Epigenetics of Aging (eBook)

Preface 5
Contents 7
Contributors 10
Epigenetics and the Aging Process 14
Introduction 14
DNA Methylation and Histone Modifications in Aging 16
Other Epigenetic Processes and Aging 17
Impact of Epigenetics on Aging 18
Epigenetics of Age-Related Diseases 19
Epigenetic Interventions and Aging 20
Future Directions/Perspectives 20
Conclusion 21
References 21
Part I DNA Methylation and Histone Modifications in Aging 22
Age-Related Genomic Hypomethylation 23
Introduction 23
Aging and Genomic Hypomethylation 24
Mechanism of DNA Hypomethylation During Aging 25
DNA Methyltrasferases and Age-Dependent DNA Hypomethylation 25
One-Carbon Metabolism and Age-Dependent DNA Hypomethylation 27
DNA Integrity and Age-Dependent DNA Hypomethylation 27
Age-Related Diseases and DNA Hypomethylation 28
Cancer 28
Atherosclerosis 29
Alzheimer's Disease 29
Autoimmunity 31
Age-Related Macular Degeneration 31
Concluding Remarks 31
References 32
Gene-Specific Hypermethylation in Aging 40
Hypermethylation of Promoter Elements: Regulation of Gene Expression 40
Methods to Detect Methylation Status 42
Aging: Global Methylation 43
Aging: Gene-Specific Methylation 44
Liver 44
Gastrointestinal Tract 45
Other Organs 46
Conclusions 46
References 47
Aging and Non-sirtuin Histone Modifications 51
References 59
Sirtuins and Aging 61
Introduction 61
Distribution of Sirtuins in Model Organisms 62
Functions of Sirtuins 65
Sirtuins and Lifespan 65
Sirtuins and Calorie Restriction 67
Sirtuins and Transcriptional Regulation 68
Sirtuins and Apoptosis 69
Sirtuins and Metabolism 71
Sirtuins and Genomic Integrity 72
Sirtuins and Degenerative Diseases 72
Sirtuin Activators and Suppressors 73
Conclusion and Future Directions 76
References 77
Chromatin in Senescent Cells: A Conduit for the Anti-AgingEffects of Wnt Signaling? 86
An Overview of Cellular Senescence 86
Senescence, Aging, and Tumor Suppression 86
Molecular Features of Senescence 87
Senescence-Inducing Pathways 88
Chromatin Remodeling in Senescent Cells 90
Description of SAHF 90
Formation of SAHF Is a Multi-step Process 93
Chromosome Condensation Is Driven by Histone Chaperones HIRA and ASF1a 94
Activation of the HIRA/ASF1a Pathway by Wnt Signaling 97
Wnt Signaling, SAHF, and Tissue Aging 99
Summary 101
References 102
S -Adenosylmethionine: Simple Agent of Methylation and Secret to Aging and Metabolism? 115
Introduction 115
SAM-Dependent Enzymes 117
The SAM Domain/Rossmann Fold 117
Other SAM-Binding Domains 119
SAM and Radical Formation: The Iron--Sulfur Cluster 120
SAM and RNA Riboswitches 121
The Central Role of SAM in Metabolism 122
The Methionine Cycle 122
SAM and the Transsulfuration Pathway 123
SAM and the Polyamine Pathway 125
SAM and Aging 126
SAM, Mitochondria, and Life Span 128
The Yin and Yang of SAM in Real Life 130
SAM and Neurodegenerative Disease: Alzheimer and Cognitive Dysfunction 130
SAM and Dopamine Metabolism in Parkinson's Disease 131
SAM and Down's Syndrome 131
SAM and the Ames Dwarf Mouse 132
SAM and Mutations in DNA Repair Genes 132
Conclusion 133
References 133
Part II Other Epigenetic Processes and Aging 140
Polycomb Group of Genes and the Epigenetics of Aging 141
Epigenetic Cellular Memory System 141
How Do Cells Senesce? 145
Role of Polycomb Group Genes in Rb-Induced Senescence 146
Polycomb and Sir2 Connection 149
Polycomb System and DNA Repair 150
Conclusions 151
References 153
Chromosomal Position Effect and Aging 157
Introduction 157
Aging and Senescence in Budding Yeast 159
Yeast Aging Revealed the Role of the Sir2 NAD-Dependent Deacetylase 160
Yeast Senescence: A Link with TPE? 161
Consequences of Telomere Attrition in Senescence and Aging in Higher Eukaryotes 163
Does Telomere Shortening Modulate Expression of Subtelomeric Genes? 165
