Hormesis (eBook)

Mark P. Mattson, Ph.D. is Chief of the Laboratory of Neurosciences at the National Institute on Aging in Baltimore, where he leads a multi-faceted research team that applies cutting-edge technologies in research aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. He is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine. He has published more than 450 original research articles and numerous review articles, and has edited 10 books in the areas of mechanisms of aging and neurodegenerative disorders. Dr. Mattson has trained more than 60 postdoctoral and predoctoral students who have contributed to his being the most highly cited neuroscientist in the world. Edward J. Calabrese, Ph.D. is a Professor and Program Director ofEnvironmental Health Science, at the University of Massachusetts in Amherst. His research focuses on environmental toxicology with an emphasis on biological factors including genetic and nutritional factors that enhance susceptibility to pollutant toxicity and the environmental implications of toxicological hormesis. Dr. Calabrese has researched extensively in the area of host factors affecting susceptibility to pollutants, and is the author of more than 300 papers in scholarly journals, as well as 24 books in the field of toxicology and environmental pollution. Dr. Calabrese has received numerous awards including, most recently, the prestigious Marie Curie Prize.

Hormesis 1
Preface 4
Contents 7
About the Editors 8
Contributors 9
Hormesis: What It Is and Why It Matters 11
Hormesis Is a Fundamental Feature of Biological Systems 12
Hormesis Is a Manifestation of a Fundamental Feature of Evolution 14
Cellular and Molecular Mediators of Hormetic Responses 16
Hormesis in Medicine: Dose and Frequency of Treatment Are Both Important 17
Are Beneficial Chemicals in Fruits and Vegetables Toxins Acting at Low Doses? 19
Hormesis Is Not Homeopathy 20
Implications of Hormesis for the Practices of Environmental Protection and Medicine 20
References 21
Hormesis: Once Marginalized, Evidence Now Supports Hormesis as the Most Fundamental Dose Response 24
Introduction 25
Historical Antipathies, Rather Than Science, Determined Which DoseResponse Model Would Dominate Biology 26
The Hormetic Dose-Response Relationship 29
The Hormesis Database 31
The Frequency of Hormesis in Toxicology and Pharmacology 39
Implications of Hormesis 40
Impact on Biological Concepts 41
Hormesis Measures Performance 41
Hormesis Provides Quantitative Estimates of Biological Plasticity 41
Adaptive Response/Preconditioning: Manifestations of Hormesis 42
Hormesis as an Expression of Allometry 42
Toxicological/Pharmacological Implications 43
Factors Affecting the Recognition of Hormetic Dose-Response Relationships 43
Use of Multiple Terms 43
Modest Stimulation and Historically Weak Study Designs 43
Control Group: High Variation 43
Low Background Disease Incidence 44
Lack of Temporal Component 44
Summary 44
Chemical Potency and Hormesis 44
Hormesis: A Novel Concept of Synergy/Potentiation 45
Interindividual Variation and Hormesis 46
Epidemiology and Hormesis 47
Hormesis and Medicine 47
Low-Dose Stimulation of Tumor Cells 47
Low-Dose Stimulation of Microbes by Antibiotics 48
Anxiolytic Drugs 48
Antiseizure Drugs 49
Memory-Enhancing Drugs 49
Stroke Medications 50
Osteoporosis 50
Hair Growth 51
Pulmonary Hypertension 51
Fibrotic Diseases (e.g., Dupuytren's Contracture) 51
Avoidance of Undesirable Side Effects 51
Environmental Risk Assessment 52
Discussion 59
References 60
The Fundamental Role of Hormesis in Evolution 66
Introduction 66
The Biphasic Dose Response and Evolution 68
Cellular and Molecular Hormetic Mechanisms 71
Hormesis and Evolutionary Strategies: Diversification and Specialization 72
Conclusions and Future Directions 75
References 75
Transcriptional Mediators of Cellular Hormesis 78
Introduction 78
Nature of Transcriptional Regulation 79
Hormetic Signaling Pathways 80
Nuclear Factor--Erythroid 2p45 (NF-E2)--Related Factor (Nrf2)/Antioxidant Response Element (ARE) Signaling Pathway 81
Nrf2, Keap1, and Regulation of the ARE Pathway 81
Hormetic Inducers of the Nrf2/ARE Pathway 83
Forkhead Box O (FOXO) Transcription Factors 85
FOXO, Oxidative Stress, and Longevity 88
