Reviews on New Drug Targets in Age-Related Disorders (Advances in Experimental Medicine and Biology Book 1260)

Aging is an inevitable part of life and is becoming a worldwide social, economic and health problem. This is mainly due to the fact that the increasing proportion of individuals in the advanced age category have a higher probability of developing age-related disorders, such as type II diabetes mellitus, cardiovascular disorders, sarcopenia, and neurodegenerative conditions. New therapeutic approaches are still needed to decrease or slow the effects of such diseases. Advances in -omic technologies, such as genomics, transcriptomics, proteomics and metabolomics, have significantly advanced our understanding of disease in multiple medical areas, as the analysis of multiple molecular networks has simultaneously provided a more integrated view of disease pathways. 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. In turn, this will lead to new therapeutic strategies as well as drug development projects by the pharmaceutical industry. This book presents a series of reviews describing studies that have resulted in identification of new potential 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 new therapeutic approaches. Authored by experts from around the globe, each chapter is presented in the context of specific chronic diseases or therapeutic strategies. This book is designed for researchers in the areas of aging and chronic disease, as well as clinical scientists, physicians and stakeholders in major drug companies. Preface 6 Contents 8 Chapter 1: Targeting ROS-Mediated Crosstalk Between Autophagy and Apoptosis in Cancer 10 1 Introduction 10 2 The Function of ROS in Cancer Development and Treatment 12 3 ROS-Mediated Cancer Cell Autophagy 13 4 ROS-Mediated Cancer Cell Apoptosis 15 5 ROS-Mediated Complex Interplay Between Autophagy and Apoptosis in Cancer Cells 16 6 Conclusions 18 References 18 Chapter 2: Micronutrients that Affect Immunosenescence 22 1 Introduction 22 2 The Immune System in Aging 23 3 Intake of Micronutrients in the Elderly 26 3.1 Micronutrient Requirements and Reported Deficiencies 26 3.2 Clinical Effects of Micronutrient Deficiencies and Supplementation 26 4 Conclusions 34 References 34 Chapter 3: Bioactive Lipids in Age-Related Disorders 41 1 Introduction 41 2 Essential Fatty Acid Metabolism 43 3 Actions of Bioactive Lipids 48 4 Inflammation 49 5 Bioactive Lipids and the Immune Response 52 6 IL-6, TNF-α and Corticosteroids Induce a Bioactive Lipid Deficiency State 56 7 Bioactive Lipids Modulate Immune Response 59 8 Bioactive Lipids in the Immune Response and Cancer 60 9 Cancer and Auto-immune Diseases Are Two Sides of the Same Coin 65 10 Ion Channels and Bioactive Lipids 70 11 Connecting the Cell Membrane to the Nucleus 73 12 Polyunsaturated Fatty Acids and Bioactive Lipids Are Involved in Mitochondrial Processes 74 13 Bioactive Lipids Modulate G-Protein-Mediated Signals 74 14 Age-Related Disorders Are Inflammatory Conditions and Can Be Modulated by Bioactive Lipids 75 15 Conclusions and Future Perspectives 75 References 77 Chapter 4: Effect of Short Chain Fatty Acids on Age-Related Disorders 92 1 Introduction 92 2 SCFAs and Metabolic Diseases 94 3 SCFAs and Hypertension and CVDs 96 4 SCFAs and Neurodegenerative Disease 97 5 SCFAs and Cancer 100 6 Conclusions 104 References 104 Chapter 5: The Effects of Parabiosis on Aging and Age-Related Diseases 113 1 Introduction 113 2 Organ and Tissue Rejuvenation via Heterochronic Parabiosis 115 2.1 Liver 115 2.2 Skeletal Muscle 115 2.3 Nervous System 118 2.4 Endocrine Pancreas 120 2.5 Heart 121 2.6 Bone 122 3 Looking for a “Silver Bullet” 123 3.1 GDF11: A Controversial Hero 123 3.2 Other Contenders 125 4 Conclusions 126 References 126 Chapter 6: Skeletal Muscle Aging Atrophy: Assessment and Exercise-Based Treatment 129 1 Introduction 129 2 Skeletal Muscle Aging Atrophy 130 3 Basic and Instrumental Activities of Daily Living Assessment 131 3.1 Barthel Index 131 3.2 Katz Index 133 3.3 Lawton and Brody Scale 134 4 Physical Performance Assessment 134 4.1 Grip Strength Test 134 4.2 Gait Speed Test 134 4.3 Timed Up and Go Test 135 4.4 Unipedal Stance Test 135 4.5 Tinetti Scale 135 4.6 Short Physical Performance Battery 136 4.7 Senior Fitness Test 136 5 Cognitive Assessment 138 5.1 Mini Mental State Examination 138 5.2 Pfeffer Scale 138 5.3 Geriatric Depression Scale 139 6 Skeletal Muscle Atrophy: Aging and Hospitalization Combined 139 6.1 Sarcopenia and Costs Associated with Hospitalization 140 6.2 Decrease in Skeletal Muscle Mass and Strength: Clinical Evaluation in the Hospital Context 140 MRC-SS 141 Grip Strength in the Hospital 142 Ultrasonography 142 7 Techniques of Skeletal Muscle Mass Assessment 143 7.1 Body Composition 144 7.2 Multi-compartment Model 144 7.3 Body Imaging Techniques 144 MRI 145 CT 145 DXA 