Life-Span Extension (eBook)

Sell_Ch01_O.pdf 1
Sell_Ch01_O.pdf 1
Chapter 1 17
Reprogramming Cell Survival and Longevity: The Role of Tor, Sch9, Ras, and Sir2 17
1.1 Introduction 17
1.2 The S. cerevisiae Chronological Life Span 18
1.3 High-Metabolism Survival in Synthetic Dextrose Complete Medium 19
1.4 Severe Calorie Restriction: Survival in Water 21
1.5 Yeast Replicative Life Span 21
1.6 Evolutionarily Conserved Proaging Pathways 22
1.7 The Genetics of Chronological Aging: Reprogramming Stress Resistance and Cell Survival 22
1.8 Sir2 and Yeast Chronological Aging 25
1.9 Evolutionary Conserved Proaging Pathways 26
1.10 Conclusions 28
References 28
Sell_Ch02_O.pdf 1
Chapter 2 34
Common Aging Mechanisms: Energy Metabolism and Longevity in Caenorhabditis elegans 34
2.1 Introduction 35
2.2 The Insulin Signaling Pathway 35
2.3 Caloric Restriction 38
2.4 Mitochondrial Dynamics 39
2.5 Conclusions 41
References 42
Sell_Ch03_O.pdf 1
Chapter 3 46
Conserved Mechanisms of Life-Span Regulation and Extension in Caenorhabditis elegans 46
3.1 Caenorhabditis elegans as a Discovery Engine 47
3.2 The Major Axes of Life-Span Regulation in C. elegans 47
3.2.1 The Genetics of Aging 48
3.2.2 Endocrine Signaling 49
3.2.2.1 Insulin-Like Signaling 50
3.2.2.2 Transforming Growth Factor-b-Like Signaling 52
3.2.2.3 Tissue Specificity of Endocrine Signaling 53
3.2.2.4 C. elegans Insulin Signaling and Human Disease 54
3.2.3 Reproduction 54
3.2.4 Dietary Restriction 55
3.2.5 Mitochondria 57
3.3 Next Generation Studies to Identify Life-Span Regulators 58
3.3.1 RNA Interference 58
3.3.1.1 RNAi Screens for Increased Life-Span Phenotypes 59
3.3.1.2 Specialized RNAi Screens for Life-Span Phenotypes 60
3.3.2 Chemical Screens 62
References 63
Sell_Ch04_O.pdf 1
Chapter 4 71
The Genetic Architecture of Longevity 71
4.1 The Three Types of Longevity Responses 72
4.2 The Three Phases of the Life Span 76
4.2.1 The Developmental Span 76
4.2.2 The Health Span 76
4.2.3 The Senescent Span 78
4.3 The Genetic Architecture of Longevity 82
References 84
Sell_Ch05_O.pdf 1
Chapter 5 86
Mild Stress and Life Extension in Drosophila melanogaster 86
5.1 Introduction 86
5.2 Hypergravity 87
5.2.1 Hypergravity Increases Longevity of Males 87
5.2.2 Hypergravity Can Delay Behavioral Aging 89
5.2.3 Hypergravity Increases Resistance to Heat But Not to Other Stresses 89
5.3 Heat 91
5.3.1 Heat Can Slightly Increase Longevity 91
5.3.2 Heat Does Not Clearly Delay Behavioral Aging 91
5.3.3 Heat Increases Resistance to Some Stresses 92
5.4 Cold 92
5.4.1 Cold Increases Longevity 92
5.4.2 Cold Can Delay Behavioral Aging 92
5.4.3 Cold Increases Resistance to Some Stresses 92
5.5 Irradiation 94
5.5.1 Irradiation at the Egg Stage Increases Longevity 94
5.5.2 Can Irradiation Delay Behavioral Aging? 94
5.5.3 Irradiation Decreases Resistance to Heat and Desiccation 95
5.6 What Are the Causes of Hormesis? 96
5.7 Conclusions 97
References 98
Sell_Ch06_O.pdf 1
Chapter 6 101
Global Food Restriction 101
6.1 Overview 102
6.1.1 Life Extension 102
6.1.2 Retardation of Physiological Deterioration 103
6.1.3 Retardation of Age-Associated Diseases 103
6.2 Responsible Dietary Factor 103
