The eighth edition of this very successful handbook on how basic aging processes and medical physiology affect biological systems includes new discussions of a variety of topics, including longevity pathways and interventions that modulate aging, innovative new tools that facilitate systems-level approaches to aging research and more.

Table of Contents

• Foreword
• Preface
• About the Editors
• List of Contributors
• Part I Basic Mechanisms of Aging: Models and Systems
• 1. Longevity as a Complex Genetic Trait
• Introduction
• Defining the Aging Gene-Space
• Direct Screens for Genetic Longevity Determinants
• RNAi Screens in Nematodes
• Knockout Screens in Budding Yeast
• Overexpression Screens in Fruit Flies
• Leveraging Genetic Diversity to Identify Aging Loci
• Mapping Longevity Genes in Human Populations
• Mapping Longevity Genes in Mouse Populations
• Mouse–Human Concordance
• Age-Associated Gene Expression Studies
• Non-Genetic Sources of Complexity
• Tissue-Specific Aging
• Tissue-Specific Age-Related DNA Methylation
• Telomere Shortening and Telomerase
• Tissue-Specific Responses of Aging Pathways
• Gene–Environment Interaction
• Genetic Response to DR
• DR: Quantity, Composition, and Timing
• Environmental Temperature
• Environmental Oxygen and the Hypoxic Response
• Other Environmental Factors That Influence Aging
• Emerging Tools for Studying Aging as a Complex Genetic Trait
• High-Throughput Lifespan Assays in Yeast and Worms
• Genome-Scale Mouse Knockout Collection
• Collaborative Cross and Diversity Outbred Mice
• Expression QTLs
• Aging Biomarkers
• Conclusions
• References
• 2. The mTOR Pathway and Aging
• Introduction
• mTOR Signaling Pathway
• Molecular Composition of mTOR Complex
• Upstream Regulators of mTOR Complexes
• Substrates and Actions of mTORC1
• Substrates and Actions of mTORC2
• Genetic Modulation of Longevity by TOR Signaling in Model Organisms
• Rapamycin
• Rapalogs
• Potential Mechanisms of Life Span Extension by mTOR Inhibition
• Translation
• Autophagy
• Anticancer Effect
• Stem Cell Maintenance
• mTOR in Age-Related Diseases
• Cancer
• Metabolic Disease
• Cardiovascular
• Neurodegeneration and Cognitive Decline
• Immune Response
• Conclusion
• References
• 3. Sirtuins, Healthspan, and Longevity in Mammals
• Introduction
• Sirtuin-Driven Lifespan Extension in Invertebrates
• Sirtuin Enzymatic Activity
• Sirtuins and Mammalian Longevity
• SIRT1
• SIRT2
• SIRT6
• Genetic Variation of Human Sirtuins
• SIRT1
• SIRT3
• Sirtuins as Modulators of Responses to CR
• SIRT1
• SIRT2
• SIRT3
• SIRT4
• SIRT5
• SIRT6
• Roles for Sirtuins in Diverse Disease States
• Cancer
• SIRT1
• SIRT2
• SIRT3
• SIRT4
• SIRT6
• SIRT7
• Metabolic Syndrome
• SIRT1
• SIRT2
• SIRT3
• SIRT4
• SIRT5
• SIRT6
• SIRT7
• Cardiovascular Dysfunction
• SIRT1
• Other Sirtuins
• Inflammatory Signaling
• Neurodegenerative Disease
• SIRT1
• SIRT2
• SIRT3
• Sirtuin-Activating Compounds
• Conclusion
• Acknowledgments
• References
• 4. The Hypoxic Response and Aging
• Introduction
• The Hypoxic Response
• Signal Transduction Pathway
• Hypoxic Signaling in Disease
• VHL Disease
• Cancer
• Environmental Modifiers
• Physiological Roles for the Hypoxic Response
• Hypoxia
• Development/Stem Cell Maintenance
• Immunity
• A Direct Role for the Hypoxic Response in Aging
• The Hypoxic Response in Aging of Other Non-Mammalian Organisms
• Interactions with Other Longevity Pathways
• Sirtuins
• Long-Lived Mitochondrial Mutants
• Target of Rapamycin
• HIF in Mammalian Aging
• Positive Effects of Hypoxia
• Conclusion
• Acknowledgments
• References
• 5. The Role of Neurosensory Systems in the Modulation of Aging
• Introduction
• Peripheral Systems of Sensory Perception
• Environmental Sensing and the Regulation of Aging
• Mechanisms of Sensory-Mediated Lifespan Regulation
• The Next Steps in Mapping Sensory-Mediated Lifespan Circuits
• Synthesis and Perspectives
• References
• 6. The Naked Mole-Rat: A Resilient Rodent Model of Aging, Longevity, and Healthspan
• What Is a Naked Mole-Rat?
