Ageing Lessons from C elegans 1st Edition by Anders Olsen, Matthew S. Gill 3319447032 9783319447032

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ISBN 10: 3319447032 

ISBN 13: 9783319447032

Author: Anders Olsen, Matthew S. Gill

This book brings together in one volume the current state of ageing research in the nematode Caenorhabditis elegans. The authors are leading researchers in the field, placing this topic in the context of human ageing, describing how and why basic discoveries in this simple organism have impacted our prospects for intervention in the ageing process. The authors cover a broad range of topics with regards to organismal and reproductive ageing including anatomical, physiological and biochemical changes, as well as genetic and environmental interventions that promote longevity and ameliorate age-related disease. Ageing is the single most important factor determining the onset of human disease in developed countries. With current worldwide demographic trends indicating that the number of individuals over the age of 65 will continue to rise, it is clear that an understanding of the processes that underpin ageing and age-related disease represents a key challenge in the biomedical sciences. In recent years there have been huge advances in our understanding of the ageing process and many of these have stemmed from genetic analysis of C. elegans. With no analogous book in this subject area this work will be of interest to a wide audience, ranging from academic researchers to the general public.

Ageing Lessons from C elegans 1st table of contents: 

Chapter 1: Introduction
1.1 C. elegans: A Most Excellent Model Organism
1.2 C. elegans as Model Organism for Studying Ageing
1.2.1 Measurement of Ageing in C. elegans
1.3 Public or Private?
1.4 State of the Art in the C. elegans Ageing Field
1.5 Concluding Remarks
References
Chapter 2: Effects of Ageing on the Basic Biology and Anatomy of C. elegans
2.1 Introduction
2.2 Introduction to the Life History of C. elegans
2.3 Anatomic Changes That Accompany Ageing
2.3.1 Cuticle
2.3.1.1 Ageing of the Cuticle
2.3.2 Hypodermis
2.3.2.1 Ageing of the Hypodermis
2.3.3 Muscle
2.3.3.1 Ageing of Body Wall Muscle
2.3.4 Pharynx
2.3.4.1 Ageing of the Pharynx
2.3.5 Nervous System
2.3.5.1 Ageing of the Nervous System
2.3.5.2 Synaptic Decline During Ageing
2.3.5.3 Changes in the Neuronal Processes During Ageing
2.3.5.4 Changes in Neuronal Soma
2.3.6 Glia
2.3.6.1 Ageing of Glia
2.3.7 Intestine
2.3.7.1 Ageing of the Intestine
2.3.7.2 Bacterial Infection
2.3.8 Excretory System
2.3.8.1 Ageing of the Excretory System
2.3.9 Pseudocoelom and Coelomocytes
2.3.9.1 Ageing in the Pseudocoelomic Space
2.3.10 Germline
2.3.10.1 Ageing of the Germline
2.4 End of Life Issues in C. elegans
2.5 Comparisons Between C. elegans and Human Ageing
2.6 Conclusions
References
Chapter 3: Dauer Formation and Ageing
3.1 Introduction
3.2 Natural History of Dauer Formation
3.3 Physiology and Genetics of Dauer Formation
3.3.1 Physiological Changes in the Dauer Larva
3.3.2 Sensory Inputs Affecting Dauer Formation
3.3.3 Insulin Signalling
3.3.4 TGF-β Signalling
3.3.5 HEN-1/SCD-2
3.3.6 Steroid Hormone Signalling
3.3.7 Dauer Entry Versus Reproductive Growth
3.4 Diapause Versus Ageing
3.4.1 Sensory Control of Ageing
3.4.2 Insulin Signalling and Ageing
3.4.3 TGF-β Pathway and Ageing
3.4.4 Steroid Hormone Signalling and Ageing
3.4.5 Are Long-Lived Daf-c Mutants Just Dauers in Disguise?
3.5 Conserved Mechanisms of Mammalian Ageing
References
Chapter 4: Longevity Regulation by Insulin/IGF-1 Signalling
4.1 Introduction