6.3 Mechanisms Underlying Life Extension and Related Antiaging Actions 104
6.3.1 Growth Retardation Hypothesis 104
6.3.2 Reduced Body Fat Hypothesis 105
6.3.3 Decreased Metabolic Rate Hypothesis 106
6.3.4 Oxidative Damage Attenuation Hypothesis 108
6.3.5 Decreased Glycemia Hypothesis 110
6.3.6 Insulin Hypotheses 111
6.3.6.1 Increased Insulin Sensitivity Hypothesis 111
6.3.6.2 Decreased Insulin Signaling Hypothesis 112
6.3.6.3 Reconciling the Two Hypotheses 112
6.3.7 The Growth Hormone/Insulin-Like Growth Factor I Hypothesis 112
6.3.8 The Hormesis Hypothesis 114
6.3.8.1 Hormesis: Definitions and Concepts 114
6.3.8.2 Caloric Restriction, A Low-Intensity Stressor 115
6.3.8.3 Caloric Restriction, A Hormetic Agent 115
6.3.8.4 Relevance of the Hormetic Action of Caloric Restriction to Life Extension and Aging 115
6.4 Conclusions: Synthesis of Current Knowledge 116
References 118
Sell_Ch07_O.pdf 1
Chapter 7 125
Growth Hormone and Aging in Mice 125
7.1 Introduction 126
7.2 Life Span 127
7.3 Mechanisms Contributing to Aging Processes 129
7.3.1 Growth and Body Size 129
7.3.2 Reproduction 130
7.3.3 Metabolism 130
7.3.4 Stress Resistance 131
7.4 Premature or Accelerated Aging 133
7.5 Conclusions 134
References 135
Sell_Ch08_O.pdf 1
Chapter 8 142
Exploiting Natural Variation in Life Span to Evaluate Mechanisms of Aging 142
8.1 Introduction 142
8.2 Relation Between MLS and Body Size 143
8.3 Comparative Approach 145
8.4 Animal Models 145
8.5 Insights from Comparative Studies 146
8.6 Conclusions 147
References 148
Sell_Ch09_O.pdf 1
Chapter 9 149
Slow Aging: Insights from an Exceptionally Long-Lived Rodent, the Naked Mole-Rat 149
9.1 Introduction 150
9.2 Biological Features of the Naked Mole-Rat 153
9.3 Age-related Changes in Mortality Rate 154
9.4 Reproductive Function and Age 155
9.5 Age-related changes in physiology 156
9.6 Age-related Changes in Biochemical and Molecular Markers 159
9.7 Conclusions 161
References 162
Sell_Ch10_O.pdf 1
Chapter 10 165
Life Extension in the Short-Lived Fish Nothobranchius furzeri 165
10.1 Introduction 166
10.2 Teleost Fishes as a Model for Studies of Aging 166
10.3 N. furzeri: An Extremely Short-Lived Vertebrate 167
10.4 Age-related Markers in N. furzeri 170
10.5 Life Extension by Temperature 171
10.6 Life Extension by Resveratrol 172
10.7 The Mechanism(s) of Action of Resveratrol 172
10.8 Nothobranchius as a Genetic Model for Aging Studies 174
10.9 Conclusions and Future Perspectives 175
References 175
Sell_Ch11_O.pdf 1
Chapter 11 181
Aging and Longevity in Animal Models and Humans 181
11.1 Human Aging and Longevity Within an Evolutionary Perspective 182
11.2 Advantages and Successes of Model Systems: The Crucial Importance of the Reductionist Approach 183
11.3 Disadvantages and Intrinsic Constraints of Model Systems 184
11.4 Studies on Human Aging and Longevity 186
11.5 Similar Results on Longevity Among Species 187
11.5.1 SIRT3 187
11.5.2 Insulin and Insulin-Like Growth Factor-I Signaling Pathway 187
11.5.3 TP53 188
11.5.4 Nuclear Factor-k?B System 190
11.6 Conflicting or Unavailable Results on Longevity in Different Species 191
11.6.1 p66Shc 191
11.6.2 PON1 191
11.6.3 Caloric Restriction 191
11.7 Conclusions 192
References 193