86
9.2.7.3;Cardiovascular;87
9.2.7.4;Neurodegeneration and Cognitive Decline;88
9.2.7.5;Immune Response;90
9.2.8;Conclusion;90
9.2.9;References;91
9.3;3 Sirtuins, Healthspan, and Longevity in Mammals;100
9.3.1;Introduction;101
9.3.2;Sirtuin-Driven Lifespan Extension in Invertebrates;101
9.3.3;Sirtuin Enzymatic Activity;103
9.3.4;Sirtuins and Mammalian Longevity;107
9.3.4.1;SIRT1;107
9.3.4.2;SIRT2;109
9.3.4.3;SIRT6;109
9.3.5;Genetic Variation of Human Sirtuins;111
9.3.5.1;SIRT1;111
9.3.5.2;SIRT3;112
9.3.6;Sirtuins as Modulators of Responses to CR;113
9.3.6.1;SIRT1;114
9.3.6.2;SIRT2;114
9.3.6.3;SIRT3;115
9.3.6.4;SIRT4;115
9.3.6.5;SIRT5;115
9.3.6.6;SIRT6;116
9.3.7;Roles for Sirtuins in Diverse Disease States;116
9.3.8;Cancer;116
9.3.8.1;SIRT1;116
9.3.8.2;SIRT2;118
9.3.8.3;SIRT3;118
9.3.8.4;SIRT4;119
9.3.8.5;SIRT6;120
9.3.8.6;SIRT7;121
9.3.9;Metabolic Syndrome;121
9.3.9.1;SIRT1;121
9.3.9.2;SIRT2;123
9.3.9.3;SIRT3;123
9.3.9.4;SIRT4;124
9.3.9.5;SIRT5;124
9.3.9.6;SIRT6;125
9.3.9.7;SIRT7;126
9.3.10;Cardiovascular Dysfunction;127
9.3.10.1;SIRT1;127
9.3.10.2;Other Sirtuins;128
9.3.11;Inflammatory Signaling;129
9.3.12;Neurodegenerative Disease;130
9.3.12.1;SIRT1;130
9.3.12.2;SIRT2;131
9.3.12.3;SIRT3;132
9.3.13;Sirtuin-Activating Compounds;132
9.3.14;Conclusion;134
9.3.15;Acknowledgments;136
9.3.16;References;137
9.4;4 The Hypoxic Response and Aging;150
9.4.1;Introduction;150
9.4.2;The Hypoxic Response;151
9.4.2.1;Signal Transduction Pathway;151
9.4.3;Hypoxic Signaling in Disease;155
9.4.3.1;VHL Disease;155
9.4.3.2;Cancer;156
9.4.3.3;Environmental Modifiers;156
9.4.4;Physiological Roles for the Hypoxic Response;159
9.4.4.1;Hypoxia;159
9.4.4.2;Development/Stem Cell Maintenance;159
9.4.4.3;Immunity;159
9.4.5;A Direct Role for the Hypoxic Response in Aging;160
9.4.5.1;The Hypoxic Response in Aging of Other Non-Mammalian Organisms;162
9.4.6;Interactions with Other Longevity Pathways;163
9.4.6.1;Sirtuins;163
9.4.6.2;Long-Lived Mitochondrial Mutants;164
9.4.6.3;Target of Rapamycin;165
9.4.7;HIF in Mammalian Aging;165
9.4.8;Positive Effects of Hypoxia;167
9.4.9;Conclusion;168
9.4.10;Acknowledgments;168
9.4.11;References;168
9.5;5 The Role of Neurosensory Systems in the Modulation of Aging;178
9.5.1;Introduction;178
9.5.2;Peripheral Systems of Sensory Perception;179
9.5.3;Environmental Sensing and the Regulation of Aging;180
9.5.4;Mechanisms of Sensory-Mediated Lifespan Regulation;182
9.5.5;The Next Steps in Mapping Sensory-Mediated Lifespan Circuits;186
9.5.6;Synthesis and Perspectives;188
9.5.7;References;191
9.6;6 The Naked Mole-Rat: A Resilient Rodent Model of Aging, Longevity, and Healthspan;196
9.6.1;What Is a Naked Mole-Rat?;198
9.6.1.1;Ecophysiology and Tolerance to Hypoxia;199
9.6.1.2;Eusociality;201
9.6.2;Successful Aging;202
9.6.2.1;Naked Mole-Rat Aging Biology;202
9.6.2.2;The Aging Brain;202
9.6.2.3;The Aging Heart;203
9.6.2.4;Aging Reproductive Profile;203
9.6.2.5;End of Life Pathology;203
9.6.2.6;Resistance to Toxins;204
9.6.2.7;Cancer Resistance in the Naked-Mole Rat;206
9.6.2.8;Maintenance of Genomic and Proteomic Integrity;208
9.6.3;Mechanisms in Successful Aging;208
9.6.3.1;Insulin mTOR Signaling;209
9.6.3.2;Oxidative Stress;210
9.6.3.3;Proteolytic Degradation Pathways Include Autophagy and UPS;213
9.6.3.4;Cytoprotective Signaling—Nrf2 Activity;214
9.6.4;Summary;215
9.6.5;References;216
9.7;7 Contributions of Telomere Biology to Human Age-Related Disease;222
9.7.1;Introduction;223
9.7.2;Telomere Structure and Function;223
9.7.3;Telomerase Structure, Function, and Regulation;225
