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

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