Chromosomal Instability and Position Effect 167
Heterochromatin Is Reorganized in Response to Senescence 167
Loss of Silencing and Chromatin Changes 168
Aging and X Inactivation 170
Causes and Consequences of Environmental Adaptation on Aging Organisms 170
Aging and Inflammation 172
Conclusions 173
References 174
Noncoding RNA for Presymptomatic Diagnosisof Age-Dependent Disease 182
Introduction 182
Midlife Deregulation of Programmatic Control 184
MicroRNA and Epigenetic Regulation 184
MicroRNAs as Hubs for Programmatic Control of Signaling Pathways 187
MicroRNAs as Biomarkers for Presymptomatic Diagnosis 188
Noncoding RNA: From Diagnosis to Therapeutic Treatment 190
Challenges of MicroRNAs as Presymptomatic Biomarkers: From Cultured Cell and Animal Model Studies to Human Application 190
References 191
Part III Impact of Epigenetics on Aging 194
Telomerase Control by Epigenetic Processes in Cellular Senescence 195
Introduction 195
Pathways Involved in Cellular Senescence 196
Telomeres and Telomerase 197
Telomerase Control by Genetic Processes 200
Gains of Copy Number of TERT and TERC 200
Genetic Variation 200
Genetic Regulation on Transcription 200
Telomerase Control by Epigenetic Processes in Cellular Senescence 201
Methylation of CpG Islands 201
Histone Modification of Chromatin 202
Histone Methylation and Acetylation 203
Epigenetic Control of Accessibility of Telomeres to Telomerase 204
Conclusion 204
References 205
Telomeres, Epigenetics, and Aging 209
Introduction 209
Telomere Length: A Biomarker for Human Aging 211
Genetics of Telomere Length 211
Epigenetics of Telomeres 213
Telomeres Bear Heterochromatic Marks 213
Telomere-Associated RNA 215
Shelterin: A Target for Epigenetic Modification 216
Epigenetics and the Telomere State 217
Telomere Position Effect (TPE) 218
Impact of Telomeres on Aging and Disease 219
Concluding Remarks 222
References 222
Contributions of Tumor Suppressors to the Epigenetic Regulation of Aging Cells 230
Introduction 230
Linkage Between Replicative Senescence and Organismal Aging 232
Chromatin Structure Modification: Epigenetics at Work 233
Aging: A Change in the Epigenome 234
SAHF Formation 235
Major Tumor Suppressor Pathways Contributing to the Senescence Phenotype 236
p16/Rb Pathway 237
p53/p21 Pathway 238
The Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) 239
Promyelocytic Leukemia (PML) 241
ING Proteins Effect Epigenetic Changes Occurring During Senescence 242
HDACs and Senescence 244
Conclusions 248
References 249
Epigenetic Drift and Aging 259
Introduction 259
DNA Methylation 260
Histone Modification 262
Epigenetics and Aging 263
Epigenetic Changes During Development and Aging 264
The Role of Environment in Aging-Dependent Epigenetic Changes 267
The Impact of Epigenetic Alteration on the Aging Phenotype 270
Intergenerational Transmission of Epigenetic Changes Accumulated During Development and Aging 272
Concluding Remarks 273
References 273
Role of Epigenetics in Age-Related Long-Term Memory Loss 276
Introduction 276
DNA Methylation in Memory Formation 278
Histone Acetylation in Memory Formation 279
Age-Associated Memory Loss 280
Conclusions 281
References 281
Part IV Epigenetics of Age-Related Diseases 283
The Epigenetics of Age-Related Cancers 284
Introduction 284
Epigenetic Changes in Aging and Cancer 285
DNA Methylation and Histone Modifications 286
Polycomb Group Proteins 287
Chromatin States and Cellular Function 288
Known Contributors to Epigenetic Alterations 288
DNA Damage Repair and Inflammation 288
Proinflammatory Signaling 290
Epigenetics in Embryogenesis 292
Differences in Cancers of Young and Adult Patients 293
The Spectrum of Acute Lymphoblastic Leukemia Over a Lifetime 297
In Utero Development of ALL 299
Childhood and Adult ALL 300