4.2 Components That Influence Lifespan in the Insulin/IGF-1 Signalling Pathway
4.3 Sensory Neural Regulation of Longevity
4.4 Endocrine Signalling and Tissue Specificity for IIS-­Mediated Longevity Regulation
4.5 The Role of IIS in Stress Resistance and Age-Related Disease Models
4.6 Conclusions
References
Chapter 5: Mitochondrial Longevity Pathways
5.1 Mitochondrial Origin, Structure and Functions
5.2 Mitochondrial Stress Control of Longevity
5.3 Mitochondrial Interventions Leading to Lifespan Extension
5.3.1 Interventions that Target the Mitochondria
5.3.1.1 Gene Silencing
5.3.1.2 Genetic Mutations
5.3.1.3 Pharmacological Interventions
5.3.2 Threshold, Time and Tissue Requirements
5.3.2.1 Mitochondrial Threshold Effect or Mitochondrial Hormesis
5.3.2.2 Time: From Development to Ageing
5.3.2.3 Tissues: Nervous System and Intestine
5.4 Mitochondrial Stress Response Signalling Leading to Lifespan Extension
5.4.1 From Mitochondria to Cellular Reprogramming
5.4.1.1 ROS and Antioxidant Defence Mechanisms
5.4.1.2 Mitochondrial Unfolded Protein Response
5.4.1.3 Iron, Hypoxia and Induction of Autophagy/Mitophagy
5.4.1.4 ATP and Metabolic Reprogramming
5.4.2 Less Investigated Mechanisms Causally Involved in Mit Mutants’ Longevity
5.4.3 Diversity of RNAi vs Genetic Mit Mutants
5.5 Relevance for Humans
References
Chapter 6: Influences of Germline Cells on Organismal Lifespan and Healthspan
6.1 Introduction
6.2 The Influence of Germline Stem Cells on Ageing of Somatic Tissues
6.3 A Network of Transcription Factors Mediates Germline-­Less Longevity
6.3.1 DAF-16/FOXO3A and TCER-1/TCERG1
6.3.2 DAF-12/VDR, microRNAs and Steroid Signalling
6.3.3 NHR-49/PPARα, NHR-80/HNF4 and NHR-71/HNF4
6.3.4 PHA-4/FOXA, HLH-30/TFEB, MML-1 and MXL-2
6.3.5 SKN-1/NRF2, HSF-1/HSF
6.4 Cellular Processes Mobilized in Response to Germline Depletion
6.4.1 Lipid Metabolism and the Reproductive Control of Longevity
6.4.2 Coordinate Induction of Lipogenesis and Lipolysis Following GSC Loss
6.4.2.1 de novo Fatty-Acid Synthesis and TAG Production
6.4.2.2 Fatty-Acid Desaturation
6.4.2.3 Mitochondrial β-Oxidation
6.4.2.4 Lipolysis
6.4.3 Role of Autophagy in Linking Germline Status to Lifespan
6.4.4 Proteasome Activity in Germline-Less Animals
6.4.5 Stress-Response Mechanisms and GSC-Less Longevity
6.4.6 Pathways Repressed Upon GSC Loss
6.5 Contributions from C. elegans to the Reproductive Control of Ageing
References
Chapter 7: Reproductive Ageing
7.1 Introduction
7.2 Reproduction vs Reproductive Ageing
7.3 Measurements of Reproductive Ageing in C. elegans
7.4 Conditions, Genetic Pathways, and Tissues That Affect Reproductive Span
7.4.1 Conditions That Affect Reproductive Span
7.4.2 Genetic Pathways That Affect Reproductive Lifespan
7.5 Comparisons of Reproductive Ageing in C. elegans and Humans
7.5.1 Germline Stem Cells
7.5.2 Oocyte Quality Is the Limiting Factor for Reproductive Span in Worms and Women
7.5.3 Oogenesis and Cell Cycle Arrest
7.5.4 Shared Mechanisms Required for Oocyte Quality Maintenance
7.5.5 Conserved Regulatory Pathways
7.6 Reproductive vs Somatic Ageing
7.6.1 Soma-Germline Communication
7.6.2 The “Disposable Soma” Hypothesis
7.6.3 Bloated Soma Theory (Hyperfunction Theory)
7.6.4 Somatic Reserve Hypothesis
7.7 Conclusion
References
Chapter 8: Nervous System Ageing
8.1 Introduction
8.2 Age-Related Structural and Cellular Changes in the Nervous System
8.2.1 Synaptic Deterioration in Ageing Neurons
8.2.2 Genetic Factors That Influence Morphological Ageing of the Nervous System
8.2.3 Maintenance of Adult Nervous System Architecture
8.2.4 Subcellular Changes in Ageing Neurons
