This book provides a state-of-the-art overview of key areas of subcellular aging research in human cells.
The reader is introduced to the historical development and progress in biomedical aging research and learns, for example, about the role of microRNAs, circRNAs, mitochondria and extracellular vesicles in cellular senescence. The reader will also learn more about how gap junctions, the nuclear pore complex and the proteasome are affecting the ageing processes. In addition, novel therapeutic opportunities through modulation of cellular senescence are discussed.
The book follows on from Parts I and II of Biochemistry and Cell Biology of Ageing (Volumes 90 and 91 of the Subcellular Biochemistry book series) by covering interesting and significant biomedical ageing topics not included in the earlier volumes. Comprehensive and cutting-edge, this book is a valuable resource for experienced researchers and early career scientist alike, who are interested in learning more about the fascinating and challenging question of why and how our cells age.
Author(s): J. Robin Harris, Viktor I. Korolchuk
Series: Subcellular Biochemistry, 102
Publisher: Springer
Year: 2023
Language: English
Pages: 423
City: Cham
Preface
Contents
About the Editors
Chapter 1: Introduction: Progression of the Science of Ageing
Introduction
References
Chapter 2: Chromatin Structure from Development to Ageing
Introduction
Nuclear Architecture
The Nuclear Envelope
Nuclear Lamina
Chromosome Territories
Chromatin 3D Organization and Dynamics
Compartments
Topologically Associated Domains (TADs)
Lamina-Associated Domains (LADs)
Chromatin Restructuring During Development
DNA Methylation
Histone Variants
Histone Modifications
Nuclear Remodeling in Development
Lamins Regulate Nuclear Structure and Chromatin Organization During Development
Programmed Cellular Senescence
Chromatin Remodeling in Ageing
Persistent Cellular Senescence
Changes in Chromatin Structure and Histone Variants in Cellular Senescence
DNA Methylation
Histone Variants and Modifications
Nuclear and 3D Genome Remodeling in Ageing
The Role of Lamins in Regulating Chromatin Organization During Ageing
Concluding Remarks
References
Chapter 3: The Nuclear Envelope in Ageing and Progeria
Introduction
The Nuclear Lamina in Ageing and Premature Ageing Syndromes
Nuclear Pore Complex Turnover and Decline in Ageing
The Implication of Nucleocytoplasmic Transport in Neurodegenerative Disease
RNA-Binding Proteins and Neurodegenerative Diseases
Peptide Repeat Toxicity and NPC Function
Additional Implications of NCT in Neurodegenerative Diseases
Concluding Remarks
References
Chapter 4: Mitochondrial DNA Mutations and Ageing
Introduction
Mitochondrial Structure and Function
Oxidative Phosphorylation
Mitochondrial Genetics
Mitochondrial DNA Mutations in Ageing
MtDNA Deletions
MtDNA Point Mutations
Mouse Models of Mitochondrial Alterations with Ageing
Mitochondrial Function and Stem Cell Ageing
MtDNA Mutations and Stem Cell Ageing
Mitochondrial Regulation of the Ageing Immune System
Targeting Mitochondria in Ageing
Concluding Remarks
References
5: The Proteasome and Ageing
Introduction
The Proteasome: A Brief Overview
Cellular Senescence and the Proteasome
Muscle Ageing and the Proteasome
Skin Ageing and the Proteasome
Brain Ageing and the Proteasome
Proteasome and Age-Related Neurodegenerative Diseases
Proteasome and Longevity
Other Components of the Ubiquitin-Proteasome Pathway Implicated in Ageing
Activating the Proteasome to Decelerate the Ageing Process
Conclusion and Future Directions
References
6: Gap Junctions and Ageing
Introduction
Gap Junctions and the Connexin Family
Regulation of Gap Junctions at the Molecular Level
Gene Structure and Transcription
Translation
Trafficking
Posttranslational Modification of Connexins
Heart
Brain
The Ocular System
Bone
Other Tissues
Concluding Remarks
References
Chapter 7: Cellular Senescence and Ageing
What Is Cellular Senescence?