• Ecophysiology and Tolerance to Hypoxia
• Eusociality
• Successful Aging
• Naked Mole-Rat Aging Biology
• The Aging Brain
• The Aging Heart
• Aging Reproductive Profile
• End of Life Pathology
• Resistance to Toxins
• Cancer Resistance in the Naked-Mole Rat
• Maintenance of Genomic and Proteomic Integrity
• Mechanisms in Successful Aging
• Insulin mTOR Signaling
• Oxidative Stress
• Proteolytic Degradation Pathways Include Autophagy and UPS
• Cytoprotective Signaling—Nrf2 Activity
• Summary
• References
• 7. Contributions of Telomere Biology to Human Age-Related Disease
• Introduction
• Telomere Structure and Function
• Telomerase Structure, Function, and Regulation
• Cellular Consequences of Telomere Dysfunction
• Age-Related Changes in Telomere Length
• Connections Between Human Age-Related Disease and Telomeres
• Overall Longevity
• Cardiovascular Diseases
• Reproductive Aging
• Type 2 Diabetes Mellitus
• Osteoporosis
• Idiopathic Pulmonary Fibrosis
• Environmental Exposures
• Cirrhosis
• Cancer
• Centenarians
• Human Progeroid Disorders
• p16 and Aging
• Mouse Models
• Pathologies Associated with Long Telomeres
• Prospects for Prognostication and Intervention
• Acknowledgments
• References
• 8. Systems Approaches to Understanding Aging
• Introduction
• Transcriptomic Approaches Toward Understanding Aging
• Gene Expression Profiles Related to Aging
• Inferring Aging Regulators from Gene Expression Profiles
• Regulatory Networks of Aging
• MicroRNA, Systems Biology, and Aging
• Knockdown or Knockout of miRNA Machinery
• Finding Aging-Related miRNAs by High-Throughput Technologies
• Searching for miRNA Targets In Silico and In Vivo
• miRNA as Aging Biomarkers
• Epigenomics and Aging
• DNA Methylation and Aging
• Histone Modification and Aging
• Approaches to Detecting the Crosstalk of Epigenomic Markers
• Integrated Microfluidic Systems for Studying Aging
• Microfluidic Devices for Yeast Aging Study
• Microfluidic Devices for C. elegans Aging Study
• Conclusions
• Acknowledgments
• References
• 9. Integrative Genomics of Aging
• Introduction
• Post-Genome Technologies and Biogerontology
• Genome-Wide Approaches and the Genetics of Aging and Longevity
• Surveying the Aging Phenotype on a Grand Scale
• Challenges in Data Analysis
• Data Integration
• Data and Databases
• Finding Needles in Haystacks: Network Approaches and Multi-Dimensional Data Integration
• Construction of Longevity Networks
• Topological Features
• Network Modularity
• Multi-Dimensional Data Integration
• Predictive Methods and Models
• Concluding Remarks
• Acknowledgments
• References
• 10. NIA Interventions Testing Program: A Collaborative Approach for Investigating Interventions to Promote Healthy Aging
• Introduction
• Features of the ITP Experimental Design
• Types of Intervention Proposals Sought by the ITP
• Challenges Encountered Implementing Testing Protocols
• Summary of ITP Findings
• Stage II Studies
• The ITP at 10 Years: Synopsis and Future Goals
• References
• 11. Comparative Biology of Aging: Insights from Long-Lived Rodent Species
• Introduction
• Rodents as Models for Comparative Research
• Cross-Species Biological Comparisons
• Telomerase Maintenance and Replicative Senescence
• Mechanisms for Controlling Cell Proliferation
• Body Mass and Lifespan Shape Tumor Suppressor Mechanisms
• Lifespan and Genome Stability
• NMRs and BMRs
• Hyaluronan Mediates Cancer Resistance in the NMR
• Accurate Protein Synthesis in the NMR
