Epigenetics of Aging and Longevity

Description

Epigenetics of Aging and Longevity provides an in-depth analysis of the epigenetic nature of aging and the role of epigenetic factors in mediating the link between early-life experiences and life-course health and aging. Chapters from leading international contributors explore the effect of adverse conditions in early-life that may result in disrupted epigenetic pathways, as well as the potential to correct these disrupted pathways via targeted therapeutic interventions. Intergenerational epigenetic inheritance, epigenetic drug discovery, and the role of epigenetic mechanisms in regulating specific age-associated illnesses—including cancer and cardiovascular, metabolic, and neurodegenerative diseases—are explored in detail.

This book will help researchers in genomic medicine, epigenetics, and biogerontology better understand the epigenetic determinants of aging and longevity, and ultimately aid in developing therapeutics to extend the human life-span and treat age-related disease.

Offers a comprehensive overview of the epigenetic nature of aging, as well as the impact of epigenetic factors on longevity and regulating age-related disease
Provides readers with clinical and epidemiological evidence for the role of epigenetic mechanisms in mediating the link between early-life experiences, life-course health and aging trajectory
Applies current knowledge of epigenetic regulatory pathways towards developing therapeutic interventions for age-related diseases and extending the human lifespan

Front Cover 2
Epigenetics of Aging and Longevity 3
Translational Epigenetics Series 4
Epigenetics of Aging and Longevity: Translational Epigenetics Series 5
Copyright 6
Contents 7
List of Contributors 21
Preface 25
1 - EPIGENETIC MECHANISMSIN AGING 27
- 1 - AGING EPIGENETICS: CHANGES AND CHALLENGES 29
  - 1. INTRODUCTION 30
  - 2. EPIGENETIC ALTERATIONS AND THE AGING PROCESS 31
    - 2.1 THE ‘AGING EPIGENOME’ 31
      - 2.1.1 Histone Deposition and Chromatin Structure in Aging 31
      - 2.1.3 Posttranslation Modifications of Histone Proteins 36