9.7.4;Cellular Consequences of Telomere Dysfunction;227
9.7.5;Age-Related Changes in Telomere Length;229
9.7.6;Connections Between Human Age-Related Disease and Telomeres;231
9.7.6.1;Overall Longevity;233
9.7.6.2;Cardiovascular Diseases;233
9.7.6.3;Reproductive Aging;235
9.7.6.4;Type 2 Diabetes Mellitus;235
9.7.6.5;Osteoporosis;236
9.7.6.6;Idiopathic Pulmonary Fibrosis;236
9.7.6.7;Environmental Exposures;237
9.7.6.8;Cirrhosis;237
9.7.6.9;Cancer;238
9.7.6.10;Centenarians;240
9.7.6.11;Human Progeroid Disorders;241
9.7.6.12;p16 and Aging;243
9.7.6.13;Mouse Models;244
9.7.6.14;Pathologies Associated with Long Telomeres;245
9.7.7;Prospects for Prognostication and Intervention;246
9.7.8;Acknowledgments;247
9.7.9;References;247
9.8;8 Systems Approaches to Understanding Aging;258
9.8.1;Introduction;259
9.8.2;Transcriptomic Approaches Toward Understanding Aging;260
9.8.2.1;Gene Expression Profiles Related to Aging;260
9.8.2.2;Inferring Aging Regulators from Gene Expression Profiles;261
9.8.2.3;Regulatory Networks of Aging;262
9.8.3;MicroRNA, Systems Biology, and Aging;264
9.8.3.1;Knockdown or Knockout of miRNA Machinery;264
9.8.3.2;Finding Aging-Related miRNAs by High-Throughput Technologies;265
9.8.3.3;Searching for miRNA Targets In Silico and In Vivo;265
9.8.3.4;miRNA as Aging Biomarkers;267
9.8.4;Epigenomics and Aging;267
9.8.4.1;DNA Methylation and Aging;267
9.8.4.2;Histone Modification and Aging;269
9.8.4.3;Approaches to Detecting the Crosstalk of Epigenomic Markers;271
9.8.5;Integrated Microfluidic Systems for Studying Aging;271
9.8.5.1;Microfluidic Devices for Yeast Aging Study;272
9.8.5.2;Microfluidic Devices for C. elegans Aging Study;273
9.8.6;Conclusions;274
9.8.7;Acknowledgments;274
9.8.8;References;274
9.9;9 Integrative Genomics of Aging;280
9.9.1;Introduction;280
9.9.2;Post-Genome Technologies and Biogerontology;281
9.9.2.1;Genome-Wide Approaches and the Genetics of Aging and Longevity;281
9.9.2.2;Surveying the Aging Phenotype on a Grand Scale;284
9.9.3;Challenges in Data Analysis;287
9.9.4;Data Integration;288
9.9.4.1;Data and Databases;288
9.9.4.2;Finding Needles in Haystacks: Network Approaches and Multi-Dimensional Data Integration;289
9.9.4.2.1;Construction of Longevity Networks;290
9.9.4.2.2;Topological Features;291
9.9.4.2.3;Network Modularity;293
9.9.4.2.4;Multi-Dimensional Data Integration;293
9.9.4.3;Predictive Methods and Models;295
9.9.5;Concluding Remarks;296
9.9.6;Acknowledgments;297
9.9.7;References;297
9.10;10 NIA Interventions Testing Program: A Collaborative Approach for Investigating Interventions to Promote Healthy Aging;304
9.10.1;Introduction;305
9.10.2;Features of the ITP Experimental Design;305
9.10.3;Types of Intervention Proposals Sought by the ITP;308
9.10.4;Challenges Encountered Implementing Testing Protocols;309
9.10.5;Summary of ITP Findings;310
9.10.6;Stage II Studies;314
9.10.7;The ITP at 10 Years: Synopsis and Future Goals;316
9.10.8;References;319
9.11;11 Comparative Biology of Aging: Insights from Long-Lived Rodent Species;322
9.11.1;Introduction;322
9.11.2;Rodents as Models for Comparative Research;324
9.11.3;Cross-Species Biological Comparisons;326
9.11.3.1;Telomerase Maintenance and Replicative Senescence;327
9.11.3.2;Mechanisms for Controlling Cell Proliferation;327
9.11.3.3;Body Mass and Lifespan Shape Tumor Suppressor Mechanisms;328
9.11.3.4;Lifespan and Genome Stability;328
9.11.4;NMRs and BMRs;329
9.11.4.1;Hyaluronan Mediates Cancer Resistance in the NMR;330
9.11.4.2;Accurate Protein Synthesis in the NMR;331
9.11.4.3;Interferon Mediates Cancer Resistance in the BMR;332
