Protein Metabolism and Homeostasis in Aging (eBook)

Nektarios Tavernarakis is a Research Director (Professor) at the Institute of Molecular Biology and Biotechnology, in Heraklion, Crete, Greece, heading the Caenorhabditis elegans molecular genetics laboratory. He earned his PhD degree at the University of Crete, studying gene expression regulation in yeast, and trained in C. elegans genetics and molecular biology at Rutgers University, New Jersey, USA. His research focuses on studies of neuronal function and dysfunction, using the nematode Caenorhabditis elegans as a model organism. His main interests are the molecular mechanisms of necrotic cell death in neurodegeneration and senescent decline, the molecular mechanisms of sensory transduction and integration by the nervous system, the interplay between cellular metabolism and aging, and the development of novel genetic tools for C. elegans research. He is the recipient of a European Research Council (ERC ) Advanced Investigator grant award, a European Molecular Biology Organisation (EMBO) Young Investigator award, an International Human Frontier in Science Program Organization (HF SPO) long‑term award, the Bodossaki Foundation Scientific Prize for Medicine and Biology, the Alexander von Humboldt Foundation, Friedrich Wilhelm Bessel research award, and is member of EMBO.

Title Page 3
Copyright Page 4
DEDICATION 5
PREFACE 6
ABOUT THE EDITOR... 8
PARTICIPANTS 9
Table of Contents 13
ACKNOWLEDGEMENTS 18
Chapter 1 Synthesis, Modification and Turnoverof Proteins during Aging 19
Introduction 19
Efficiency and Accuracy of Protein Synthesis during Aging 19
Altered Protein Synthesis during Aging 20
Post-Translational Modifications during Aging 22
Phosphorylation 22
Oxidation 23
Glycation 24
Deamidation, Racemization and Isomerization 24
ADP-Ribosylation 25
Methylation 25
Proteolytic Processing 26
Other Modifications 26
Protein Turnover during Aging 27
Conclusion 27
References 27
Chapter 2 Regulation of mRNA Translationas a Conserved Mechanismof Longevity Control 32
Introduction 32
Genome Scale Longevity Screens in Yeast and Nematodes 34
mRNA Translation is a Public Determinant of Longevity 35
Is DR Mediated by Reduced mRNA Translation? 35
Possible Mechanisms for How Translation Influences Aging 38
Does mRNA Translation Modulate Aging in Mammals? 41
mRNA Translation and Cancer 41
mRNA Translation and Diabetes 42
mRNA Translation and Cardiovascular Disease 42
mRNA Translation and Neurodegenerative Disease 42
Conclusion 43
References 43
Chapter 3 Protein Synthesis and the AntagonisticPleiotropy Hypothesis of Aging 48
Evolution of Aging 48
Insulin-Like Signaling (ILS) 49
TOR Pathway 49
Protein Synthesis 50
Direct Screens to Identify Genes That Antagonistically Regulate Growth and Longevity 50
Dietary Restriction (DR), Protein Synthesis and Antagonistic Pleiotropy 51
Mechanism of Lifespan Extension by Inhibition of Protein Synthesis 52
Conclusion 53
References 53
Chapter 4 Proteasome Function DeterminesCellular Homeostasis and the Rateof Aging 56
Protein Homeostasis and Aging: Which Are the Key Players? 56
An Introduction to the Proteasome Biology 57
Proteasome during Aging 59
Proteasome Activation: Is There a Way to Restore Proteasome Function? 60
Genetic Activation of the Proteasome 60
Proteasome Activation by Natural or Chemical Compounds 60
In Vivo Evidence of Proteasome Activation 61
Conclusion 62
References 62
Chapter 5 Autophagy and Longevity:Lessons from C. elegans 65
Introduction 65
DAF-2 Insulin/IGF-1-Like Signaling 66
Dietary Restriction 70
Mitochondrial Activity 70
Autophagy 71
Autophagy and C. elegans Longevity Pathways 72
Conclusion 75
References 75
Chapter 6 Autophagy and Aging:Lessons from Progeria Models 79
Introduction 79
Autophagy and Physiological Aging 80
Autophagy and Premature Aging 82
Conclusion 84
References 84
Chapter 7 Regulation of Protein Turnoverby Longevity Pathways 87
Protein Metabolism and Aging 87
Longevity Pathways That Promote Protein Synthesis 92
Insulin/IGF-1 Signaling 92
TOR Signaling 93
RAS/ERK Signaling 94
TGF-ß Signaling 94
JNK Kinase-Mediated Signaling 94
Mitochondrial Respirtory Chain 95
