Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging

Description

Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging is a comprehensive and timely book on all aspects of anti-aging strategies. The book provides comprehensive, foundational knowledge on the mechanisms of aging and current anti-aging strategies and approaches developed. Aging research has experienced an unprecedented advance over recent years with the discovery that the rate of aging is determined, at least to some extent, mainly by our genetics and modulated by environmental factors. The hallmarks of aging describe the molecular and cellular processes that govern biological aging and their variation in individuals. Anti-aging Drug Discovery on the Basis of Hallmarks of Aging Copyright Contents List of contributors Preface 1 The aging: introduction, theories, principles, and future prospective 1.1 Introduction 1.2 Modern theories of aging in biology 1.2.1 Three subcategories exist in programmed theory 1.2.1.1 Programmed longevity 1.2.1.2 Endocrine theory 1.2.1.3 Immunological theory 1.2.2 The error or damage theory has the following subcategories 1.2.2.1 Wear and tear theory 1.2.2.2 Rate of living theory 1.2.2.3 Cross-linking theory 1.2.2.4 Free radical theory 1.2.2.5 Somatic DNA damage theory 1.3 Principles 1.4 Extrinsic and intrinsic factors on aging 1.4.1 Circles and systems of social support on aging 1.4.2 Smoking on aging 1.4.3 Leisure activities on aging 1.4.4 Diet on aging 1.4.5 Physical health effects of exercise on aging 1.4.6 Cognitive health effects of exercise on aging 1.4.7 Aging intervention and future stem cell research 1.5 Future perspective (aging therapies) 1.5.1 Caloric restriction 1.5.2 Stem cell therapies 1.5.3 Hormonal therapies 1.5.4 Telomere-based therapies 1.5.5 Therapies to come 1.6 Summary References 2 Impact of aging at cellular and organ level 2.1 Introduction 2.2 Multicellular organization: human body 2.3 Changes associated with aging 2.4 Aging in cells 2.5 Aging in tissue and organs 2.6 Models to study aging 2.7 Antiaging therapy/treatment 2.8 Conclusion Competing interests Declaration of interest Financial support Authors’ contributions References 3 Brief about hallmarks of aging 3.1 The nine hallmarks of aging 3.1.1 Stem cell exhaustion 3.1.1.1 DNA damage on stem cell survival 3.1.2 Genomic instability 3.1.2.1 Genetic deterioration and somatic mutations 3.1.3 Telomere attrition 3.1.3.1 Structure and function of telomeres 3.1.3.2 Telomere aging and cellular senescence 3.1.4 Epigenetic alterations 3.1.4.1 DNA methylation 3.1.4.2 Histone modifications 3.1.5 Deregulated nutrient sensing 3.1.5.1 Lipid sensing 3.1.5.2 Amino acid sensing 3.1.5.3 Glucose sensing 3.1.6 Altered intercellular communication 3.1.6.1 Inflammaging 3.1.7 Loss of proteostasis 3.1.7.1 Molecular chaperones 3.1.7.2 Proteolytic systems 3.1.7.3 Autophagy 3.1.8 Cellular senescence 3.1.8.1 Triggers of senescence 3.1.8.2 Senolytics 3.1.9 Mitochondrial dysfunction 3.1.9.1 Mitochondrial DNA 3.1.9.2 Mitohormesis 3.2 Conclusions References 4 Overview of various antiaging strategies 4.1 Introduction 4.2 Modulation of autophagy for successful aging 4.3 Elimination of senescent cells for successful aging 4.4 Plasma transfusion for successful aging 4.5 Intermittent fasting as a means for successful aging 4.6 Regular exercise for successful aging 4.7 Role of antioxidants for successful aging 4.8 Stem cell therapy for successful aging 4.9 Summary References 5 Elimination of damaged cells-dependent antiaging strategy 5.1 Introduction 5.2 Aging-associated disease and physiological changes 5.2.1 Changes in nervous system 5.2.1.1 Cognition 5.2.1.2 Memory, learning, and intelligence 5.2.2 Special senses 5.2.2.1 Vision 5.2.2.2 Hearing 5.2.2.3 Taste acuity 5.2.2.4 Smell 5.2.2.5 Touch 5.2.3 Changes in musculoskeletal system 5.3 Antiaging strategies 5.3.1 Senescent cell elimination as an antiaging therapy 5.3.2 Transfusion of plasma from young individuals to promote successful aging 5.3.3 Intermittent fasting as a means to combat aging 5.3.4 Promise of neurogenesis enhancement for successful aging and preventing AD 5.3.5 Physical exercise for modulating aging and preventing dementia 5.3.6 Promising antioxidants and herbals for promoting successful