9.11.4.4;Hyaluronan Evolved in Long-Lived Subterranean Rodents;333
9.11.5;Comparative Genomics of Aging and Cancer;333
9.11.5.1;Strategies for Comparative Genomics;333
9.11.5.2;Genomics of the NMR;334
9.11.5.3;Genomics of the BMR;335
9.11.5.4;Independent Adaptations to Subterranean Life;335
9.11.5.5;Comparative Genomics of Rodents and Other Mammals;335
9.11.6;Conclusion;336
9.11.7;References;338
10;II. The Pathobiology of Human Aging;342
10.1;12 Genetics of Human Aging;344
10.1.1;Introduction;344
10.1.2;Genetic Variation in Aging;345
10.1.3;Phenotypes of Human Aging;346
10.1.4;Experimental Models for Studying Human Aging;348
10.1.5;Study Designs for Discovering Genes Related to Human Aging;350
10.1.6;Genetic Linkage Analysis;352
10.1.7;Genetic Association Analysis;354
10.1.8;Genome-Wide Association Studies;355
10.1.9;Rare Variants in Aging;357
10.1.10;Candidate Studies in Aging;359
10.1.11;Functional Analysis;361
10.1.11.1;In Silico Analysis of Genetic Variants;362
10.1.11.2;Functional Analysis of Genetic Variants in In Vitro and In Vivo Models;366
10.1.12;Summary and Perspectives;369
10.1.13;References;370
10.2;13 The Aging Arterial Wall;376
10.2.1;Introduction;377
10.2.2;Proinflammatory Molecular Signature of the Aging Arterial Wall;378
10.2.2.1;Renin–Angiotensin System;378
10.2.2.2;Aldosterone and Mineralocorticoid Receptor-Mediated Signaling;378
10.2.2.3;Endothelin-1 Signaling;378
10.2.2.4;Adrenergic Receptor Signaling;379
10.2.2.5;Monocyte Chemoattractant Protein-1;380
10.2.2.6;Transforming Growth Factor-?1;380
10.2.2.7;Bone Morphogenetic Proteins;380
10.2.2.8;Platelet-Derived Growth Factor;380
10.2.2.9;Interleukin-6 and Tissue Necrosis Factor-Alpha;381
10.2.2.10;Matrix Metalloproteinases;381
10.2.2.11;Calpain-1/Calpastatin;381
10.2.2.12;Milk Fat Globule EGF-8 and Integrins;382
10.2.2.13;Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1;382
10.2.2.14;Reactive Oxygen Species;382
10.2.2.15;Nitric Oxygen and Bioavailability;382
10.2.2.16;Cell Cycle Promoter Molecules;383
10.2.2.17;Intracellular Matrix Messenger Molecules, SMADs;383
10.2.2.18;Cell Cycle Inhibitory Molecules;383
10.2.2.19;Proinflammation Transcription Factors Ets-1 and NF-?B;384
10.2.2.20;Anti-Inflammatory Factors Nrf2, PPAR?, SIRT1, and FOXO3;384
10.2.2.21;Proliferation Transcription Factor AP-1;384
10.2.3;Macroscopic Age-Associated Altered Arterial CELL Phenotypes;385
10.2.3.1;Arterial Cellular Phenotypes;385
10.2.3.1.1;Endothelial Cells;385
10.2.3.1.1.1;EC Morphology and Junctions;385
10.2.3.1.1.2;EC Stiffening;385
10.2.3.1.1.3;EC Apoptosis;385
10.2.3.1.1.4;EC Senescence;385
10.2.3.1.1.5;EC Impairment;386
10.2.3.1.2;Vascular Smooth Muscle Cells;386
10.2.3.1.2.1;VSMC Proliferation;386
10.2.3.1.2.2;VSMC Senescence;387
10.2.3.1.2.3;VSMC Migration/Invasion;387
10.2.3.1.2.4;ECM Secretion;388
10.2.3.1.2.5;VSMC Stiffening;388
10.2.3.1.3;Fibroblasts;388
10.2.3.2;Arterial Wall Phenotypes;388
10.2.3.2.1;Endothelial Barrier Dysfunction;388
10.2.3.2.2;Prothrombosis;389
10.2.3.2.3;Fibrosis;389
10.2.3.2.4;Calcification;389
10.2.3.2.5;Elastin Fragmentation;389
10.2.3.2.6;Amyloidosis;390
10.2.3.2.7;Glycoxidization;390
10.2.3.2.8;Arterial Tissue Senescence;390
10.2.4;Clinical Signs of Arterial Wall Aging;391
10.2.4.1;Blood Pressure;391
10.2.4.2;Intimal-Medial Thickness;391
10.2.4.3;Pulse Wave Velocity;392
10.2.4.4;Endothelial Dysfunction;393
10.2.5;Interaction of Aging, Hypertension, and Atherosclerosis;393
10.2.5.1;Hypertension and Aging;393
10.2.5.2;Atherosclerosis and Aging;393