• Interferon Mediates Cancer Resistance in the BMR
• Hyaluronan Evolved in Long-Lived Subterranean Rodents
• Comparative Genomics of Aging and Cancer
• Strategies for Comparative Genomics
• Genomics of the NMR
• Genomics of the BMR
• Independent Adaptations to Subterranean Life
• Comparative Genomics of Rodents and Other Mammals
• Conclusion
• References
• Part II The Pathobiology of Human Aging
• 12. Genetics of Human Aging
• Introduction
• Genetic Variation in Aging
• Phenotypes of Human Aging
• Experimental Models for Studying Human Aging
• Study Designs for Discovering Genes Related to Human Aging
• Genetic Linkage Analysis
• Genetic Association Analysis
• Genome-Wide Association Studies
• Rare Variants in Aging
• Candidate Studies in Aging
• Functional Analysis
• In Silico Analysis of Genetic Variants
• Functional Analysis of Genetic Variants in In Vitro and In Vivo Models
• Summary and Perspectives
• References
• 13. The Aging Arterial Wall
• Introduction
• Proinflammatory Molecular Signature of the Aging Arterial Wall
• Renin–Angiotensin System
• Aldosterone and Mineralocorticoid Receptor-Mediated Signaling
• Endothelin-1 Signaling
• Adrenergic Receptor Signaling
• Monocyte Chemoattractant Protein-1
• Transforming Growth Factor-β1
• Bone Morphogenetic Proteins
• Platelet-Derived Growth Factor
• Interleukin-6 and Tissue Necrosis Factor-Alpha
• Matrix Metalloproteinases
• Calpain-1/Calpastatin
• Milk Fat Globule EGF-8 and Integrins
• Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1
• Reactive Oxygen Species
• Nitric Oxygen and Bioavailability
• Cell Cycle Promoter Molecules
• Intracellular Matrix Messenger Molecules, SMADs
• Cell Cycle Inhibitory Molecules
• Proinflammation Transcription Factors Ets-1 and NF-κB
• Anti-Inflammatory Factors Nrf2, PPARγ, SIRT1, and FOXO3
• Proliferation Transcription Factor AP-1
• Macroscopic Age-Associated Altered Arterial Phenotypes
• Arterial Cellular Phenotypes
• Endothelial Cells
• Vascular Smooth Muscle Cells
• Fibroblasts
• Arterial Wall Phenotypes
• Endothelial Barrier Dysfunction
• Prothrombosis
• Fibrosis
• Calcification
• Elastin Fragmentation
• Amyloidosis
• Glycoxidization
• Arterial Tissue Senescence
• Clinical Signs of Arterial Wall Aging
• Blood Pressure
• Intimal-Medial Thickness
• Pulse Wave Velocity
• Endothelial Dysfunction
• Interaction of Aging, Hypertension, and Atherosclerosis
• Hypertension and Aging
• Atherosclerosis and Aging
• Interventions on Arterial Wall Aging
• Blockade of Ang II Signaling, Adverse Remodeling, and Proinflammation
• MMP Inhibition, Elastin Fragmentation, and ECM Deposition
• Breakers of AGEs, RAGE and arterial stiffening
• Caloric Restriction, Resveratrol, and Adverse Remodeling
• Physical Conditioning and Proinflammation
• Concluding Remarks and Future Perspectives
• Acknowledgment
• References
• 14. Age-Related Alterations in Neural Plasticity
• Introduction
• Short (Milliseconds) Timeframe: Paired-Pulse Facilitation and Paired-Pulse Depression
• Intermediate (Seconds) Timeframe: Frequency Facilitation (FF) and the Post-Burst Afterhyperpolarization
• Frequency Facilitation
• Post-Burst Afterhyperpolarization
• Long (Minutes to Days) Timeframe: Long-Term Potentiation and Long-Term Depression
• Neural Plasticity and the Calcium Dysregulation Hypothesis of Aging
• References
• 15. The Aging Immune System: Dysregulation, Compensatory Mechanisms, and Prospects for Intervention
• Introduction
• Innate and Adaptive Immunity
• Age and Immunity