146 Bioelectrical Impedance Analysis (BIA) 147 Anthropometry 147 7.4 Invasive Evaluation of Skeletal Muscle Mass 148 Skeletal Muscle Biopsy 148 8 Physical Exercise as a Drug to Combat Skeletal Muscle Atrophy in the Older Population 149 8.1 Modalities of Physical Exercise in Older People 149 Resistance Exercise Training (RET) or Muscle Strength 149 Aerobic Exercise Training (AET) or Endurance 152 Stretching or Flexibility Training 152 Balance Training 153 Final Considerations 154 9 Conclusions 154 References 155 Chapter 7: Polyphenols as an Effective Therapeutic Intervention Against Cognitive Decline During Normal and Pathological Brain Aging 165 1 Introduction 165 2 Polyphenols 166 3 Polyphenols and the Normal Aging Brain 167 4 Polyphenols and Neurodegenerative Diseases 168 5 Polyphenols and Exercise for Aging Brain 170 6 Conclusions 170 References 174 Chapter 8: Early Diagnosis and Targeted Treatment Strategy for Improved Therapeutic Outcomes in Alzheimer’s Disease 181 1 Introduction 181 2 Alzheimer’s Disease Pathophysiology and Biomarkers 183 2.1 Aβ Plaques 183 2.2 Neurofibrillary Tangles 183 2.3 Neuroinflammation 184 3 What Comes First – Aβ Plaques or Neurofibrillary Tangles? 185 3.1 Age-Related Alzheimer’s Disease 185 3.2 Familial Alzheimer’s Disease 186 4 New Targets to Delay or Prevent Onset of Alzheimer’s Disease 186 4.1 The Potential Benefits of Early Detection 186 4.2 Targeting Soluble Aβ Oligomers 187 4.3 Targeting Soluble Tau Oligomers 188 4.4 Targeting Neuroinflammation 189 5 Biomarkers and the Importance of Patient Stratification 189 5.1 Biomarkers in Body Fluids 190 5.2 Imaging Biomarkers 191 6 Conclusions and Future Perspectives 191 References 192 Chapter 9: Resetting the Aging Clock: Implications for Managing Age-Related Diseases 198 1 Introduction 198 2 Modern Challenges and Factors Contributing to Circadian and Sleep Disorders 199 2.1 Life in Modern Society Undermines Circadian Entrainment 199 2.2 Working Hours and Non-standard Work Schedules 201 2.3 Social Jetlag 202 3 Anatomy and Physiology of the Mammalian Clock 202 3.1 Neural Architecture of the Mammalian Circadian System 202 3.2 Molecular Machinery of the Cellular Clock 204 3.3 Coupling Between Central and Peripheral Oscillators in Mammals 206 3.4 Non-photic Entrainment of Peripheral Oscillators 207 4 Reciprocal Interactions Between the Circadian System and Aging 208 4.1 Effects of Aging on the Central Clock and Circuit Connectivity 209 4.2 Aging Impairs Resynchronization of Circadian Oscillators 209 4.3 Aging Differentially Affects Peripheral Oscillators and Tissues 211 Aging Affects Core Oscillator Gene Expression in a Tissue Dependent Manner 211 Aging Affects Clock-Controlled Gene Expression 213 4.4 The Circadian Clock Mediates Lifespan and Health Span 213 4.5 Aging and Circadian Disruption Affect the Response to Physiological Challenges 215 4.6 Circadian Disruption as a Predictor of Neurodegenerative Pathologies 217 5 Potential Interventions and Treatments 220 5.1 Behavioral Reinforcement of the Circadian System 221 Targeting Symptoms of Aging Using Bright Light Therapy (Table 9.1) 221 Time-Restricted Feeding Reinforces Synchrony Among Peripheral Oscillators and Mitigates the Onset and Progression of Metabolic Disorders (Table 9.2) 226 5.2 Pharmacological Targeting of Clock Components for Age-Related Pathologies (Table 9.3) 229 6 Future Perspectives 236 References 236 Chapter 10: The Challenge of Antidepressant Therapeutics in Alzheimer’s Disease 271 1 Introduction 271 2 Common Mechanisms Underlying Depression and Alzheimer’s Disease 272 3 Antidepressant Drug Mechanisms in Alzheimer’s Disease 274 4 The Classical Treatment and the Antidepressant Challenge in Alzheimer’s Disease 277 5 Conclusions 278 References 280 Chapter 11: Anxiolytic Terpenoids and Aromatherapy for Anxiety and Depression 286 1 Introduction 286 2 Anxiolytic Effects 288 3 Anxiety and Depression 289 4 Monoterpenols 292 5 Conclusions 294 References 295 Chapter 12: The Role of Nutrition in Attenuating Age-Related Skeletal Muscle Atrophy 300 1 Introduction 300 2 The Role of Nutrition 302 2.1 Amino Acid Supplementation 302 2.2 Protein 303 2.3 Beta-Hydroxy-Beta-Metylbutyrate (HMB) 304 2.4 Creatine 304 2.5 Long-Chain Polyunsaturated Fatty Acids (LCPUFAs) 305 2.6 Antioxidant Supplementation 306 2.7 Vitamin D 308 2.8 Ursolic Acid 309 3 Caloric Restriction (CR) 310 4 Dietary Patterns 311 5 Exercise Training 312 6 Malnutrition-Sarcopenia Syndrome 313 7 Conclusions 314 References 314 Chapter 13: The Use of Metformin to Increase the Human Healthspan 322 1 Introduction 322 2 Metabolic Effects of Metformin 323 3 Cardiovascular Disease 324 4 Inflammation 325 5 Cancer 325 6 Frailty 327 7 Modulation of the Microbiome 328 8 Safety Considerations 328 9 Metformin, Survival and Longevity 329 10 Conclusions and Future Perspectives 329 References 330 Index 336