Front Cover 2
Epigenetics of Aging and Longevity 3
Translational Epigenetics Series 4
Epigenetics of Aging and Longevity: Translational Epigenetics Series 5
Copyright 6
Contents 7
List of Contributors 21
Preface 25
1 - EPIGENETIC MECHANISMSIN AGING 27
- 1 - AGING EPIGENETICS: CHANGES AND CHALLENGES 29
  - 1. INTRODUCTION 30
  - 2. EPIGENETIC ALTERATIONS AND THE AGING PROCESS 31
    - 2.1 THE ‘AGING EPIGENOME’ 31
      - 2.1.1 Histone Deposition and Chromatin Structure in Aging 31
      - 2.1.3 Posttranslation Modifications of Histone Proteins 36
      - 2.1.2 DNA Methylation 36
    - 3. SIGNIFICANCE OF THE AGING EPIGENOME 37
      - 3.2 LINKS BETWEEN EPIGENETIC AND GENOMIC INSTABILITY WITH AGE 38
      - 3.1 AGE-RELATED LOSS OF TRANSCRIPTIONAL PRECISION 38
    - 4. THE POWER OF GENOMICS: GLOBAL VERSUS GENOME-WIDE LOCUS-SPECIFIC AGE-RELATED CHANGES 39
      - 4.1 DNA-METHYLATION PROFILING IN AGED HUMAN CELLS 39
      - 4.2 LESSONS FROM GENOME-WIDE PROFILING OF CHROMATIN LANDSCAPE WITH AGING 40
      - 4.3 ADVANCES IN EPIGENOME PROFILING IN HUMAN CELLS 41
    - 5. EMERGING CHALLENGES IN THE FIELD OF AGING EPIGENOMICS 42
      - 5.1 TOWARD EPIGENETIC LONGEVITY DRUGS? 43
      - 5.2 SEX-DIMORPHISM AND IMPLICATIONS 43
      - 5.3 EPIGENOMICS OF IMMUNE SYSTEM AGING 44
      - 5.5 ACCOUNTING FOR CELL INTRINSIC VERSUS CELL COMPOSITION–DERIVED CHANGES WITH EPIGENOMIC AGING 45
      - 5.4 THE CHALLENGES OF MULTIOMIC DATA INTEGRATION AND INTERPRETATION 45
    - 6. CONCLUSIONS 46
    - GLOSSARY 47
    - ACKNOWLEDGMENTS 47
    - LIST OF ACRONYMS AND ABBREVIATIONS 47
    - REFERENCES 48
  - 2 - DEFECTIVE DNA METHYLATION/DEMETHYLATION PROCESSES DEFINE AGING-DEPENDENT METHYLATION PATTERNS 59
    - 1. INTRODUCTION 59
    - 2. DNA METHYLATION/DEMETHYLATION IN MAMMALS 60
      - 2.1 DNA METHYLATION PROCESSES 60
      - 2.2 DISTRIBUTION OF THE DNA METHYLATION SIGNAL IN THE GENOME 62
      - 2.3 DNA DEMETHYLATION PROCESSES 63
      - 2.4 DISTRIBUTION OF THE 5HMC SIGNAL IN THE GENOME 64
    - 3. EFFECT OF ENVIRONMENTAL FACTORS ON DNA EPIGENETIC MODIFICATIONS 65
    - 4. THE IMPACT OF AGING ON DNA EPIGENETIC MODIFICATION PATTERNS 66
      - 4.1 AGE-ASSOCIATED DNA HYPOMETHYLATION 67
      - 4.2 AGE-ASSOCIATED DNA HYPERMETHYLATION 68
      - 4.3 THE “EPIGENETIC CLOCK” 68
      - 4.4 DNA HYDROXYMETHYLATION IN AGING 69
    - 5. TOWARD MOLECULAR MECHANISMS FOR THE AGING-RELATED CHANGES OF DNA EPIGENETIC MODIFICATION PATTERNS 69
    - 6. CONCLUSIONS 74
    - LIST OF ABBREVIATIONS 75
    - GLOSSARY 77
    - REFERENCES 77
  - 3 - S-ADENOSYLMETHIONINE METABOLISM AND AGING 85
    - 1. INTRODUCTION 86
    - 2. THIS REVIEW 88
    - 3. WELL-KNOWN PATHWAYS OF SAM IN CENTRAL METABOLISM 89
