Handbook of the Biology of Aging (eBook)

Front Cover 1
Handbook of the Biology of Aging 4
Copyright Page 5
Contents 6
Contributors 8
Foreword 12
Preface 14
About the Editors 16
Part 1: Basic Aging Processes 18
Chapter 1. The Genetic Network of Life-Span Extension by Dietary Restriction 20
Introduction 20
The DR Network in C. elegans 21
DR Nodes Conserved in Other Species 29
Why are there Differences between DR Regimens? 31
Conclusions 34
References 34
Chapter 2. Role of the Somatotropic Axis in Mammalian Aging 42
Introduction 42
Body size and composition 43
Glucose metabolism and insulin sensitivity 44
Oxidative metabolism and related factors of stress resistance 45
Cognitive function 47
Immune function 49
Age-related pathology and neoplasia 51
Conclusion 52
References 52
Chapter 3. Mechanisms of Mitochondrial Free Radical Production and their Relationship to the Aging Process 64
Introduction 64
Mitochondrial generation of free radicals 65
Major sites of mitochondrial ROS generation 65
Mitochondrial antioxidant systems 69
Free radical theories of aging 71
Conclusions 73
Acknowledgments 74
References 74
Chapter 4. Aging and Apoptosis in Muscle 80
Overview of apoptosis in aging muscles 81
Intrinsic apoptotic pathway 83
Extrinsic apoptotic signaling in skeletal muscle 94
Sarcoplasmic/endoplasmic reticulum–calcium stress apoptotic signaling 99
Apoptosis occurs in satellite cells/muscle precursor stem cells 101
Modulation of apoptosis in aging muscle 102
Aging and cardiomyocyte apoptosis 113
Conclusions 117
Acknowledgments 118
References 118
Chapter 5. Aging and Adipose Tissue 136
Introduction 136
Fat tissue 137
Aging, lipotoxicity, and fat tissue 139
Obesity and aging 140
Fat cell function and turnover 142
Preadipocytes 145
Conclusions and future areas of research 147
Acknowledgments 147
References 148
Chapter 6. Aging of Stem Cells: Intrinsic Changes and Environmental Influences 158
Introduction 158
Aging 161
Concluding remarks 173
References 173
Chapter 7. Leukocyte Telomere Dynamics, Human Aging, and Life Span 180
Introduction 180
Human aging and longevity, life span, and life expectancy 181
Telomere shortening, replication, and evolution 182
Comparative telomere biology between mouse and human 183
Why do humans have relatively short telomeres? 183
The end replication problem vs oxidative stress 184
Telomere dynamics in human leukocytes 184
Leukocyte telomere length dynamics: the gender and race effects 185
Leukocyte telomere length and atherosclerosis 186
Hematopoietic stem cell telomere dynamics and the human life span 187
Ramifications 187
Conclusion 188
Acknowledgment 188
References 188
Chapter 8. An Objective Appraisal of the Free Radical Theory of Aging 194
Introduction 194
Antioxidant supplementation extends life span only in relatively short-lived mouse strains 195
Effects of antioxidant enzyme overexpression on life span in mice 203
The effect of antioxidant enzyme reduction on mouse life span 206
Knockouts of oxidative damage repair enzymes 209
Facts and artifacts of oxidative damage markers and their relation to the free radical theory of aging 210
Synopsis, conclusions, and perspectives 212
References 213
Chapter 9. TOR: A Conserved Nutrient-Sensing Pathway that Determines Life-Span Across Species 220
Introduction 220
Target of rapamycin (Tor) couples nutrients to growth 220
Tor: A hub protein that relays signals from nutrients, growth factors, and various stresses 221
Links between nutrients, tor, and life-span in D. melanogaster 222
Links between nutrients, tor, and life-span in S. cerevisiae 223
Links between nutrients, tor, and life-span in C. elegans 224
Links between tor and life-span in Mus musculus 226
Conclusions and outlook 226
Acknowledgments 227
References 227
Chapter 10. Comparative Genetics of Aging 232
Introduction 232
Common nonmammalian models of aging 233
Conserved longevity interventions 238
Quantitative evidence for conserved mechanisms of longevity control 243
Interaction between dietary restriction and conserved longevity pathways 245
Conclusions 248
References 248
Chapter 11. Sirtuins in Aging and Age-Related Diseases 260
Introduction 260
Discovery of sirtuins 261
Sirtuin enzymology 262
Sirtuins and aging 263
Sirtuins and calorie restriction 263
Endogenous modulators of sirtuins 265
Chemical inhibitors and activators of sirtuins 267
Sirtuins and energy metabolism 268
Sirtuins in cell survival and apoptosis 272
Sirtuins and the aging cardiovascular system 275
Sirtuins in inflammation and immunity 277
