Reviews on New Drug Targets in Age-Related Disorders: Part II (Advances in Experimental Medicine and Biology, 1286)

Aging is an inevitable part of life, and is becoming a worldwide social, economic and health problem due to the fact that an increasing proportion of individuals in the advanced age category have a higher probability of developing age-related disorders. New therapeutic approaches are still in need to decrease or slow the effects of such diseases in this aging society. Advances in ‘omic technologies such as genomics, transcriptomics, proteomics and metabolomics have significantly advanced our understanding of diseases in multiple medical areas. It is hoped that emerging hits from these analyses might be prioritized for further screening as potential novel drug targets for increasing the human healthspan in line with the lifespan, which will in turn lead to new therapeutic strategies and drug development projects by the pharmaceutical industry. This new book presents a series of reviews describing studies which have resulted in the identification of potential new drug targets for age-related disorders. Much of this information has come from ‘omic comparisons of healthy and disease states or from testing the effects of potential new therapeutic approaches. Each chapter will be presented in the context of specific chronic diseases or different therapeutic strategies, providing important information on disease mechanisms related to the aging process. This book will be of interest to researchers in the areas of aging and chronic disease, as well as clinical scientists, physicians, and major drug companies. With contributors from Australia, Brazil, Canada, France, Germany, India, Iran, Iraq, South Africa, South Korea, Thailand, Ukraine, United Kingdom, United States of America, Uruguay and Vietnam, this is a timely follow up to Guest’s previous book Reviews on New Drug Targets in Age-Related Disorders. Preface Contents 1: New Therapeutic Approaches and Biomarkers for Increased Healthspan 1.1 Introduction 1.2 Body Composition 1.2.1 Adiposity 1.2.2 Muscle Mass 1.2.3 Therapeutic Approaches Targeting Body Composition 1.2.3.1 Resistance Exercise 1.2.3.2 Dietary Methods 1.2.3.3 Pharmaceuticals and Natural Compounds 1.2.3.4 Combination Approaches 1.3 Biomarkers 1.3.1 Physical Function and Body Composition 1.3.2 Circulating Molecular Biomarkers 1.3.3 Genes 1.3.3.1 FOXO 1.3.3.2 APOE 1.3.3.3 KL 1.3.3.4 ACE 1.3.3.5 IL-6 1.3.3.6 Genetic Networks 1.4 Conclusions and Future Perspectives References 2: Targeting Cancer Metabolism and Current Anti-Cancer Drugs 2.1 Introduction 2.2 Glycolysis 2.2.1 Hexokinase 2.2.2 Pyruvate Kinase 2.2.3 Lactate Dehydrogenase-A 2.2.4 Monocarboxylate Transporters (MCTs) 2.3 Mitochondrial Metabolism 2.3.1 Pyruvate Dehydrogenase Kinase 2.3.2 TCA Cycle 2.3.3 Oxidative Phosphorylation 2.4 Glutaminolysis 2.4.1 Glutaminase (GLS) 2.5 De Novo Fatty Acid Synthesis 2.5.1 ATP-Citrate Lyase 2.5.2 Acetyl-CoA Carboxylase 2.5.3 Fatty Acid Synthase 2.6 Conclusion and Future Perspectives References 3: A Review of Monoclonal Antibody-Based Treatments in Non-small Cell Lung Cancer 3.1 Introduction 3.2 Targeted Therapies and their Approved Antibodies 3.2.1 Epidermal Growth Factor Receptor (EGFR) 3.2.1.1 Cetuximab 3.2.1.2 Nimotuzumab 3.2.1.3 Matuzumab 3.2.1.4 Necitumumab 3.2.1.5 Panitumumab 3.2.2 Vascular Endothelial Growth Factor (VEGF) 3.2.2.1 Bevacizumab 3.2.2.2 Ramucirumab 3.2.3 PD-1 and PD Ligands 1 and 2 (PD-L1 and L2) 3.2.3.1 Pembrolizumab 3.2.3.2 Nivolumab 3.2.3.3 Atezolizumab 3.2.3.4 Durvalumab 3.2.3.5 Avelumab 3.2.4 IGF-1R 3.2.4.1 Figitumumab 3.2.5 RANKL 3.2.5.1 Denosumab 3.2.6 HGF 3.2.6.1 Ficlatuzumab 3.2.6.2 Rilotumumab 3.2.7 CTLA-4 3.2.7.1 Ipilimumab 3.2.7.2 Tremelimumab 3.2.8 Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Receptor 2 (TR-2) or Death Receptor 