      - 3.1 THE METHIONINE CYCLE 89
      - 3.2 THE TRANSSULFURATION PATHWAY TO GSH 89
      - 3.3 THE POLYAMINE CYCLE 90
    - 5. RADICAL SAM PROTEINS WITH IRON–SULFUR (FES) CLUSTERS 90
      - 5.1 FES PROTEINS 90
      - 5.3 TYPES OF RADICAL SAM ENZYMES 91
      - 5.2 SAM-DEPENDENT RADICAL FES PROTEINS 91
      - 5.4 RADICAL SAM ENZYMES IN HUMAN DISEASE 92
      - 5.6 RADICAL SAM METHYLTRANSFERASES AND MMTASES 93
      - 5.5 RADICAL SAM ENZYMES THAT MODIFY MAMMALIAN TRNAS 93
    - 4. SAM AND RNA-BASED CONTROL BY RIBOSWITCHES 90
    - 6. SAM AND ITS ROLE IN AGING AND LONGEVITY 94
      - 6.1 SAM, MITOCHONDRIA, AND AGING 95
      - 6.2 SAM AND NEURODEGENERATION 95
      - 6.4 SAM, THE MICROBIOME AND AGING 96
      - 6.5 SAM AND THE ESTABLISHMENT AND MAINTENANCE OF THE MICROBIOME 96
      - 6.3 SAM AND LONG-LIVED RODENTS 96
    - 7. CONCLUSION 97
    - LIST OF ABBREVIATIONS 98
    - REFERENCES 99
  - 4 - THE EPIGENETIC CLOCK AND AGING 121
    - 3. SITE-SPECIFIC DNA METHYLATION CHANGES IN FUNCTION OF AGE 122
    - 1. INTRODUCTION 122
    - 2. GLOBAL DNA METHYLATION CHANGES IN FUNCTION OF AGE 122
    - 4. THE EPIGENETIC CLOCK 124
    - 5. DESYNCHRONIZATION OF EPIGENETIC AGE FROM CHRONOLOGICAL AGE 125
      - 5.1 AGING ABNORMALITIES 125
      - 5.2 NEUROLOGICAL DISORDERS 126
      - 5.3 HORMONES 127
      - 5.4 OBESITY AND DIET 127
      - 5.5 VIRAL INFECTION 128
      - 5.6 CANCERS 129
      - 5.7 INDUCTION OF PLURIPOTENCY 129
    - 7. THE EPIGENETIC AGING OF IN VITRO-CULTURED CELLS 130
    - 6. EPIGENETIC AGE AND MORTALITY 130
    - 8. THE EPIGENETIC CLOCK AT THE CELLULAR LEVEL 131
      - 8.1 HOW THE CLOCK TICKS 132
      - 8.2 THE LEGACY OF LIFE 133
    - 9. EPIGENETIC AGING AND CELLULAR SENESCENCE 134
    - 10. EPIGENETIC AGING, TELOMERE, AND TELOMERASE 135
    - 11. TWO ROUTES TO AGING 135
    - 12. CONCLUSION 137
    - LIST OF ACRONYMS AND ABBREVIATIONS 138
    - REFERENCES 139
    - GLOSSARY 139
  - 5 - THE EPIGENETIC REGULATION OF TELOMERE MAINTENANCE IN AGING 145
    - 1. INTRODUCTION 145
    - 2. EPIGENETICS OF AGING AND LONGEVITY 146
    - 3. THE EPIGENETIC AGING CLOCK 147
    - 5. TELOMERE ATTRITION AS AN AGING HALLMARK 148
    - 4. TELOMERES AND AGING 148
      - 4.1 TELOMERE STRUCTURE 148
      - 4.2 TELOMERASE STRUCTURE 148
    - 6. SHELTERIN COMPLEX AND TELOMERASE ENZYME IN AGING 150
    - 8. ANIMAL MODELS IN TELOMERES AND AGING STUDIES 151
    - 7. TELOMERE LENGTH AND LONGEVITY 151
    - 9. EPIGENETICS AND TELOMERES 152
      - 9.2 EPIGENETIC REGULATION OF TELOMERES 152
      - 9.1 TELOMERE MAINTENANCE 152
    - 10. EPIGENETIC MODIFICATIONS IN TELOMERES 153
      - 10.1 HISTONE MODIFICATIONS 153
      - 10.2 DNA METHYLATION 154
      - 10.3 RNA INTERFERENCE 154
