Neuroendocrine Immune Network in Ageing (eBook)

Cover 3
List of Contributors 5
Contents 11
I. Introduction 15
Evolutionary Aspects for the Neuroendocrine Immune Network in Ageing 17
Abstract 17
Adeing of One Supersystem Affects Ageing of Another Supersystem 17
Advantageous Mechanisms for Ageing and Longevity are not Evolutionarily Conserved 18
Review for this Book 19
References 19
II. Ageing of the Immune System 21
lmmunosenescence 23
Abstract 23
Introduction 23
The Effect of Ageing on Thymopoiesis 24
Senescence of Naive T Cells 25
Signal Transduction in Aged T Lymphocytes 26
Age-Associated Alterations of Alpha/Beta T Lymphocytes 26
Age-Associated Alterations in the T Cell Repertoire 28
"Replicative Senescence" of in Vivo Expanded T Cells 28
Age-Associated Alterations of Gamma/Delta T Lymphocytes and NKT Cells 29
Funtional Changes Resulting from the above Age-Associated Alternators and the Effect of Pyschological Factors 29
Conclusion: How Important is Imminosenescence Clinically? 30
Acknowledgements 30
References 31
Zinc-Binding Proteins (Metallothionein and Alpha-2 Macroglobulin) as Potential Biological Markers of Immunosenescence 37
Abstract 37
Introduction 37
The Biology of Zinc 38
The Biology of Zinc-Binding Proteins 40
Metallothioneins 40
Alpha-2 Macroglobulin 41
Zinc, Immune System and Ageing 42
Metallothionein, The Immune System and Ageing 44
Alpha-2 Macroglobulin, the Immune System and Ageing 45
Zinc Supplementation 47
Conclusions and Predictions for the Future 48
Acknowledgments 49
References 49
Neutrophil Ageing and Immunosenescence 55
Abstract 55
The Ageing Process 55
Ageing and Infectious Disease 56
Neutrophils and Neutrophil Ageing 57
Ageing and Neutrophil Function 59
Neutrophil Production 59
Neutrophil Extravasation and Chemotaxis 60
Neutrophil Phagocytosis of Pathogens 60
Neutrophil Intracellular Bactericidal Processes 61
Neutrophil Priming 61
Mechanisms Underlying Reduced Neutrophil Phagocytosis 62
Ageing and Adrenal Steriod Production 63
DHEA Supplementation and Immune Function 64
Trauma Responses in the Elderly 65
Concluding Remarks 66
Acknowledgements 66
References 66
Apoptosis and Ageing 71
Abstract 71
Introduction 71
T Cell Apoptosis and Ageing 72
Death Receptor Pathway 73
TNF-Alpha, Apoptosis and Ageing 73
Signalling through TNF-RI 73
Signalling through TNF-RII 74
The Fas/FasL Receptors and Ageing 75
Receptors and Lipid Rafts 76
The Mitochondrial Pathway 77
Role of Free Radicals in Inducing Apoptosis 77
Apoptosis Polymorphonuclear Neutrophils (PMN) and Ageing 78
Apoptosis of PMNs 78
GM-CSF and PMN Apoptosis 79
Free Radical Production of PMNs 80
Conclusions and Future Perspectives 80
Acknowledgements 81
References 81
MHC-Unrestricted Cytotoxicity in Ageing 87
Abstract 87
Premises 87
Macrophages 88
Polymorphonuclear Leukocytes 89
Natural Killer Cells 90
GammaSigma T Cells 93
MHC-Unrestricted Immunity: Impact on the Senescence of Adaptive Immune Responses 94
References 95
Major Histocompatibility Complex Polymorphisms and Ageing 105
Abstract 105
Introduction: The Major Histocompatibility Complex 105
HLA IA & II Class Alleles in Ageing
HLA IB Alleles in Ageing 109
HLA III Class Alleles in Ageing 110
Concluding Remarks 112
Acknowledgements 112
References 112
III. Ageing of the Endocrine System 117
Neuroplasticity in the Human Hypothalamus During Ageing 119
Abstract 119
Introduction 120
Preoptic or Chiasmatic Region 120
Suprachiasmatic Nucleus 120
Sexually Dimorphic Nucleus (Intermediate Nucleus, INAH-1) 123
Supraoptic and Paraventricular Nuclei 124
Nucleus Basalis of Meynert 125
Tuberal Region 127
Ventromedial and Dorsomedial Nuclei 127
Arcuate (Infundibular) Nucleus 128
Lateral Tuberal Nucleus 129
Concluding Remarks 129
Acknowledgements 130
References 130
The Role of Growth Hormone Signaling in the Control of Ageing 137
Abstract 137
Introduction 137
Studies of Longevity Genes Link IGF Signaling to the Control of Ageing 138
Search for Mechanisms that Link Reduced GH and IGF-1 Signaling with Delayed Ageing 139
Activity of the Somatotropic Axis, Growth and Adult Body Size 140
Reduced Insulin Levels and Increased Sensitivity to Insulin 141
Body Temperature, Metabolic Rate, and Oxidative Stress 141
Conflicting Findings 142
GH Levels Decline with Age 143
Potential Use of GH in Anti-Ageing Medicine 143
Possible Protective Role of Age-Related Decline in Somatotropic Activity 144
Relationship of GH Actions during Different Stages of Life History to the Regulation of Ageing and Longevity Evolutionary Considerations
Implications for Possible Anti-Ageing Strategies 146
Acknowledgements 146