8.2.5 Relevance to Cellular Changes in the Human Nervous System
8.3 Axon Regeneration and Ageing
8.3.1 Age-Dependent Decline of Regeneration
8.3.2 Relevance to Axon Regeneration in Ageing Humans
8.4 Functional Decline of the Ageing Nervous System
8.5 Learning and Memory in Ageing
8.5.1 Thermotaxis Learning and Memory in Ageing
8.5.2 Positive Olfactory Associative Learning and Memory
8.5.3 Habituation (Non-associative Learning)
8.5.4 Mechanisms of Age-Related Learning and Memory Decline
8.5.5 Relevance to Learning and Memory in Humans
8.6 Neurodegenerative Diseases
8.6.1 C. elegans Models of Neurodegenerative Disease
8.6.2 Ageing Pathways and Neurodegenerative Disease
8.7 Concluding Remarks
References
Chapter 9: Stress Response Pathways
9.1 Introduction
9.2 The Relationship(s) Between Stress Response Pathways and Ageing
9.3 Stress Response Strategies
9.3.1 Avoidance
9.3.2 Anticipation
9.3.3 Compensate or Defend
9.4 Stress Response Pathways in Action
9.4.1 Thermal Stress
9.4.2 Oxidative Stress
9.4.2.1 Environmental Oxidative Stressors
9.4.2.2 SKN-1/Nrf Coordinates a Transcriptional Response to Oxidative Stress
9.4.2.3 Oxidative Stress Responses and Ageing
9.4.3 Protein Folding Stress
9.4.4 Concluding Remarks
References
Chapter 10: Oxidative Stress
10.1 Reactive Oxygen Species (ROS)
10.2 Antioxidants
10.3 ROS Quantification
10.3.1 Superoxide
10.3.2 Hydrogen Peroxide
10.4 The Oxidative Damage Theory
10.5 Oxidative Damage and Ageing in C. elegans
10.6 Manipulating ROS and Its Effect on Ageing
10.6.1 Genetic Interventions
10.6.2 Pharmacological Interventions
10.7 The Oxidative Stress Response and Hormesis
10.8 New Horizons
10.8.1 ROS Are Signalling Molecules
10.8.2 Developmental Programmes Gone Wild
10.9 Relevance to Human Ageing
References
Chapter 11: Genome Stability and Ageing
11.1 DNA Damage and Repair in C. elegans
11.2 Changes in DNA Damage Levels and Mutation Frequency with Age
11.3 DNA Repair Capacity with Age
11.4 DNA Repair Pathways and Ageing
11.4.1 Base Excision Repair (BER)
11.4.2 Nucleotide Excision Repair (NER)
11.4.3 Homologous Recombination (HR)
11.4.4 Non-homologous End Joining (NHEJ)
11.5 DNA Damage Response (DDR) and Ageing
11.6 Conclusions and Future Perspectives
References
Chapter 12: Protein Homeostasis and Ageing in C. elegans
12.1 Introduction
12.2 Protein Homeostasis and Protein Aggregation
12.2.1 Stress Response: The Repair System
12.2.2 Ubiquitin/Proteasome System: The Degradation System
12.2.3 Autophagy: The Disposal System
12.3 Protein Homeostasis in C. elegans
12.4 C. elegans as a Model for Human Disease
12.4.1 Worm Models of Neurodegenerative Diseases
12.4.2 ß-Amyloid and Tau Aggregation: Alzheimer’s Disease and Tauopathies
12.4.3 Polyglutamine Repeat Disease; Huntington’s Disease
12.4.4 α-Synuclein Toxicity: Parkinson’s Disease
12.5 Conclusions and Perspectives
References
Chapter 13: Translational Control of Longevity
13.1 Introduction
13.2 Environmental Inputs and Signalling Pathways That Modulate Translation
13.2.1 Translation Changes in Response to Environmental Stress
13.2.2 Translational Regulation via Stress-Sensing Kinases That Target the Ternary Complex
13.2.3 Growth and Developmental Pathways Regulating Longevity Help Orchestrate Translational Respon
13.2.4 The Influence of Noncoding RNA on Translation and Longevity
13.3 Towards a Mechanistic Understanding of Translation’s Role in Lifespan Regulation
13.3.1 RNAi in C. elegans Helped Establish the Connection Between Translation and Longevity
13.3.2 Translation Diagnostics: Methods to Understand the Connection Between Translation and Lif