5 (DR5) 3.2.8.1 Conatumumab 3.3 Conclusions References 4: Parkinson’s Disease and Impairment in Mitochondrial Metabolism: A Pathognomic Signature 4.1 Introduction 4.2 Impaired Mitochondrial Metabolism Etiologies 4.2.1 Mutations in the OxPhos System 4.2.2 Defects in Complex 1 and PD Prognosis: A Pathognomic Signature 4.2.3 Intracellular ROS 4.2.4 Impaired Calcium Balance 4.2.5 Mitochondrial ETC Inhibitors and Environmental Toxicants 4.2.6 Increased Fat Diet Uptake 4.3 PD and Perturbed Mitochondrial Metabolism 4.4 Conclusions and Future Perspectives References 5: Targeted Treatment of Age-Related Fibromyalgia with Supplemental Coenzyme Q10 5.1 Introduction 5.2 Pathogenesis of Fibromyalgia 5.3 Fibromyalgia and Aging 5.4 Nutritional Supplementation and Aging 5.5 CoQ10 5.6 Clinical Studies on CoQ10 Supplementation in Fibromyalgia 5.7 Safety and Bioavailability of CoQ10 5.8 Conclusions References 6: Immunoregulatory Effects of Tolerogenic Probiotics in Multiple Sclerosis 6.1 Introduction 6.2 MS and the Immune System 6.2.1 Th1 and Th17 in MS 6.2.2 Th9 and Th22 in MS 6.2.3 CD8+ T Cells and B Cells in MS 6.2.4 T Regulatory (Treg) and Th2 Cells in MS 6.3 Risk Factors of MS 6.4 Therapeutics Approaches for MS 6.4.1 Probiotics and Autoimmune Diseases 6.4.2 Cross-Talk of Multiple Sclerosis and Microbiota 6.4.3 Modulatory Effects of Tolerogenic Probiotics on CNS 6.4.4 Modulatory Effects of Tolerogenic Probiotics on Treg Cells 6.4.5 Modulatory Effects of Tolerogenic Probiotics on Th1 and Th17 6.5 Concluding Remarks References 7: Multifaceted Roles of Long Non-coding RNAs in Head and Neck Cancer 7.1 Introduction 7.2 Structure and Characteristics of lncRNAs 7.3 lncRNAs Associated with Tumorigenesis and Development of Head and Neck Cancer (HNC) 7.4 lncRNAs Associated with Invasion and Metastasis of HNC 7.5 lncRNAs Associated with Treatment Resistance in HNC 7.6 Prognostic Role of lncRNAs in HNC 7.7 Conclusions References 8: A Systematic Review on the Genotoxic Effects of Selective Serotonin Reuptake Inhibitors 8.1 Introduction 8.2 Methods 8.2.1 Literature Search Strategy 8.2.2 Inclusion and Exclusion Criteria 8.2.3 Data Extraction 8.3 Results 8.3.1 Literature Search 8.3.2 Citalopram 8.3.3 Escitalopram 8.3.4 Fluoxetine 8.3.5 Fluvoxamine 8.3.6 Paroxetine 8.3.7 Sertraline 8.4 Discussion 8.5 Conclusions References 9: Toward a New Era for the Management of Circulating Tumor Cells 9.1 Introduction 9.2 Historical Background 9.3 Detection Methods 9.3.1 Biological Properties 9.3.1.1 Density Gradient Centrifugation 9.3.1.2 Filtration 9.3.2 Physical Properties 9.3.2.1 Negative Selection 9.3.2.2 Positive Selection 9.4 Research of Circulating Tumor Cells in Several Types of Cancers 9.4.1 Breast Cancer 9.4.2 Colorectal Cancer 9.4.3 Lung Cancer 9.4.4 Prostate Cancer 9.4.5 Melanoma 9.4.6 Sarcomas 9.4.7 Head and Neck Cancer 9.5 Clinical Applications and Limitations 9.6 Conclusion References 10: Telomerase: A Target for Therapeutic Effects of Curcumin in Cancer 10.1 Introduction 10.2 In Vitro Studies on Telomerase Inhibition 10.3 In Vivo Studies 10.4 Conclusions References 11: Aspirin as a Potential Geroprotector: Experimental Data and Clinical Evidence 11.1 Introduction 11.2 Mechanisms of Action 11.3 Lifespan Extension in Model Organisms 11.3.1 Caenorhabditis elegans 11.3.2 Drosophila melanogaster 11.3.3 Rodents 11.4 Health Benefits of Aspirin: Evidence from Clinical Trials 11.4.1 Aspirin and CVD Prevention in Elderly 11.4.2 Anti-Cancer Effects of Aspirin 11.4.3 Anti-inflammatory Properties of Aspirin 11.4.4 Aspirin and Cognitive Function 11.5 Adverse Effects of Aspirin 11.5.1 Aspirin and Risk of Bleedings 11.5.2 Low-Dose Aspirin on Intracranial Hemorrhage (ICH) and Cerebral Microbleeds 11.5.3 Adverse Effects of Aspirin in Elderly Patients Having Surgical Procedures 11.5.4 Aspirin and Potential Drug–Drug Interactions 