    - 11. TELOMERES AS EPIGENETIC AGENTS 155
    - 12. EPIGENETICS OF AGING AND ITS RELEVANCE TO TELOMERE LENGTH 155
    - 13. CONCLUSION 156
    - REFERENCES 157
    - LIST OF ACRONYMS AND ABBREVIATIONS 157
    - GLOSSARY 157
  - 6 - LIVING LONG AND AGING WELL: ARE LIFESTYLE FACTORS THE EPIGENETIC LINK IN THE LONGEVITY PHENOTYPE? 163
    - 1. INTRODUCTION 163
    - 2. KEEPING PHYSICALLY ACTIVE 165
      - 2.1 EXERCISE AS AN EPIGENETIC MODIFIER 165
      - 2.2 MUSCLES ARE REMODELED 165
      - 2.3 EXERCISE REVITALIZES MITOCHONDRIA 166
    - 3. MAINTAINING GOOD MENTAL ACTIVITY 167
      - 3.1 THE BRAIN–EXERCISE EPIGENETIC LINK 167
      - 3.2 BRAIN-DERIVED NEUROTROPHIC FACTOR 168
    - 4. EATING WELL 169
      - 4.1 DIET AND EPIGENETICS 169
      - 4.2 CALORIE INTAKE AND EPIGENETICS 171
    - 5. CONCLUSION 171
    - LIST OF ABBREVIATIONS 173
    - REFERENCES 174
    - ACKNOWLEDGMENTS 174
  - 7 - EPIGENETIC BIOMARKERS FOR BIOLOGICAL AGE 179
    - 1. INTRODUCTION: BIOLOGICAL AGE IS A METAPHOR FOR HETEROGENEITY OF HEALTH OF PEOPLE AT THE SAME CHRONOLOGICAL AGE 180
    - 2. MULTIPLE BIOLOGICAL MARKERS (BATTERY OF BIOMARKERS) AS AGE PREDICTORS 181
    - 3. ESTIMATION OF BIOLOGICAL AGE 182
    - 5. DNAM AGE OF HORVATH 183
    - 4. EPIGENETIC METHYLATION MARKERS—DNA METHYLATION LEVEL CHANGES WITH AGE 183
    - 6. DNAM AGE OF HANNUM 185
    - 7. DNAM AGE OF WEIDNER 186
    - 8. DELTA AGE–AGE ACCELERATION 186
      - 8.1 GESTATIONAL AGE 187
    - 9. MORBIDITY, DNAM AGE, AND AGE ACCELERATION 187
      - 9.3 INSOMNIA 187
      - 9.1 ALZHEIMER’S DISEASE 187
      - 9.4 LUNG CANCER 187
      - 9.2 PARKINSON’S DISEASE 187
      - 9.6 COGNITIVE IMPAIRMENT 188
      - 9.9 DOWN SYNDROME (DS) 188
      - 9.7 REPRODUCTIVE FUNCTION IN WOMEN 188
      - 9.5 OSTEOARTHRITIS (OA) 188
      - 9.8 CORONARY HEART DISEASES 188
      - 9.11 POSTTRAUMATIC STRESS DISORDER (PTSD) 189
      - 9.12 HUNTINGTON’S DISEASE (HD) 189
      - 9.10 CEREBELLUM AGING 189
      - 9.13 HIV 189
    - 10. DNAM AGE IN SEMISUPERCENTENARIANS 189
    - 11. CLINICAL USE: PERSPECTIVES 190
    - 12. DNAM AGE AND FRAILTY 190
    - 13. DNAM AGE AND MORTALITY 191
    - 14. BIOLOGICAL AGE: ONE OR MANY? 192
    - 15. CONCLUSION 193
    - LIST OF ACRONYMS AND ABBREVIATIONS 193
    - REFERENCES 193
  - 8 - THE ROLE OF NONCODING RNAS IN GENOME STABILITY AND AGING 197
    - 1. INTRODUCTION 198
    - 2. GENOMIC DNA ELIMINATION IN CILIATES 198
    - 3. THE REGULATION OF GENOME STABILITY THROUGH MIRNAS 199
      - 3.2 DNA REPAIR PROTEINS REGULATE MIRNA BIOGENESIS 199
      - 3.1 AN INDIRECT ROLE OF MIRNAS IN GENOME STABILITY 199
      - 3.3 MIRNAS REGULATE THE ACTIVITY OF DNA DAMAGE SENSORS AND EFFECTORS 202
        