Interactions between Molecular Mechanisms Involved in Protein Synthesis and Degradation 95
Conclusion 96
References 97
Chapter 8 Protein Metabolism and Lifespanin Caenorhabditis elegans 99
Introduction 99
C. elegans as a Model Organism 99
The Protein Homeostasis and Longevity Hypotheses 100
Error Catastrophe and Oxidative Damage Accumulation 100
Protein Turnover Hypothesis 101
Dietary Restriction, TOR Signaling and Protein Homeostasis 101
Dietary Restriction 101
TOR 101
Reduced Protein Synthesis Extends Lifespan 102
Lowering the Rate of Translation Induces Increased Stress Resistance 102
Protein Synthesis and Reproduction 103
Protein Synthesis and Mitochondrial Dysfunction 103
Translation Initiation 103
Complex Interaction between Translation Initiation Factors, TOR Signaling and DR 103
Interaction between Translation Initiation Factors with IIS 112
A Model for Translation Inhibition Induced Longevity 112
HSF-1 Mediated Defense against Proteotoxicity 114
Autophagy 115
Autophagy Regulates Aging in C. elegans 115
Autophagy 115
Autophagy Is Required for Longevity in IIS Mutants 115
Autophagy and DR 116
Autophagy and p53 116
Interaction between DR, IIS and Autophagy 116
Autophagy and Neuropathology 116
Huntington and Alzheimer 118
Parkinson’s Disease 118
Autophagy and Neuronal Cell Death 118
Proteasome Function in Proteotoxicity and Longevity 119
Conclusion 119
References 120
Chapter 9 Mitochondrial Protein Quality ControlSystems in Aging and Disease 126
Introduction 126
Mitochondrial Chaperones Are Necessary for Regulated Mitochondrial PQC 128
Role of the Mitochondrial Proteases in Maintaining Mitochondrial Functions 130
Membrane-Bound AAA Proteases 131
Soluble Matrix Proteases 134
Role of the Membrane-Bound AAA Proteases on Diseases, Apoptosis and Aging 135
Mitochondrial Lon Protease Activity and Aging 136
Conclusion 138
References 138
Chapter 10 p38MAPK in the Senescence of Humanand Murine Fibroblasts 144
Introduction 144
Senescence Is the Hardest Word to Say 144
The Role of DNA Damage Checkpoint Genes in Senescence 145
Signal Transduction and Gene Expression in SIPS: Central Role of p38MAPK 145
TGF-B1 and p38MAPK in H2O2- and UVB-Induced SIPS 147
p38MAPK, p53 and Rb 149
Role of Caveolin-1 in Cellular Senescence and Interplay with p38MAPK 149
Premature Senescence as an Anti-Oncogenic Defense Mechanism 150
Signaling Pathway Mediating Ras-Induced Premature Senescence— The Tumor Suppressing Function of p38MAPK 150
Conclusion: The Next Steps… 151
References 153
Chapter 11 Protein Homeostasis in Modelsof Aging and Age-RelatedConformational Disease 156
Protein Folding Problem in Aging 156
Sources of Protein Damage—Oxidative Modifications 157
Sources of Damaged Proteins—Misfolding 159
Proteostasis Regulation in Aging and Late Onset Diseases 160
Late Onset Diseases are Mainly Protein Folding Diseases 161
Invertebrate Models of Late Onset Conformational Diseases 163
PolyQ 163
AB 164
Tau 164
Alpha-Synuclein 164
SOD1 164
Failure of Homeostasis in Conformational Disease of Aging 166
Failure of Adaptive Stress Responses 166
Disruption of Proteostasis by Chronic Misfolding 167
Modifiers of Conformational Disease 167
Genetic Screens for Modifiers of Disease-Related Phenotypes 167
Small Molecule Drug Screens 170
Conclusion 171
References 171
Chapter 12 Roles for SUMO Modificationduring Senescence 178
Introduction to the SUMO Modification System 178
SUMO Isoforms 178
Conjugation of SUMO to Target Proteins 179
Protein Recognition Sites 180
Links with Other Post-Translational Protein Modifications 180
De-Conjugation of SUMO from Substrate 180
Physiological Functions of SUMO Modification 180
Cellular Senescence 181
Senescence as a Model for Aging 181
Characteristics of Senescent Cells 181
Replicative and Stress-Induced Senescence 182
Pathways Mediating Stress Response 182
SUMO and Senescence 182
SUMO Molecules in Senescence 183
SUMO-Specific E3 Ligase PIASY and Senescence 184
SUMO Proteases (SENP Family) and Senescence 185
SUMO and Maintenance of Telomere Length 185
Changes in Global Protein SUMOylation during Aging 185
Conclusion 185
References 186