11.6 Conclusions and Future Directions References 12: Targeting Stem Cells in Chronic Inflammatory Diseases 12.1 Introduction 12.2 Mesenchymal Stem Cells 12.3 Dysregulation of MSCs’ Immunomodulatory Properties 12.4 Methodological Considerations in the Interpretation of Intervention Strategy Outcomes 12.5 Interventions 12.5.1 Pharmacological Blocking of NFкB Signalling 12.5.2 Natural Antioxidants and/or Anti-inflammatory Agents 12.5.3 Biological Agents 12.5.3.1 Microvesicles and Exosomes 12.5.3.2 Probiotics: An Emerging Therapeutic Hope? 12.6 Conclusion References 13: Therapeutic Strategies and Nano-Drug Delivery Applications in Management of Aging Alzheimer’s Disease 13.1 Introduction 13.2 Targeting the Amyloid Cascade 13.3 Nanomaterials Against Amyloid Diseases 13.4 Nanotechnologies for AD Treatment 13.4.1 Targeting Androgen and Estrogen NPs 13.4.2 Polymeric Nanoparticles 13.4.3 Inorganic Nanoparticles 13.4.4 Mitochondrial Targeting 13.5 Targets for Future Drugs 13.6 Conclusion, Challenges, and Future Perspectives References 14: Psychometric Evaluation of Stress in 17,414 Critical Care Unit Nurses: Effects of Age, Gender, and Working Conditions 14.1 Introduction 14.2 Methods 14.2.1 Design, Setting, and Procedures 14.2.2 Ethical Considerations 14.2.3 Sample Size 14.2.4 Measurements 14.2.5 Statistical Analyses 14.3 Results 14.3.1 Content Validity 14.3.2 Construct Validity 14.3.3 Reliability 14.3.4 Convergent Validity 14.3.5 Discriminate Validity (the Fornell-Larcker Criterion) 14.3.6 Relationship Between Stress Components and Background Variables 14.4 Discussion 14.5 Conclusion References 15: Targeting Age-Related Neurodegenerative Diseases by AAV-Mediated Gene Therapy 15.1 Introduction 15.2 AAV-Based Gene Therapy 15.3 Optimizing AAV Capsids for Efficient CNS Transduction 15.4 AAV-Based Gene Therapy for AD, PD, and ALS: Highlights from the Clinic 15.4.1 Alzheimer’s Disease (AD) 15.4.2 Parkinson’s Disease (PD) 15.4.3 Amyotrophic Lateral Sclerosis (ALS) 15.5 Conclusions References 16: Is Adipose Tissue the Fountain of Youth? The Impact of Adipose Stem Cell Aging on Metabolic Homeostasis, Longevity, and Cell-Based Therapies 16.1 Introduction 16.2 The Effects of Chronological Aging on ASC Biology and Function 16.2.1 Age-Induced ASC Senescence 16.2.1.1 Senescence Mechanisms: A Brief Overview 16.2.1.2 Markers of Senescence 16.2.1.3 Characterization of Age-Associated Senescence in ASCs 16.2.2 Downregulation of the Adipogenic Gene Program 16.2.3 Age, Senescence, and Inflammation in ASCs 16.2.4 The Role of ASCs in the Age-Related Loss of Lipid Storage Capacity in Adipose Tissue 16.3 Adipose Tissue as a Source of Longevity Signals 16.3.1 Adipose Depot-Specific Contributions to Lifespan Determination 16.3.2 Circulating Factors and Longevity 16.3.3 Molecular Mediators of Longevity: Dicer and Cdc42 16.3.4 Calorie Restriction: Guardian of SAT Function? 16.4 Alleviating the Effects of Senescent ASCs In Vivo 16.4.1 Targeting Senescent ASC: Senolytics 16.4.2 Targeting the SASP 16.5 Implications of Age for the Use of ASCs in Cell-Based Therapy 16.5.1 Therapeutic Implications of Donor Age 16.5.1.1 Loss of Function (Passive Dysfunction) 16.5.1.2 Acquisition of Pathological Features (Active Dysfunction) 16.5.1.3 Transplanted ASCs as a Treatment for Metabolic Syndrome? 16.5.2 Ex Vivo Rejuvenation of ASCs 16.6 Concluding Remarks References 17: Proteomics for Target Identification in Psychiatric and Neurodegenerative Disorders 17.1 Introduction 17.2 Overview of Proteomic Technologies 17.2.1 Proteomic Methods 17.2.2 The Use of Proteomics in Target Identification 17.3 Proteomics in Psychiatric and Neurodegenerative Disorders 17.3.1 Schizophrenia 17.3.2 Parkinson’s Disease 17.3.3 Alzheimer’s Disease 17.3.4 Shared and Distinct Molecular Pathways Between SCZ, PD, and AD 17.4 Conclusions References Index