Molecular, Cellular, and Metabolic Fundamentals of Human Aging

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MOLECULAR, CELLULAR, AND METABOLIC FUNDAMENTALS OF HUMAN AGING
MOLECULAR, CELLULAR, AND METABOLIC FUNDAMENTALS OF HUMAN AGING
Copyright
Contents
List of contributors
Foreword
Preface
1 - The hallmarks of aging: decoding aging's mystery
1. Aging
2. Aging research
3. Life span and health span
4. The hallmarks of aging
References
I - The genome
2 - Epigenetic aging and its reversal
1. Introduction to epigenetics
1.1 Chromatin structure
1.2 Histone variants
1.3 Histone posttranslational modifications
1.4 Deoxyribonucleic acid modifications
1.5 Noncoding ribonucleic acids
1.6 Models of human aging research
2. Changes in chromatin structure during aging
2.1 Age-associated loss of heterochromatin
2.2 Changes in chromatin accessibility and nucleosome remodeling
3. Changes in histones during aging
3.1 Changes in histone expression levels
3.2 Changes in histone variants
3.2.1 Histone 2A variants
3.2.2 Histone 3 variants
4. Changes in histone posttranslational modifications
4.1 Histone methylation
4.2 Histone acetylation
5. Deoxyribonucleic acid methylation in aging
5.1 Deoxyribonucleic acid methylation changes with age
5.2 Methylation clocks and predictors of health span and lifespan
6. Noncoding ribonucleic acids in aging
7. Reversal of epigenetic aging
8. Conclusions and perspectives
References
II - Metabolism, homeostasis, and communication
3 - Nutrient sensing and aging
1. AMPK signaling pathway
2. mTOR pathway
3. SIRT pathway
4. IGF-1 pathway
5. Calorie restriction and aging
6. Conclusion
References
4 - Dysregulated proteostasis: mechanisms and links to aging
1. Introduction
2. Functional modules of the proteostasis network
2.1 Synthesis module
2.2 Folding module
2.2.1 De novo folding
2.2.2 Conformational maintenance and misfolded protein triage
2.2.3 Spatial sequestration and resolution
2.3 Clearance module
2.3.1 Ubiquitin–proteasome system
2.3.2 Autophagy–lysosome system
2.3.3 Terminal sequestration
2.3.4 Other clearance mechanisms
2.4 Extended modules for eukaryotic proteostasis
2.4.1 Targeting
2.4.2 Protein complex assembly
2.5 Executive modules to regulate the proteostasis network
2.5.1 Stress responses remodel the proteostasis network to restore proteostasis
2.5.2 Organism-wide proteostasis control
3. Proteostasis network dysregulation in aging
3.1 Proteostasis network size as determinant of species life span
3.2 Proteostasis network remodeling with age
3.2.1 Dysregulation of core proteostasis network modules
3.2.1.1 Decline in protein synthesis
3.2.1.2 Remodeling of chaperone-mediated protein quality control
3.2.1.3 Shifting degradation and sequestration machineries
3.2.2 Dysregulation of extended and executive modules
3.2.2.1 Protein targeting defects
3.2.2.2 Loss of protein complex stoichiometry
3.2.2.3 Decline in stress resilience
4. Interplay with other aging hallmarks
5. Targeting proteostasis for healthy aging
6. Concluding remarks
Acknowledgments
References
III - Autophagy and bioenergetics
5 - Autophagy and bioenergetics in aging
1. Compromised autophagy and mitophagy in aging and disease
1.1 Autophagy, mitophagy, and aging
1.2 Tissue-specific autophagy and mitophagy in aging
1.3 Compromised autophagy or mitophagy is a hallmark of aging
1.4 Dysfunctional autophagy and mitophagy lead to accelerated aging
2. Mitochondrial dysfunction
2.1 Mitochondrial biology
2.2 Mitochondrial bioenergetics
2.3 Mitochondrial dysfunction in aging
3. Mechanisms of mitochondrial dysfunction
3.1 Reduced mitochondrial biogenesis and integrity
3.2 Reduced mitochondrial dynamics
3.3 Compromised mitophagy
3.4 Accumulation of mutations in mitochondrial deoxyribonucleic acid
3.5 Mitochondrial oxidative phosphorylation dysfunctions
3.6 High levels of reactive oxygen species
3.7 Low levels of nicotinamide adenine dinucleotide
4. Dysfunctional mitochondria contribute to energy shortages and aging cells
4.1 Interfering with intracellular signaling
4.2 Triggering apoptosis and inflammatory reactions
5. Conclusions and future perspectives
Acknowledgments
References
IV - Senescence
6 - Senescence in aging
1. What is senescence?
1.1 Characteristics of senescent cells
1.2 p53 and p16: hallmarks of senescence
1.3 SASP and its constituents
1.3.1 Proinflammatory interleukins and cytokines
1.3.2 Chemokines
1.3.3 Insulin-like growth factor–binding proteins
1.3.4 Extracellular proteases
1.3.5 Fibronectin
1.3.6 Nonprotein secretion
2. Current concepts of senescence in aging
2.1 Mouse models revealing the impact of senescence on aging
2.1.1 Senescence and its links to age-related diseases
2.2 Senescence and neurodegeneration
3. Factors driving and/or triggering senescence in aging
3.1 Genomic instability as a trigger and sign of cellular senescence
3.2 Telomere attrition
3.3 Compromised mitophagy and impaired mitochondrial function
3.3.1 Mitochondrial dysfunction-induced senescence phenotype
3.3.2 Macroautophagy and senescence
3.3.3 Mitophagy and senescence
3.4 Oncogene-induced senescence and activation of tumor suppressors
4. Stem cell exhaustion in aging
4.1 Stem cell therapy and senescence
5. To develop senotherapies (senolytics and senomorphics) against age-related diseases and beyond
6. Methods for analyzing and quantifying senescence in vitro and in vivo
6.1 Methods for evaluating senescence in vitro
6.2 Evaluation of senescence in vivo
7. Concluding remarks
Acknowledgments
References
V - Applications
7 - Aging and the immune system
1. Overview of immunosenescence
2. Aging-related lymphoid organs and immunity
2.1 Lymphoid organs
2.1.1 Bone marrow
2.1.2 Thymus
2.1.3 Spleen
2.1.4 Lymph nodes
2.2 Immunity
2.2.1 Innate immunity
2.2.1.1 Neutrophils
2.2.1.2 Natural killer cells
2.2.1.3 Monocytes and macrophages
2.2.1.4 Dendritic cells
2.2.2 Adaptive immunity
2.2.2.1 B cells
2.2.2.2 T cells
3. Interplay between immunosenescence and aging process
3.1 Inflammaging and immunosuppressive network
3.2 Feed-forward regulation between cellular senescence and immunosuppression
3.3 Immunosenescence and age-associated diseases
3.3.1 Neurodegenerative diseases
3.3.2 Rheumatoid arthritis
3.3.3 Cancer
3.3.4 Cardiovascular diseases
3.3.5 Metabolic diseases
4. Conclusions
References
8 - Canonical and novel strategies to delay or reverse aging
1. Approaching aging as a treatable disease
2. Nonpharmaceutical interventions against aging
2.1 Calorie restriction and fasting
3. Pharmaceutical treatments against aging
3.1 Rapamycin and rapalogs
3.2 Mitophagy inducers
3.2.1 Oxidized nicotine adenine dinucleotide
3.2.2 Urolithin A
3.2.3 Actinonin
4. Novel approaches to slow or reverse aging
4.1 Cellular reprogramming
4.2 Senolytics
5. Outstanding questions and future perspectives
Acknowledgments
References
Index
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