10.2.6;Interventions on Arterial Wall Aging;396
10.2.6.1;Blockade of Ang II Signaling, Adverse Remodeling, and Proinflammation;396
10.2.6.2;MMP Inhibition, Elastin Fragmentation, and ECM Deposition;396
10.2.6.3;Breakers of AGEs, RAGE and arterial stiffening;397
10.2.6.4;Caloric Restriction, Resveratrol, and Adverse Remodeling;397
10.2.6.5;Physical Conditioning and Proinflammation;397
10.2.7;Concluding Remarks and Future Perspectives;397
10.2.8;Acknowledgments;398
10.2.9;References;398
10.3;14 Age-Related Alterations in Neural Plasticity;408
10.3.1;Introduction;408
10.3.2;Short (Milliseconds) Timeframe: Paired-Pulse Facilitation and Paired-Pulse Depression;410
10.3.3;Intermediate (Seconds) Timeframe: Frequency Facilitation (FF) and the Post-Burst Afterhyperpolarization;412
10.3.3.1;Frequency Facilitation;412
10.3.3.2;Post-Burst Afterhyperpolarization;413
10.3.4;Long (Minutes to Days) Timeframe: Long-Term Potentiation and Long-Term Depression;415
10.3.5;Neural Plasticity and the Calcium Dysregulation Hypothesis of Aging;418
10.3.6;References;419
10.4;15 The Aging Immune System: Dysregulation, Compensatory Mechanisms, and Prospects for Intervention;424
10.4.1;Introduction;425
10.4.2;Innate and Adaptive Immunity;425
10.4.3;Age and Immunity;427
10.4.4;Effect of Age on Hematopoiesis;428
10.4.5;Effect of Age on Innate Immunity;431
10.4.5.1;NK Cells;431
10.4.5.2;Dendritic Cells;432
10.4.6;Effect of Age on Adaptive Immunity;432
10.4.6.1;Impact of Thymic Involution and Thymectomy on T Cells;433
10.4.7;Immune Cell Function;436
10.4.7.1;T-Cell Function;436
10.4.7.2;B-Cell Function;437
10.4.8;Clinical Consequences of Immunosenescence;437
10.4.9;Effect of Age on Vaccination;438
10.4.10;Immune Senescence and All-Cause Mortality;440
10.4.11;Interventions to Restore Appropriate Immunity;441
10.4.12;Perspectives;443
10.4.13;References;444
10.5;16 Vascular Disease in Hutchinson Gilford Progeria Syndrome and Aging: Common Phenotypes and Potential Mechanisms;450
10.5.1;Introduction;451
10.5.2;Progeria as a Model for Studying Vascular Disease;451
10.5.3;Vascular Pathology in Progeria and Aging;451
10.5.3.1;Hypertension;452
10.5.3.2;Adventitial Fibrosis;452
10.5.3.3;Medial Cell Death;454
10.5.4;Atherosclerosis in Progeria and Aging;455
10.5.5;ECM Changes in Progeria and Aging and Their Potential Contribution to Atherosclerosis;457
10.5.6;Potential Molecular Mechanisms Driving Vascular Disease in Progeria;460
10.5.6.1;A-Type Lamin Mutation and Progerin Processing;460
10.5.6.2;Progerin Expression in Normal Aging Vasculature;461
10.5.6.3;Chromatin Reorganization;462
10.5.6.4;Altered Transcription Factor Regulation;462
10.5.6.5;DNA Damage and Dysfunctional Telomeres;463
10.5.6.6;Mechanosensitivity;463
10.5.6.7;Dysfunctional Stem Cell Niche;464
10.5.6.8;Mouse Models of Progeria;465
10.5.7;Current Status of Clinical Intervention Trials for Progeria;465
10.5.8;Concluding Remarks;467
10.5.9;References;468
10.6;17 Cardiac Aging;476
10.6.1;Introduction;477
10.6.2;Cardiac Aging in Humans;477
10.6.3;Murine Model of Cardiac Aging;480
10.6.4;Molecular Mechanisms of Cardiac Aging;482
10.6.4.1;Role of Mitochondria and ROS in Cardiac Aging;482
10.6.4.2;Nutrient Signaling in Cardiac Aging;483
10.6.4.3;Neurohormonal Regulation of Cardiac Aging;485
10.6.4.3.1;Renin–Angiotensin–Aldosterone System (RAAS);485
10.6.4.3.2;Adrenergic Signaling;485
10.6.4.3.3;Insulin/IGF-1 Signaling;486
10.6.4.4;Aging of Cardiac Stem/Progenitor Cells;486
10.6.4.5;Decreased Cardiac Functional Reserve in Aging;487
10.6.5;Mechanisms of Progression to Heart Failure in Old Age;488