• Effect of Age on Hematopoiesis
• Effect of Age on Innate Immunity
• NK Cells
• Dendritic Cells
• Effect of Age on Adaptive Immunity
• Impact of Thymic Involution and Thymectomy on T Cells
• Immune Cell Function
• T-Cell Function
• B-Cell Function
• Clinical Consequences of Immunosenescence
• Effect of Age on Vaccination
• Immune Senescence and All-Cause Mortality
• Interventions to Restore Appropriate Immunity
• Perspectives
• References
• 16. Vascular Disease in Hutchinson Gilford Progeria Syndrome and Aging: Common Phenotypes and Potential Mechanisms
• Introduction
• Progeria as a Model for Studying Vascular Disease
• Vascular Pathology in Progeria and Aging
• Hypertension
• Adventitial Fibrosis
• Medial Cell Death
• Atherosclerosis in Progeria and Aging
• ECM Changes in Progeria and Aging and Their Potential Contribution to Atherosclerosis
• Potential Molecular Mechanisms Driving Vascular Disease in Progeria
• A-Type Lamin Mutation and Progerin Processing
• Progerin Expression in Normal Aging Vasculature
• Chromatin Reorganization
• Altered Transcription Factor Regulation
• DNA Damage and Dysfunctional Telomeres
• Mechanosensitivity
• Dysfunctional Stem Cell Niche
• Mouse Models of Progeria
• Current Status of Clinical Intervention Trials for Progeria
• Concluding Remarks
• References
• 17. Cardiac Aging
• Introduction
• Cardiac Aging in Humans
• Murine Model of Cardiac Aging
• Molecular Mechanisms of Cardiac Aging
• Role of Mitochondria and ROS in Cardiac Aging
• Nutrient Signaling in Cardiac Aging
• Neurohormonal Regulation of Cardiac Aging
• Renin–Angiotensin–Aldosterone System (RAAS)
• Adrenergic Signaling
• Insulin/IGF-1 Signaling
• Aging of Cardiac Stem/Progenitor Cells
• Decreased Cardiac Functional Reserve in Aging
• Mechanisms of Progression to Heart Failure in Old Age
• Mitochondrial Dysfunction and Abnormalities in Energetics
• Increased Cardiomyocyte Death and ECM Remodeling
• Alteration of Calcium Handling Proteins
• Hypoxic Response and Angiogenesis
• Other Models of Cardiac Aging
• Drosophila: An Invertebrate Model of Cardiac Senescence
• Normal Aging of the Drosophila Heart
• Genetic Regulation
• Large Animal Models of Cardiac Aging
• Interventions to Delay or Reverse Vertebrate Cardiac Aging
• Calorie Restriction and Its Mimetics
• Mitochondrial Intervention
• Antioxidants
• SS-31
• Inhibition of Renin–Angiotensin–Aldosterone signaling
• Other Novel Agents
• References
• 18. Current Status of Research on Trends in Morbidity, Healthy Life Expectancy, and the Compression of Morbidity
• Introduction
• Dimensions of Morbidity
• The Length of Life Cycles and Population Health
• Trends in Population Prevalence of Physiological Dysregulation, Diseases and Conditions, Functioning Loss and Disability, and Life Expectancy
• Length of Life and Length of Healthy Life
• Conclusions
• References
• 19. On the Compression of Morbidity: From 1980 to 2015 and Beyond
• Introduction
• Compression of Morbidity
• The Science of Postponement of Disability
• Synonyms and Antonyms
• Human Aging
• Themes and Paradigms
• Longitudinal Study of Human Aging
• Long-Distance Runners Versus Community Controls
• Two or More Risk Factors (Smoking, Inactivity, or Obesity) Versus None of These
• Morbidity is Best Compressed by Regular, Vigorous, and Sustained Exercise
• Disease, Diagnosis, Morbidities, and Trajectories
• Delayed Aging
• Concluding Remarks
• State of the Evidence
• Possibilities and Uncertainties
• References
• Subject Index