aging 5.3.7 Stem-cell therapy for promoting healthy brain aging and reversing AD 5.4 Hallmarks of aging 5.4.1 Genomic instability 5.4.2 Telomere attrition 5.4.3 Epigenetic alterations 5.4.4 Loss of proteostasis 5.4.5 Deregulated nutrient-sensing 5.4.6 Mitochondrial dysfunction 5.4.6.1 Reactive oxygen species 5.4.6.2 Mitochondrial integrity and biogenesis 5.4.6.3 Mitohormesis 5.4.7 Cellular senescence 5.4.8 Stem-cell exhaustion 5.4.9 Altered intercellular communication 5.4.9.1 Inflammation 5.5 Cellular reprogramming 5.6 Models of premature aging based on cellular reprogramming 5.6.1 Progeroid syndromes 5.7 Cellular rejuvenation by partial reprogramming 5.8 Implications for regenerative medicine: successes and limitations of in vivo reprogramming 5.9 Conclusion Acknowledgments References 6 Telomerase reactivation for anti-aging 6.1 Introduction 6.2 Aging 6.3 Aging—a telomere–mitochondria relation 6.4 Telomerase and its possible role in antiaging therapies 6.5 Tapping the potential of telomerase 6.6 Stem cells and aging 6.7 Future aspects in antiaging Acknowledgments Competing interests Funding Authors’ contribution References 7 Epigenetic drugs based on antiaging approach: an overview 7.1 Introduction 7.2 The first wave of epigenetic drugs 7.2.1 DNA methyltransferase inhibitors 7.2.2 Histone deacetylase inhibitors 7.3 The second wave of epigenetic drugs 7.3.1 DNA methyltransferase inhibitors 7.3.2 Histone deacetylase inhibitors 7.4 The third wave of epigenetic drugs 7.4.1 Histone methyltransferase inhibitors 7.4.2 Histone demethylase inhibitors 7.4.3 Bromodomains 7.5 The fourth wave of epigenetic drugs 7.5.1 Revolution in biomedical sciences 7.5.2 Target selection 7.5.3 Enzyme isoform selectivity and drug designing 7.6 Conclusion References 8 Exploring the role of protein quality control in aging and age-associated neurodegenerative diseases 8.1 Proteins misfolding in aging and diseases 8.2 Protein quality control 8.2.1 Components of the protein quality control 8.2.1.1 Molecular chaperones 8.2.1.2 Ubiquitin-proteasome system 8.2.1.3 Autophagy-lysosomal pathway 8.3 Altered protein quality control in aging and diseases: lessons learned from in vitro and in vivo models 8.3.1 Aging 8.3.2 Alzheimer’s disease 8.3.3 Parkinson’s disease 8.3.4 Amyotrophic lateral sclerosis 8.3.5 Polyglutamine diseases 8.4 Therapeutic perspectives 8.4.1 Small molecules 8.4.2 Natural products serve as modifiers of an altered protein quality control system 8.4.2.1 Natural products as chaperone modifiers 8.4.2.2 Natural products targeting the UPS 8.4.2.3 Natural products targeting the autophagy-lysosomal pathway 8.5 Emerging techniques 8.6 Conclusion Acknowledgments Conflict of interest Author’s contributions References 9 Dietary restriction and mTOR and IIS inhibition: the potential to antiaging drug approach 9.1 Introduction 9.2 The antiaging drug discovery 9.2.1 The nutrient-signaling mechanism of the antiaging process 9.2.1.1 Dietary restriction 9.2.2 The insulin/insulin-like growth factor signaling (IIS) pathway 9.3 The mechanism of pharmacological strategies in antiaging process 9.3.1 The mechanistic target of rapamycin 9.4 Conclusion References 10 Antiaging drugs, candidates, and food supplements: the journey so far 10.1 Introduction 10.1.1 Some of the factors that contribute to aging process but not limited to this 10.2 Antiaging drugs 10.2.1 FDA approved 10.2.1.1 Metformin 10.2.1.2 Rapamycin 10.2.1.3 L. Carnosine 10.2.1.4 Isotretinoin 10.2.1.5 Cycloastragenol 10.2.1.6 Urolithin-A 10.2.1.7 Quercetin caprylate 10.2.1.8 Acarbose 10.2.1.9 Crocin 10.2.1.10 Hyaluronic acid 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.2 Food supplements 10.2.3 Astaxanthin 10.2.4 Vitamin C/L-ascorbic acid 10.2.5 Vitamin E—concoction of tocopherols and tocotrienols 10.2.6 Vitamin A 10.2.7 Poly-phenols 10.2.8 Flavonoids 10.2.9 Resveratrol (Stilbenes) 10.2.10 Curcumin 10.2.11 Pathways targeted and their cross talks 10.3 Aging—molecular and biochemical significance 10.4 Summary References 11 Role of AMP-activated protein kinase and sirtuins as antiaging proteins 11.1 Introduction 11.2 AMP-activated protein kinase and its functions 11.3 Sirtuins: role of SIRT1 11.4 Correlation between AMP-activated protein kinase and sirtuins 11.5 