        3.3.2 The Regulation of Effectors by miRNAs 202
        
        3.3.1 The Regulation of Sensors by miRNAs 202
      - 4. THE ROLE OF PIRNAS IN THE INTEGRITY OF THE GENOME IN THE GERMLINE 203
        
        4.1 PIRNAS IN DROSOPHILA 203
        
        4.2 PIRNAS IN MAMMALS 207
        
        4.3 PIRNAS IN TRANSGENERATIONAL RESPONSE 207
      - 5. THE MAINTENANCE OF GENOME STABILITY BY SMALL INTERFERING RNAS 208
        
        5.1 SIRNAS IN NEUROSPORA CRASSA 208
        
        5.1.1 qiRNA—DNA Damage-Induced siRNAs in Neurospora 210
        
        5.2 SMALL NCRNAS INDUCED BY DNA STRAND BREAKS IN MAMMALS AND PLANTS 210
      - 6. THE ROLE OF NCRNAS IN AGING 214
        
        6.1 THE ROLE OF MIRNAS IN AGING 214
        
        6.1.1 miRNAs Inhibiting Senescence 215
        
        6.1.2 miRNAs Promoting Senescence 215
        
        6.2 THE ROLE OF LNCRNA IN AGING 216
        
        6.3 EXTRACELLULAR RNAS IN AGING 219
      - 7. CONCLUSION 219
      - LIST OF ABBREVIATIONS 220
      - GLOSSARY 220
      - REFERENCES 221
    - 9 - INTRATISSUE DNA METHYLATION HETEROGENEITY IN AGING 227
      - 1. INTRODUCTION 227
      - 2. CHANGES IN DNA METHYLATION IN CANCER 228
      - 3. CHANGES IN DNA METHYLATION IN AGING 229
      - 4. STOCHASTIC CHANGES IN DNA METHYLATION 229
      - 5. CONCLUSION 233
      - ACKNOWLEDGMENTS 234
      - REFERENCES 234
    - 2 - EARLY-LIFE EPIGENETIC PROGRAMMING OF AGING TRAJECTORIES 237
      - 10 - EARLY-LIFE NUTRITION, EPIGENETICS, AND ALTERED ENERGY BALANCE LATER IN LIFE 239
        