Chapter 13 Post-Translational Modificationof Cellular Proteins by Ubiquitinand Ubiquitin-Like Molecules:Role in Cellular Senescence and Aging 190
Introduction 190
Ubiquitin Is Activated and Transferred by a Cascade of E1, E2 and E3 Enzymes 191
Alternative Linking of Polyubiquitin Chains Decides the Fate of the Target Protein 191
Ubiquitin Is Expressed as Fusion Protein and Is Recycled by Ubiquitin Specific Hydrolases 192
Ubiquitin-Like Proteins 192
Role of Ubiquitination, SUMOylation and ISG15 in Cellular Senescence 192
Ubiquitin, Telomeres and Telomerase 194
Regulation of DNA Repair and Growth Arrest in Cell Culture 195
Breast Cancer Associated Protein 1 (BRCA1) 195
Proliferating Cell Nuclear Antigen (PCNA) 196
Senescence Evasion Factor (SNEVPrp19/Pso4) 197
p53 Senescence and Tumor Suppressor Pathway 197
p53 197
p19(ARF) 197
Cell Cycle Inhibitors are Mainly Regulated by Ubiquitination Followed by Degradation 198
p21(WAF1/Cip1) 198
p27(KIP1) 198
Deubiquitinating Enzymes and Their Influence on the Cell Cycle 198
UchL1/PGP9.5 198
Potential Role of Other DUBs in Cellular Proliferation and Growth Arrest 199
Signal Transduction, Receptor Endocytosis—EGFR and Ras 199
Ubiquitin-Dependent and Independent Mitochondrial Protein Quality Control 199
Ubiquitination in Tissues during Aging 200
Ubiquitination in the Nervous System 200
Ubiquitination, Eye Diseases and Cataracts 200
Ubiquitination in the Liver: Aging and Calorie Restriction 201
Insulin-Like Growth Factor 1 (IGF-1) Signalling as Example of the Endocrine System 202
Ubiquitin System and the Aging Muscle 202
Age Related Changes in the Blood and Ubiquitination 203
Segmental Progeroid Syndromes and the Ubiquitin System 203
Role of Ubiquitinylation and SUMOylation in Aging of Short-Lived Model Organisms 204
Conclusion 204
References 205
Chapter 14 Sensory Influence on Homeostasisand Lifespan:Molecules and Circuits 215
Introduction 215
Internal vs. External Sensors 215
How External Sensory Cues Influence Homeostasis 216
Molecular Mechanisms Linking Sensory Transduction and Hormonal Outputs 216
Receptors That Link External Inputs to Regulated Secretion 216
Secretory Pathways for Chemical Signals 218
Regulation of Secretion by Different G-Proteins and Their Effectors 218
Specificity in Signaling and Secretion 219
Examples of Sensory Signal Transduction 219
The Circuitry Underlying the Processing of Sensory Information 219
Processing of Visual Information to Synchronize Circadian Rhythms 220
Processing of Chemosensory Information to Alter Behavior and Metabolism 220
Sensory Influence on Lifespan 222
Olfactory Influence on Signal(s) from the Reproductive System That Affect Lifespan 222
Conclusion: Connections Between the Sensory Influence on Homeostasis and Lifespan? 224
References 224
Chapter 15 Regulation of Muscle Atrophyin Aging and Disease 229
Muscle Atrophy and Wasting Diseases 229
Molecular Mechanisms of Muscle Atrophy and Wasting 230
The Calpain Pathway 230
The Caspase Pathway 231
The Ubiquitin-Proteasome and the Autophagy-Lysosome Systems 231
Modulators of Muscle Catabolic Pathways 232
Systemic Effectors of Muscle Atrophy 233
Muscle Cytoskeletal Disorders and Atrophy 234
Cellular and Molecular Bases of Muscle Repair 235
IGF-1 and Prevention of Muscle Atrophy 237
The Molecular Complexities of IGF-1 Transcription 237
IGF-1 in Skeletal Muscle Growth, Disease and Wasting 239
IGF-1 Isoforms in Therapeutic Applications 241
IGF-1: Regenerator or Tumour Promoter? 241
Gene and Cell Therapies to Rescue Muscle Atrophy and Wasting 241
Gene Therapy 242
Cell Therapy 243
Conclusion 244
References 245
Chapter 16 Confronting Cellular Heterogeneityin Studies of Protein Metabolismand Homeostasis in Aging Research 252
Analysing Aging 252
Antibody Phage Display as a Discovery Tool 254
Antibody Libraries 254
Antibody Selection against Complex Antigens 255
Selection of Antibodies against Low Abundance Proteins 255
Cell Surface Selection 256
Simple Selection on Freshly Isolated or Cultured Cells 256
Selection Using Cell Sorting Techniques, Such as MACS or FACS 257
Selection on Cells from Tissues Subjected to Laser Capture Microdissection 258
In Vivo Selection 258
Conclusion 259
References 259
Index 263