Effect of AMP-activated protein kinase and sirtuins on calorie restriction and longevity 11.6 Role of AMP-activated protein kinase and sirtuins in mitochondrial homeostasis 11.6.1 AMP-activated protein kinase in mitochondrial biogenesis 11.6.2 AMP-activated protein kinase in mitochondrial fission and mitophagy 11.6.3 Sirtuins in mitochondrial biogenesis 11.6.4 Sirtuins in mitophagy 11.7 AMP-activated protein kinase and sirtuins in age-associated neurodegenerative diseases 11.7.1 Alzheimer’s disease 11.7.2 Parkinson’s disease 11.7.3 Huntington’s disease 11.7.4 Amyotrophic lateral sclerosis 11.8 Modulation of AMP-activated protein kinase and sirtuins 11.8.1 AMP-activated protein kinase activating compounds 11.8.1.1 Direct activators of AMP-activated protein kinase 11.8.1.2 Indirect activators of AMP-activated protein kinase 11.8.2 Sirtuins-modulating compounds 11.8.3 Therapeutic perspectives: how far we have come? 11.8.3.1 Other approaches 11.9 Conclusion Acknowledgments Conflict of interest Author’s contributions References 12 Mitophagy and mitohormetics: promising antiaging strategy 12.1 Mitochondrial basis of aging 12.2 Age-associated changes in mitochondria 12.3 UPRmt and mitochondrial hormesis (mitohormesis) 12.4 Pathways involved in mitohormetic response 12.5 Mitohormetic pathways converge on the mitophagy 12.6 Antiaging strategies based on regulation of mitohormesis 12.7 Conclusion References 13 Clearance of senescent cells: potent anti-aging approach 13.1 Introduction 13.2 SASP modulators 13.3 Immunotherapeutics 13.4 Senolytics 13.5 Senolytic clinical trials 13.6 Senescence reversal 13.7 Conclusion References 14 Stem cell-based therapy as an antiaging prospective 14.1 Introduction 14.2 Classification of stem cells 14.2.1 On the basis of their differentiation 14.2.2 On the basis of origin 14.2.2.1 Embryonic stem cells 14.2.2.2 Adult stem cells 14.3 Stem cell therapy 14.3.1 Stem cell therapy for the treatment of age-related neurological disorders 14.3.2 Parkinson’s disease and stem cell therapy 14.3.3 Alzheimer’s disease and stem cell therapy 14.3.4 Stem cell therapy and stroke 14.3.5 Stem cell therapy and multiple system atrophy 14.3.6 Stem cell therapy as for antiaging for facial skin 14.3.7 Stem cell therapy for the treatment of osteoarthritis 14.3.8 Stem cell therapy in dermatology 14.4 Mechanisms of stem cell therapy in age-related diseases and antiaging 14.5 Molecular mechanism of stem cell therapy from an antiaging perspective 14.6 Limitations of the stem cell therapies References 15 Antiinflammatory therapy as a game-changer toward antiaging 15.1 Introduction 15.2 Characteristics of aging 15.3 Theories of aging 15.3.1 DNA damage 15.3.2 Telomere shortening 15.3.3 Epigenetics 15.3.4 Unfolded protein response or misfolded proteins 15.3.5 Mitochondrial dysfunction 15.3.6 Cell senescence 15.3.7 Stem-cell exhaustion 15.3.8 AMPK pathway 15.3.9 Glycation 15.3.10 Chronic inflammation and a declining immune system 15.3.11 mTOR pathway 15.3.12 Sirtuins 15.4 The free radical, oxidative, and mitochondrial theories of aging 15.5 The immune system as a homeostatic system 15.6 Oxidation and inflammation as related homeostatic mechanisms of the immune response 15.6.1 Wnt/β-Catenin pathway 15.6.2 Phosphatidylinositol 3-kinase/Akt/mechanistic target of rapamycin signaling pathway 15.6.3 Sirtuin pathway 15.6.4 Autophagic pathway 15.6.5 Nuclear factor-κB pathway 15.7 Conclusion and future perspectives Conflict of interest References 16 Invertebrate model organisms for aging research 16.1 Introduction 16.2 Invertebrate models for aging research 16.3 Caenorhabditis elegans model for aging research 16.3.1 Caenorhabditis elegans life cycle 16.3.2 Aging in C. elegans 16.3.3 Application of Caenorhabditis elegans for aging research 16.3.4 Genetic and environmental models of aging in C. elegans 16.3.5 Translational significance 16.4 Drosophila model for aging research 16.4.1 Drosophila melanogaster life cycle 16.4.2 Aging in Drosophila 16.4.3 Genetic and environmental models of aging in Drosophila melanogaster 16.4.4 Translational significance of Drosophila research on aging 16.5 Drosophila melanogaster and Caenorhabditis elegans for aging research: similarities and contrasts Acknowledgments References Index