        1. INTRODUCTION 239
        
        1.1 PROGRAMMING OF ALTERED ENERGY BALANCE: HUMAN EVIDENCE 241
        
        1.2 PROGRAMMING OF ALTERED ENERGY BALANCE: EVIDENCE FROM ANIMAL MODELS 241
        
        1.2.1 The Hypothalamus and Programmed Alterations in Feeding Circuitry 242
        
        1.2.2 Epigenetic Effects 243
        
        1.2.3 Brown Adipose Tissue and Altered Thermogenesis 245
        
        2. INTERVENTIONS 246
        
        3. CONCLUSIONS 247
        
        LIST OF ACRONYMS AND ABBREVIATIONS 248
        
        GLOSSARY 248
        
        REFERENCES 248
        
        11 - EARLY NUTRITION, EPIGENETICS, AND HUMAN HEALTH 255
        
        1. THE EARLY-LIFE ORIGINS OF DISEASE 255
        
        2. THE IMPACT OF UNDERNUTRITION 257
        
        3. THE IMPACT OF OVERNUTRITION 260
        
        4. THE CONTRIBUTION OF EPIGENETICS 263
        
        5. SUMMARY AND CONCLUSIONS 269
        
        LIST OF ABBREVIATIONS 270
        
        GLOSSARY 270
        
        REFERENCES 271
        
        FURTHER READING 276
        
        12 - BIOLOGICAL EMBEDDING OF PSYCHOSOCIAL STRESS OVER THE LIFE COURSE 277
        
        1. INTRODUCTION 277
        
        2. MALADAPTIVE STRESS RESPONSES ARE ENGENDERED BY PERSISTENT EXPOSURE TO STRESSORS 280
        
        3. THE SOCIAL GRADIENT IN HEALTH: ROLE OF LOW SOCIOECONOMIC STATUS IN EPIGENETIC EMBEDDING OF BIOLOGICAL STRESS 282
        
        4. GLUCOCORTICOID RESISTANCE, HYPERCORTISOLISM, AND DEPRESSION 283
        
        6. HYPERCORTISOLISM SYNDROMES AND THEIR EPIGENETIC IMPACTS ON MENTAL HEALTH 285
        
        5. POSTTRAUMATIC STRESS DISORDER AND EPIGENETIC MODULATION OF SENSITIVITY TO TRAUMA 285
        
        7. CHRONIC STRESS AND ITS IMPACTS ON EPIGENETIC AGE ACCELERATION 286
        
        8. CONCLUSIONS AND FUTURE PERSPECTIVES 287
        
        ACKNOWLEDGMENTS 290
        
        REFERENCES 290
        
        13 - EPIGENETICS OF LONGEVITY IN SOCIAL INSECTS 297
        
        1. INTRODUCTION 297
        
        2. EPIGENETICS OF CASTE DIFFERENTIATION 299
        
        2.1 DNA METHYLATION 299
        
        2.2 ALTERNATIVE SPLICING 302
        
        2.3 HISTONE MODIFICATIONS 302
        
        2.4 MICRO-RNAS 303
        
        2.5 CASTE-SPECIFIC DIFFERENCES IN GENE EXPRESSION PATTERNS 304
        
        3. INTERPLAY BETWEEN EPIGENETIC AND ENDOCRINE FACTORS IN REGULATION OF LONGEVITY IN SOCIAL INSECTS 307
        
        4. CONCLUSIONS AND FUTURE PERSPECTIVES 310
        
        REFERENCES 311
        
        ACKNOWLEDGMENT 311
        
        3 - EPIGENETICS OF AGING-ASSOCIATED DISEASES 317
        
        14 - DROSOPHILA MELANOGASTER AS A MODEL FOR STUDYING THE EPIGENETIC BASIS OF AGING 319
        
        1. INTRODUCTION 319
        
        2. AGE-RELATED CHROMATIN CHANGES IN D. MELANOGASTER 320
        
        2.1 DNA METHYLATION 320
        
        2.2 HISTONE METHYLATION 321
        
        2.3 HISTONE ACETYLATION AND ASSOCIATED PROCESSES 322
        
        2.4 DETERMINATION OF LIFESPAN BY HISTONE DEACETYLASES 323
        
        2.5 NUCLEOSOME REMODELING 323
        
        3. PREMATURE AGING MODELS 324
        
        4. THE ROLE OF TRANSPOSABLE ELEMENTS IN DROSOPHILA AGING 325
        
        5. ENVIRONMENTAL AND NUTRITIONAL IMPACTS ON AGING, STRESS-RESISTANCE, AND LONGEVITY 326
        
        6. PHARMACOLOGICAL INTERVENTIONS IN DROSOPHILA AGING 327
        
        7. CONCLUSIONS AND PERSPECTIVES 328
        
        REFERENCES 328
        
        15 - HISTONE MODIFICATION CHANGES DURING AGING: CAUSE OR CONSEQUENCE?—WHAT WE HAVE LEARNED ABOUT EPIGENETIC REGULATION OF AGING 335
        
        1. INTRODUCTION 336
        
        2. HISTONE POSTTRANSLATIONAL MODIFICATIONS 336
        
        2.1 HISTONE ACETYLATION 337
        
        2.2 HISTONE METHYLATION 338
        
        2.3 HISTONE PHOSPHORYLATION 339
        
        2.4 HISTONE UBIQUITYLATION AND SUMOYLATION 341
        
        3. HISTONE MODIFICATIONS CHANGE DURING AGING, FROM YEAST TO HUMANS 341
        
        3.1 AGE-RELATED HISTONE ACETYLATION 341
        
        3.1.1 Histone Acetylation Regulates Yeast Aging 341
        
        3.1.3 Histone Acetylation Regulates Aging and Associated Diseases in Mammals 344
        
        3.1.2 Age-Related Histone Acetylation in Caenorhabditis elegans and Drosophila 344
        
        3.2 AGE-RELATED HISTONE METHYLATION CHANGES 345
        
        3.2.1 Histone Methylations Regulate Yeast Lifespan 345
        
        3.2.2 Histone Methylations Regulate C. elegans Lifespan 346
        
        3.2.3 Histone Methylations Regulate Drosophila Lifespan 346
        
        3.2.4 Histone Methylation Regulates Mammalian Aging 347
        
        4. CONCLUDING REMARKS 348
        
        ACKNOWLEDGMENTS 348
        
        REFERENCES 349
        
        16 - EPIGENETICS OF BRAIN/COGNITIVE AGING 355
        
        1. BRAIN/COGNITIVE AGING 355
        
        2. DNA METHYLATION, BRAIN AGING, AND COGNITIVE IMPAIRMENT 357
        
        2.1 DNA METHYLATION 357
        
        2.1.1 5′-Methylcytosine 357
        
        2.1.2 5′-Hydroxymethylcytosine 358
        
        2.1.3 Methods to Profile the Genome-Wide DNA Pattern 358
        
        2.2 DNA METHYLATION AND BRAIN/COGNITIVE AGING 359
        
        3. HISTONE POSTTRANSLATIONAL MODIFICATIONS AND BRAIN/COGNITIVE AGING 361
        
        3.1 HISTONE POSTTRANSLATIONAL MODIFICATIONS 361
        
        3.2 HISTONE POSTTRANSLATIONAL MODIFICATIONS AND BRAIN/COGNITIVE AGING 362
        
        4. EFFECTIVE INTERVENTIONS AND DRUG DEVELOPMENT TARGETING EPIGENETIC MARKS IN BRAIN/COGNITIVE AGING 363
        
        4.1 EFFECTIVE INTERVENTIONS 363
        
        4.2 EPIGENETIC DRUG DEVELOPMENT 364
        
        5. PERSPECTIVES AND CHALLENGES 365
        
        LIST OF ACRONYMS AND ABBREVIATIONS 367

Translational Epigenetics vol 4

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