History
Characteristics and Markers
Telomere Shortening
DNA Damage
SA-B-Gal
Cyclin-Dependent Kinase Inhibitors
Morphology
Chromatin Alterations
Lack of DNA Replication/Cell Proliferation
SASP
Types and Mechanisms of Cellular Senescence
Replicative
Stress-Induced
Oncogene-Induced
Bystander-Induced
MiDAS
In Vivo Relevance of Senescent Cells
Cell Types and Tissues in Which Senescence Has Been Observed
Age-Dependent Changes in the Abundance
Senescence in Age-Related Disease
Anti-senescent Interventions
Pre-clinical Evidence
Clinical Evidence
Future Directions
How to Better Target Senescent Cells?
Important Considerations in Senolytics Treatments
Concluding Remarks
References
Chapter 8: Therapeutic Opportunities Presented by Modulation of Cellular Senescence
What Is Cell Senescence?
The Relationship Between Cell Senescence and Ageing
Therapeutic Opportunities
Osteoarthritis
Kidney Dysfunction
Liver Dysfunction
Therapeutic Strategies
Removal of Senescent Cells
Blockade of the Senescent Phenotype
Controlled Reversal of Cell Senescence
Cell Senescence as a Problem in Artificial Organs
Conclusions
References
Chapter 9: Ageing at Molecular Level: Role of MicroRNAs
MicroRNAs: Introduction
Ageing: Molecular Changes and Biomarkers
Biomarkers of Ageing
Ageing and Dicer Gene Ablation Studies
miRNAs Identified for their Role in Ageing of Different Tissues/Organs
Muscle Ageing and miRNAs
Bone Ageing and miRNAs
Heart Ageing and miRNAs
Skin Ageing and miRNAs
miRNAs in Neuronal or Brain Ageing
MiRNAs and Age-Related Cardiac Diseases
MiRNAs and Age-Related Neurodegenerative Diseases
Alzheimer´s Disease
Parkinson´s Disease
Huntington´s Disease
Amyotrophic Lateral Sclerosis
Stem Cell Development and miRNAs
Stem Cell Pluripotency and Role of miRNAs
miRNAs and Cardiovascular Differentiation
Neuronal Differentiation and miRNAs
Conclusion
References
Chapter 10: CircRNA and Ageing
Introduction
Biogenesis of circRNA
Diversity and Types of circRNA
Expression Patterns of circRNA
Function of circRNA
CircRNAs as Regulators of Transcription and Alternative Splicing
miRNA Sponges
Modulator of Protein Activity and Expression
Encoding Functional Proteins
circRNA in Ageing
circRNA Transcripts Accumulate During Ageing
Mechanisms of circRNA Accumulation
Biological Roles of circRNA in Ageing
circRNA in Age-Associated Disease
CircRNA in Neurological Disorders
CircRNA in Cardiovascular Diseases
CircRNA in Cancer
CircRNA in Diabetes
CircRNA as Biomarkers for Ageing
Perspectives and Conclusions
References
11: Extracellular Vesicles and Cellular Ageing
Intercellular Communication
Homeostasis and Intercellular Communication
Intercellular Communication and Ageing
SASP and Its Pro-inflammatory Components: Age-Related Inflammation
SASP and Pro-oncogenic Components
SASP and Paracrine Senescence
SASP and Autocrine Senescence
Stem Cells for Regenerative Medicine
Introduction to Stem Cells
Importance of Stem Cell Culture Conditions for Clinical Applications
Stem Cells in Clinical Trials
Stem Cell Properties Supporting Their Clinical Application
Stem Cell-Based Therapies: Clinical Trials
Cardiovascular Diseases
Neurological Disorders
Bone and Cartilage Diseases
Other Pathologies
Paracrine Effect of Stem Cells
Extracellular Vesicles as Tools for Intercellular Communication
EVs: Definition and Classification
A Brief History of EVs