Reconciling Development of ALL, Other Cancers, and Aging 301
The Rapidly Evolving Epigenetic Landscape During Aging and Cancer 303
References 305
DNA Methylation and Alzheimers Disease 313
Introduction 313
Aging and Alzheimers Disease 314
References 320
DNA Methylation, Age-Related Immune Defects, and Autoimmunity 325
Introduction 325
Epigenetic Regulation of T-Cell Differentiation 327
Role of DNA Demethylation in the Expression of T Effector Cell Molecules 329
Epigenetic Control of KIR Expression on T Cells 330
DNA Demethylation and Age-Associated Immune Defects 332
DNA Demethylation and Autoimmunity in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis 335
Synopsis 338
References 338
Epigenetic Silencing of Progeroid Syndromes 343
Introduction 343
DNA Methylation: From Aging to Cancer 344
Werner Syndrome: The Epigenetic Link Between Aging and Cancer 347
Epigenetic Silencing of Werner Syndrome in Human Cancer 349
Epigenetic Connection Between Lamin A/C and Cancer 353
Epigenetic Modifications in HutchinsonGuilford Cells 357
An Epigenetic Molecular Hypothesis That Accounts for Progerin Accumulation in Normal Aging Cells 358
Discussion and Conclusions 359
References 361
DNA Methylation and Osteoarthritis 368
Introduction 368
Function and Characteristics of Normal Articular Cartilage 370
Changes in Extracellular Matrix During Progression of OA 371
The Degradative Chondrocyte Phenotype 373
Reasons for Suspecting Epigenetic Changes in OA 375
Loss of DNA Methylation and Aberrant Expression of Proteases in Degradative OA Chondrocytes 376
Epigenetic Regulation of Leptin in Osteoarthritis 380
Is Downregulation of Chondrocytic Genes Associated with Silencing by DNA Hyper-methylation? 381
Summary: Is Osteoarthritis an Epigenetic Disease? 382
References 383
Part V Epigenetic Interventions and Aging 389
Histone-Modifying Drugs in Aging 390
Aging, Age-Associated Diseases and Calorie Restriction (CR) 390
Histone Modifications and Histone-Modifying Enzymes in Aging 391
Sirtuin Modulating Substances in Aging 393
Activators of SIRT1 Enzymatic Activity 393
Resveratrol 393
SRT1460, SRT1720 and SRT2183 394
Quinoxaline Derivates (Sirtuin Activator 1, 2 and 3) 396
Activators of SIRT1 Expression 396
Concluding Remarks 397
References 398
Dietary Effect on Epigenetics During the Aging Process 402
Introduction 402
Caloric Restriction (CR) and Aging 403
Diet and DNA Methylation During Aging 403
Methyl Donor Diet and Aging 404
Green Tea Component: (-)-epigallocatechin-3-gallate 405
Soybean Component: Genistein 406
Dietary Component and Histone Modifications During Aging 407
Histone Deacetylase (HDAC) Inhibitors 407
Concluding Remarks 408
References 409
Environmental Effects on Age-Associated Epigenetics 412
Introduction 412
DNA Methylation 413
X-Chromosome Inactivation 414
Histone Modifications 416
Environmental Effects and Epigenetics 416
Nickel 417
Arsenic and Cadmium 417
Lead (Pb) 418
Heat Stress 419
Environment and Epigenetic Drift in Populations 420
Conclusion 421
References 421
Part VI Future Directions/Perspectives 425
Future Directions in Research on the Epigenetics of Aging 426
Introduction 426
Technological Advances in Epigenetic Research 428
Computational Science in Future Epigenetic Research 430
Genome-Wide Epigenetic Studies 431
Biomedical and Epigenetic Studies of the Future 432
Personalized, Epigenetic-Targeted Pharmacologic Agents 433
The Roadmap Epigenomics Program 435
References 436
Perspectives in Aging and Epigenetics 440
Introduction: Epigenetics 440
The Multiple Causes of Aging 441
Biological Reasons for Aging 442
Epigenetics, Development, and Aging 442
DNA Methylation 443
Epigenetics and CellCell Signaling 445
X Chromosome Reactivation 445
Epigenetic and Nonepigenetic Events During Aging 446
References 448
Index 450