Sirtuins in the aging brain 278
Perspective 279
Acknowledgments 280
References 280
Chapter 12. Inflammation in Aging Processes: An Integrative and Ecological Perspective 292
Introduction 292
Overview of inflammatory responses 292
Systemic manifestation of inflammation and aging 295
Tissue inflammatory changes during aging 297
Inflammation in atherosclerosis and alzheimer disease 298
Cancer 299
Bone and joints 300
Blood glucose elevations in inflammatory processes of human aging 300
Diet, metabolism, and exercise 301
Genetics 302
Environmental influences: an ecological perspective 303
Conclusions 304
Acknowledgments 304
References 304
Chapter 13. Protein Homeostasis and Aging 314
Introduction: proteome maintenance 314
Protein homeostasis 315
Molecular chaperones in quality control 316
The ubiquitin/proteasome system and its changes with age 319
The autophagic/lysosomal system 322
Concluding remarks and pending questions 326
Acknowledgments 328
References 328
Part 2: Medical Physiology of Aging 336
Chapter 14. Terminal Weight Loss, Frailty, and Mortality 338
Introduction 338
Aging and body weight 338
Frailty 339
Unintentional terminal weight loss 340
Decreased food intake and terminal weight loss 342
Factors other than decreased food intake in terminal weight loss 343
What is known and what needs to be done 344
References 345
Chapter 15. Human Brain Myelination Trajectories Across the Life Span: Implications for CNS Function and Dysfunction 350
Introduction 350
Myelin in the context of human brain development and degeneration 351
The “myelin model”: implications for human brain function and dysfunction 355
Conclusions 358
References 358
Chapter 16. Aging and the cerebral microvasculature: clinical implications and potential therapeutic interventions 364
Introduction 364
Aging, endothelium, and vascular dysfunction 366
Cerebrovascular hemodynamics 366
Neurovascular coupling 366
Brain structural changes may result from chronic cerebral hypoperfusion 368
Cerebrovascular endothelial dysfunction and microvascular disease 369
Clinical implications of cerebral microvascular disease in aging 369
Potential therapeutic interventions 375
Conclusions 378
Acknowledgments 379
References 379
Chapter 17. Aging and insulin secretion 390
Introduction 390
Aging, insulin secretion, and diabetes 390
Regulation of pancreatic & #946
Pancreatic & #946
Pancreatic & #946
Relationship to insulin signaling and longevity 397
Conceptual model 398
References 399
Chapter 18. Cardiovascular Effects of Aging in Primates—Gender Differences 402
Introduction 402
Gender differences during aging 403
Limitations of models for studying gender differences during aging 406
Studies of aging in a primate model 408
Gender differences in cardiovascular aging in primates 409
References 415
Chapter 19. Cerebral Vascular Dysfunction with Aging 422
Introduction 422
Vascular remodeling 422
Blood–brain barrier 423
Cerebral blood flow 424
Endothelium-dependent responses 425
Oxidative stress 427
Peroxisome proliferator-activated receptor & #947
Vascular inflammation 429
Renin–angiotensin system 430
Conclusions 431
Acknowledgments 431
References 431
Chapter 20. Pulmonary Function in Aging Humans 438
Introduction 438
Sensory feedback 442
Central integration 443
Controlled variables 443
Regulated variables 455
Concluding remarks 456
References 457
Chapter 21. Calorie Restriction in Nonhuman and Human Primates 464
Introduction 464
Long-term effects of calorie restriction in monkeys 465
Long-term effects of calorie restriction in humans 469
Conclusions 474
References 475
Chapter 22. Age-Related Changes in Thermoreception and Thermoregulation 480
Introduction 480
Thermoreception 481
Thermogenesis, heat gain, and heat retention 483
Heat loss and reduction of heat gain 487
Central thermoregulatory control 489
Conclusion 490
References 491
Chapter 23. Sex Differences in Longevity and Aging 496
Introduction 496
The robustness of the sex difference in survival 497
Do women age more slowly than men? 499
The mortality–morbidity paradox 501
Hypotheses for the sex difference in longevity 502
Conclusions 509
Acknowledgments 509
References 509
Author index 514
A 514
B 516
C 521
D 525
E 527
F 529
G 531
H 534
I 538
J 538
K 540
L 543
M 547
N 552
O 553
P 554
Q 557
R 558
S 560
T 566
U 568
V 569
W 570
X 572
Y 573
Z 574
Subject index 576
A 576
B 576
C 577
D 577
E 578
F 578
G 578
H 578
I 579
J 579
K 579
L 579
M 579
N 580
O 580
P 580
Q 581
R 581
S 581
T 582
U 582
V 583
W 583
X 583
Y 583