The Nuclear Factor-B Pathway 89
NF-B as a Hormetic Transducer of Exercise 90
Heat-Shock Factor Pathway 91
Conclusions 95
References 96
The Devil Is in the Dose: Complexity of Receptor Systemsand Responses 103
Introduction 103
Classic and Modern Dynamic GPCR Models 104
Receptor System Complexities and Responses 106
Multiple G Protein Coupling 106
Allosteric Receptor Modulation 107
Receptor Desensitization 109
Receptor Dimerization 110
GPCRs and Receptorsome Structures 111
Conclusions 112
References 113
Exercise-Induced Hormesis 117
Introduction 117
Effects of Exercise on the Musculoskeletal System 118
Dose-Response Characteristics of Exercise Effects on Muscle 118
Duration-Dependent Effects of Exercise on Bone 119
Effects of Exercise on the Digestive System 119
Dose-Dependent Effects of Exercise on the Stomach 119
Hormetic Effects of Exercise in the Large and Small Intestine 119
Dose-Response Characteristics of Exercise Effects on the Liver 119
Duration-Dependent Effects of Exercise on the Pancreas 120
Effects of Exercise on the Reproductive System 120
Dose-Response Characteristics of Exercise Effects on Ovarian Function 120
Duration-Dependent Effects of Exercise on the Testis 121
Effects of Exercise on the Cardiorespiratory System 121
Duration-Dependent Effects of Exercise on the Heart 121
Dose-Dependent Effects of Exercise on the Lungs 122
Effects of Exercise on the Immune System 122
Dose-Response Characteristics of Exercise Effects on the Thymus 122
Hormetic Effects of Exercise on the Spleen 122
Exercise Effects on Circulating Cytokines Conform to the Theory of Hormesis 123
Effects of Exercise on the Brain 123
Duration-Dependent Effects of Exercise on Adult Neurogenesis 123
Dose-Response Characteristics of Exercise Effects on Dendritic Spines 124
Duration-Dependent Effects on Angiogenesis 125
Duration-Dependent Effects of Running on Neurotrophic Factor Expression 125
Conclusion 126
References 127
Dietary Energy Intake, Hormesis, and Health 131
Introduction 131
CR as a Hormetic Effector 132
CR and Cellular Stress Factors 133
CR Effects Upon Cytokine Levels 134
CR and Alterations in Neurotrophic Factors 135
CR Effects Upon Glycemic Control 135
CR and Satiety/Adipose-Generated Hormones 136
CR and Ketone Body Synthesis 137
CR and Sirtuin Activity 137
CR Modulation of PPARs and Cofactors 138
CR and Transcriptional Regulation 139
Conclusions 140
References 141
Couch Potato: The Antithesis of Hormesis 146
The Couch Potato Caricature 147
Advances in Technology Reveal the Dangers of a Sedentary Lifestyle 148
Cellular and Molecular Mechanisms of Exercise Hormesis 148
Calories In, Disease Out 151
In One Ear and Out the Other 152
Implications of Hormesis for the Future of the Couch Potato 154
References 154
Hormesis and Aging 159
Introduction 159
Recapitulating the Biological Basis of Aging 160
Thermal Hormesis in Aging 163
Thermal Hormesis in Organisms 163
Thermal Hormesis in Human Cells Undergoing Aging in Vitro 164
Hypergravity Hormesis in Aging 167
Radiation Hormesis in Aging 167
Radiation Hormesis in Insects 167
Radiation Hormesis in Rodents and Other Animals 168
Radiation Hormesis in Humans 168
Calorie Restriction and Hormesis 169
Exercise Hormesis 170
Nutritional Hormesis and Hormetins 171
Other Stresses 172
Hormesis Potential, Challenges, and Unresolved Issues in Aging 173
References 175
The Hormetic Pharmacy: The Future of Natural Productsand Man-Made Drugs in Disease Prevention and Treatment 182
Introducing the Pharmacist to Hormesis 182
Why the Pharmaceutical Industry Is Missing the Hormesis Revolution 183
Hormesis and Biological Plasticity 184
Dietary Factors 184
Drugs 186
Implications of the Quantitative Features of the Hormetic Dose Response for the Pharmaceutical and Nutraceutical Worlds 187
Biological Model Selection 187
Drug-Testing Strategies 188
Drug Potency 189
Drug--Drug Interactions 189
Clinical Trials and Hormesis 190
Potentially Harmful Hormetic Responses 190
Hormesis in the Pharmaceutical Industry 193
Anxiolytic Drugs 193
Antiseizure Drugs 194
Male Sexual Dysfunction 194
Diabetes 195
Memory/Cognition 195
Osteoporosis 196
Hormesis and Neutraceuticals 196
Hormetic Mimetics 198
Discussion 199
References 200
Index 204