13.3.3 Phenomena Associated with Attenuating Translation as Potential Mediators of Increased Long
13.3.3.1 Proteostasis
13.3.3.2 Differential Translation as a Mechanism Governing Longevity Responses to Translation Att
13.3.3.3 Energy Allocation
13.4 Concluding Remarks
References
Chapter 14: Lipid Metabolism, Lipid Signalling and Longevity
14.1 Introduction
14.2 Lipids
14.2.1 Structure and Classification
14.2.1.1 Fatty Acyls
14.2.1.2 Glycerolipids
14.2.1.3 Glycerophospholipids
14.2.1.4 Sphingolipids
14.2.2 Synthesis, Storage, and Degradation of Lipids
14.2.3 Methods of Studying Lipid Metabolism
14.3 Pathways Regulating Ageing
14.3.1 Insulin/IGF-1 Signalling (IIS)
14.3.2 Dietary Restriction
14.3.3 Germline Loss
14.4 Lipids as Signalling Molecules
14.4.1 Lipid Messengers
14.4.2 Proteins as Lipid Signalling Chaperones
14.4.3 Lipid Signalling Receptors
14.5 Relevance to Humans
14.6 Conclusion and Perspectives
References
Chapter 15: Autophagy and Ageing
15.1 Introduction to Autophagy
15.2 Genetic Links Between Autophagy and C. elegans Ageing
15.2.1 Insulin/IGF-1 Signalling
15.2.2 Dietary Restriction/mTOR Signalling/S6 Kinase
15.2.3 Germline Removal
15.2.4 Mitochondrial Respiration
15.2.5 Additional C. elegans Longevity Paradigms with Autophagy Links
15.2.5.1 p53/CEP-1
15.2.5.2 SIRT1/SIR-2.1
15.2.5.3 Calcineurin/TAX-6
15.2.5.4 miR-34
15.2.5.5 Ceramide Synthetases
15.2.5.6 Glutamine-Fructose 6-Phosphate Aminotransferase/gfat-1
15.3 Pharmacological Links Between Autophagy and  C. elegans Ageing
15.3.1 Spermidine
15.3.2 Resveratrol
15.4 Concluding Remarks
References
Chapter 16: Dietary Restriction in C. elegans
16.1 Introduction
16.2 Methods of Dietary Restriction in C. elegans
16.2.1 Liquid DR
16.2.2 Eat Mutants
16.2.3 Chronic and Intermittent Fasting
16.2.4 Solid Agar-Based DR
16.2.5 Future of DR in C. elegans: A Chemically Defined Diet?
16.3 Molecular Mechanisms Underlying the Benefits of DR
16.3.1 Insulin signalling and FOXO
16.3.2 Sirtuins
16.3.3 AMPK/CRTCs
16.3.4 TOR
16.3.5 PHA-4/FOXA
16.3.6 SKN-1/Nrf
16.3.7 HSF-1
16.3.8 HIF-1
16.3.9 NHRs
16.3.10 microRNAs
16.4 Effects of DR on C. elegans Healthspan, Disease Models and Physiology
16.4.1 Healthspan
16.4.2 Models of Functional Decline and Age-Related Diseases
16.4.3 Metabolism/Metabolic Rate
16.4.4 Autophagy
16.4.5 Protein Translation
16.4.6 Lipid Metabolism
16.4.7 Mitochondrial Homeostasis
16.5 Conclusions and Future Directions
References
Chapter 17: Integration of Metabolic Signals
17.1 Introduction
17.2 Consequences of Diet Choice
17.3 SKN-1/Nrf2-Dependent Regulation of Dietary Stress
17.4 Metabolic Coordination
17.5 Human Implications
References
Chapter 18: Microbiota, Probiotic Bacteria and Ageing
18.1 Microbiota, Prebiotics and Probiotic Bacteria
18.2 Microbiota and Ageing
18.3 Diet and Microbiota of C. elegans
18.3.1 Worm Bacterial Diet
18.3.2 Digestion and Bacterial Colonization
18.3.3 Food Quality and Dietary Restriction
18.3.4 The Worm Microbiota
18.4 Probiotic Bacteria in C. elegans and Their Effect on Longevity
18.4.1 Group I: Changes in Nutritional Value
18.4.2 Group II: Antimicrobial Effect
18.4.3 Group III: Changes in Bacterial Metabolism
18.4.4 Group IV: Direct Activation of Host Signalling Pathways
18.4.5 Group V: Unknown Effect
18.5 Can Worms Teach Us How to Use Probiotics in Human Health and Disease?
18.6 Concluding Remarks and Predictions for the Future
References
Chapter 19: The Future of Worm Ageing
19.1 The Pressure for Translation into Clinically Relevant Research
19.2 Challenges for the Future
19.3 Are There Any Worm Ageing Secrets Left?

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