10.6.5.1;Mitochondrial Dysfunction and Abnormalities in Energetics;488
10.6.5.2;Increased Cardiomyocyte Death and ECM Remodeling;490
10.6.5.3;Alteration of Calcium Handling Proteins;491
10.6.5.4;Hypoxic Response and Angiogenesis;492
10.6.6;Other Models of Cardiac Aging;492
10.6.6.1;Drosophila: An Invertebrate Model of Cardiac Senescence;492
10.6.6.1.1;Normal Aging of the Drosophila Heart;492
10.6.6.1.1.1;Heart Rate;492
10.6.6.1.1.2;Rhythmicity;493
10.6.6.1.1.3;Fiber Structure;493
10.6.6.1.1.4;Stress Resistance;493
10.6.6.1.2;Genetic Regulation;493
10.6.6.1.2.1;Ion Channels;494
10.6.6.1.2.2;Contractile Proteins;494
10.6.6.1.2.3;ROS-Scavenging Proteins;495
10.6.6.1.2.4;Nutrient-Sensing Signaling Pathways;495
10.6.6.1.2.5;Exercise;496
10.6.6.2;Large Animal Models of Cardiac Aging;496
10.6.7;Interventions to Delay or Reverse Vertebrate Cardiac Aging;497
10.6.7.1;Calorie Restriction and Its Mimetics;497
10.6.7.2;Mitochondrial Intervention;498
10.6.7.2.1;Antioxidants;498
10.6.7.2.2;SS-31;499
10.6.7.3;Inhibition of Renin–Angiotensin–Aldosterone signaling;500
10.6.7.4;Other Novel Agents;500
10.6.8;References;501
10.7;18 Current Status of Research on Trends in Morbidity, Healthy Life Expectancy, and the Compression of Morbidity;512
10.7.1;Introduction;512
10.7.2;Dimensions of Morbidity;513
10.7.3;The Length of Life Cycles and Population Health;514
10.7.4;Trends in Population Prevalence of Physiological Dysregulation, Diseases and Conditions, Functioning Loss and Disability, a ...;514
10.7.5;Length of Life and Length of Healthy Life;517
10.7.6;Conclusions;521
10.7.7;References;521
10.8;19 On the Compression of Morbidity: From 1980 to 2015 and Beyond;524
10.8.1;Introduction;524
10.8.1.1;Compression of Morbidity;524
10.8.1.2;The Science of Postponement of Disability;526
10.8.1.3;Synonyms and Antonyms;526
10.8.1.4;Human Aging;528
10.8.2;Themes and Paradigms;528
10.8.2.1;Longitudinal Study of Human Aging;528
10.8.2.2;Long-Distance Runners Versus Community Controls;531
10.8.2.3;Two or More Risk Factors (Smoking, Inactivity, or Obesity) Versus None of These;533
10.8.2.4;Morbidity is Best Compressed by Regular, Vigorous, and Sustained Exercise;535
10.8.2.5;Disease, Diagnosis, Morbidities, and Trajectories;536
10.8.2.6;Delayed Aging;537
10.8.3;Concluding Remarks;538
10.8.3.1;State of the Evidence;538
10.8.3.2;Possibilities and Uncertainties;539
10.8.4;References;539
11;Author Index;542
12;Subject Index;560

Leseproben

List of Contributors
Rolf Bodmer,     Development, Aging, and Regeneration Program Sanford-Burnham Medical Research Institute, La Jolla, CA, USA Rochelle Buffenstein Barshop Institute for Aging and Longevity Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Hao Cheng,     Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Ying-Ann Chiao,     Department of Pathology, University of Washington, Seattle, WA, USA Miook Cho,     Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA Eileen M. Crimmins,     Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA Dao-Fu Dai,     Department of Pathology, University of Washington, Seattle, WA, USA João Pedro de Magalhães,     Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool, Liverpool, UK James F. Fries,     Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA William Giblin,     Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA Vera Gorbunova,     Department of Biology, University of Rochester, Rochester, NY, USA Jing-Dong J Han,     Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China David E. Harrison,     The