EVs Biogenesis
EV Composition
EV Internalization and Function
Isolation Methods
Extracellular Vesicles in Regenerative Medicine
Regenerative Medicine: From a Cell-Based to a Cell-free Approach
EVs in Regenerative Medicine: Sources and Delivery Routes
Role of EVs in the Ageing Process
EVs as Gerotherapeutics: Lifespan and Healthspan
EVs as Gerotherapeutics: Hallmarks of Ageing
EVs and Age-related Diseases
Cardiovascular Diseases
Neurodegenerative Diseases
Musculoskeletal Diseases
Other Diseases
Concluding Remarks
References
Chapter 12: Fibrinogen, Coagulation, and Ageing
Introduction
Haemostasis
Haemostatic Changes with Age
Platelet Function
Anti-aggregators of Platelets
Platelet-Endothelial-White Blood Cell Immuno-pathological Interactions
Platelet Activity and Cardiovascular Disease
Platelet Changes with Age
Laboratory Monitoring: Diagnostics, Tests, and Assays
Laboratory Principles of Tests and Assays for Fibrinogen and Coagulation
Anticoagulation Therapeutics Amongst Older Adults
Heparin
Warfarin
Direct Oral Anticoagulants (DOAC)
Point-of-Care Testing-International Normalised Ratio (INR)
Point-of-Care Testing-ROTEM and TEG
Implications and Future Directions
The Demands on Blood Supply for an Ageing Population
Reference Intervals Specific to Older Adults
COVID-19 and Vaccinations, the Prevalence of Thrombotic Events and Implications for an Older Population with and without Comor...
Conclusion
References
Chapter 13: An Insight into Platelets at Older Age: Cellular and Clinical Perspectives
Introduction
Qualitative Changes of Platelets at an Older Age
Hallmarks of Ageing
Genomic Instability and Epigenetic Alterations
Loss of Proteostasis
Mitochondrial Dysfunction
Altered Intercellular Communication
Cellular Senescence
Dysregulated Nutrient Sensing
Concluding Remarks
References
Chapter 14: Ageing Skeletal Muscle: The Ubiquitous Muscle Stem Cell
Stem Cells
Epigenetics
Epigenetics and Stem Cell Fate
Adult Stem Cells and Their Potential
Skeletal Muscle
Skeletal Muscle Development-Role of the Stem Cell
Skeletal Muscle Stem Cells
Potential of Satellite Cell Models
Skeletal Muscle Ageing
Ageing and the Skeletal Muscle Stem Cell
Ageing, Epigenetics and Skeletal Muscle
Summary
References
15: Age-Related Changes in Central Nervous System 5-Hydroxytryptamine Signalling and Its Potential Effects on the Regulation o...
Overview of 5-HT in the Central Nervous System
Discovery of 5-HT
5-HT Distribution in the CNS
5-HT Synthesis
5-HT Receptors
Effects of Age on Serotonergic Signalling
Effects of Age on Serotonergic Neuronal Number
Tryptophan Hydroxylase
Vesicular 5-HT Content
5-Hydroxytryptamine
Firing of Serotonergic Neurones
Release of 5-HT
Age-Related Changes in 5-HT Clearance from the Synapse
Effects of Age on Monoamine Oxidase A/B
Effects of Age on 5-HT Receptors
5-HT1A Receptors
5-HT1B Receptors
5-HT2A Receptors
5-HT4, 6 and 7 Receptors
Overview of Effects of Age on Serotonergic Signalling
Ability of 5-HT to Regulate Lifespan
Molecular Mechanisms Involved in Sensory Regulation of Lifespan by 5-HT
Effects of Dead Conspecifics on Lifespan and the Role of 5-HT
So How Does the Natural Ageing Process and 5-HT Signalling Interact?
References
16: Systems Biology of Ageing
Introduction
Bioinformatics
Computational Modelling
Multiscale Models of Ageing
Conclusion
References