Jackson Laboratory, Bar Harbor, ME, USA Ingrid A. Harten Matrexa LLC, Seattle, WA, USA Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA Lei Hou,     Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China F. Brad Johnson,     Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Matt R. Kaeberlein,     Department of Pathology, University of Washington, Seattle, WA, USA Brian K. Kennedy,     The Buck Institute for Research on Aging, Novato, CA, USA Ron Korstanje,     The Jackson Laboratory, Bar Harbor, ME, USA Edward G. Lakatta,     Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Biomedical Research Center, Baltimore, MD, USA Scott F. Leiser,     Department of Pathology, University of Washington, Seattle, WA, USA Morgan E. Levine,     University of California Los Angeles, Los Angeles, CA, USA Kaitlyn N. Lewis Barshop Institute for Aging and Longevity Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA David B. Lombard Department of Pathology, University of Michigan, Ann Arbor, MI, USA Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA Hillary A. Miller,     Department of Pathology, University of Washington, Seattle, WA, USA Richard A. Miller,     Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA Robert E. Monticone,     Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Biomedical Research Center, Baltimore, MD, USA Shannon J. Moore,     Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA Ludmila Müller,     Max Planck Institute for Human Development, Berlin, Germany Geoffrey G. Murphy Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA Nancy L. Nadon,     Division of Aging Biology, National Institute on Aging, Bethesda, MD, USA Monique N. O’Leary,     The Buck Institute for Research on Aging, Novato, CA, USA Michelle Olive,     National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA Graham Pawelec,     Center for Medical Research, University of Tübingen, Tübingen, Germany Scott D. Pletcher Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA Geriatrics Center, University of Michigan, Ann Arbor, MI, USA Peter S. Rabinovitch,     Department of Pathology, University of Washington, Seattle, WA, USA Katherine H. Schreiber,     The Buck Institute for Research on Aging, Novato, CA, USA Andrei Seluanov,     Department of Biology, University of Rochester, Rochester, NY, USA Shufei Song Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA, USA Randy Strong,     Department of Pharmacology, The University of Texas Health Science Center at San Antonio, and the Geriatric Research, Education and Clinical Center and Research Service of the South Texas Veterans Health Care System, San Antonio, TX, USA Yousin Suh Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA George L. Sutphin,     The Jackson Laboratory, Bar Harbor, ME, USA Hazel H. Szeto,     Department of Pharmacology, Joan and Sanford I Weill Medical College of Cornell University, New York, NY, USA Robi Tacutu,     Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool, Liverpool, UK Michael Van Meter,     Department of Biology, University of Rochester, Rochester, NY, USA Dan Wang,     Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Mingyi Wang,     Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Biomedical Research Center, Baltimore, MD, USA Michael J. Waterson,     Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA Robert J. Wessells,     Geriatrics Center and Institute of Gerontology, University of Michigan, Ann Arbor, MI, USA Thomas N. 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