References 146
Ageing and the Adrenal Cortex 153
Abstract 153
Introduction 153
Andrenal Androgen Secretion and Ageing 154
Regulation of Androgen Production 155
Extra-Adrenal Regulation of Adrenal Androgens 155
Intra-Adrenal Regulation of Adrenal Androgens 156
Adrenarche/Andropause 157
Regulation of Adrenopause 157
Functional Significance 159
Conclusion 160
References 160
Hormonal Changes in Ageing Men 167
Abstract 167
Introduction 167
Gender Related Differences of the Endocrine System during Ageing 168
Hypogonadism in Elderly Men 168
Longitudinal Endocrine Changes in Ageing Men 170
Decline in Pulsatile Hormone Secretion with Age 170
Impact of Health Status on Serum Androgen Levels 171
Androgen Supplementation in Ageing Males 172
General Considerations 172
Indications for Androgen Supplementation 172
Depression and Androgen Supplementation 173
Body Composition and Androgen Supplementation 173
Bone Metabolism and Androgen Supplementation 173
Side Effects of Androgen Supplementation 173
Senieur Protocol - An Optimised Study Population to Investigate Male Ageing 174
Conclusions 174
References 175
Ageing and the Endocrine Circadian System 179
Abstract 179
Introduction 179
Adrenal Hormones Circadian Rhythm 180
Melatonin Circadian Rhythm 182
Hypothalamic-Pituitary-Thyroid (HPT) Axis 184
Clinical Considerations 184
Thyrotropin Releasing Hormone (TRH) 185
Thyroid Stimulating Hormone (TSH) 185
Thyroid Hormone 186
Seasonal Variations and/or Circannual Rhythms of the HPT Axis 187
Prolactin (PRL) 188
Hyperprolactinemia 189
Prolactin and the Immune System 189
Catecholamines 190
Central and Tissue Catecholamines 190
Conclusion 193
References 194
Melatonin Rhythms, Melatonin Supplementation and Sleep in Old Age 209
Abstract 209
Introduction 209
The Circadian Timing System 210
Structure of the Suprachiasmatic Nucleus 210
Input to the Suprachiasmatic Nucleus 210
Output of the Suprachiasmatic Nucleus Innervating the Pineal Gland 210
The Pineal Gland and its Main Hormone Melatonin 212
Melatonin Function and Sites of Action 213
Age-Related Changes in the Circadian Timing System 213
Age-Related Changes in the Suprachiasmatic Nucleus 213
Age-Related Changes in Melatonin Levels, Amplitude and Rhythmicity 214
Functional Implications of Weak or Distributed Circadian Rhythms 215
Interactions with Drugs Frequently Used by Elderly 215
Melatonin Supplementation and Consequences for the Circadian Timing System 216
Pharmacokinetics 216
Clinical Studies on the Effects of Exogenous Melatonin on Sleep in the Elderly 217
Adverse Effects and Dosage 220
Conclusive Remarks 220
Acknowledgements 221
References 221
IV. Ageing of the Nervous System 227
Age-Related Changes of the Human Autonomic Nervous System 229
Abstract 229
Influence of Age on Autonomic Nervous System (ANS) Function: Methodological Aspects and Limitations 229
Influence of Age on the Heart and the Blood Vesels 230
Effects of Ageing on Resting Heart Rate 231
Effects of Ageing on Cardiovagal Heart Rate Tests 232
Short-Term Resting Heart Rate Variability (HRV) 232
HRV During Deep Respiration 236
Heart Rate Response to Standing 237
Valsalva-Test 239
Effects of Ageing on Baroreflexes and Blood Pressure 240
References 241
Age-Related Alterations in Autonomic Nervous Innervation 247
Abstract 247
Introduction 247
Bone Marrow 248
Age-Related Changes in Bone Marrow 248
Sympathetic Innervation of Bone Marrow 248
Age-Related Changes in Sympathetic Innervation of Bone Marrow 248
Functional Significance of NA Innervation of Bone Marrow 248
Thymus 249
Structure and Function of the Thymus 249
Age-Related Changes in the Thymus 250
Sympathetic Innervation of the Thymus 250
Sympathetic Innervation in the Ageing Thymus 251
Functional Studies and Significance 251
Spleen 253
Structure and Function of the Spleen 253
Sympathetic Innervation of the Spleen 254
Sympathetic Innervation in the Ageing Spleen 254
Can Age-Related Changes in NA Innervation be Reversed? 256
Age-Related Changes in the Spleen and Immune Function 257
Functional Studies and Significance 257
Summary and Closing Remarks 260
References 261
Ageing and the Neumendocrine System of the Gut 271
Abstract 271
Introduction 271
The Neuroendocrine System of the Gut 272
Age-Related Changes in the Gut Neuroendocrine System 274
Endocrine Cells 274
The Enteric Nervous System 276
Age-Related Changes and Gastrointestinal Disorders in the Elderly 278
Clinical Implications 280
Conclusion 281
Acknowledgement 282
References 282
Modulating Effects of Nutrition on Brain Ageing 287
Abstract 287
Introduction 288
Nutritional Interventions and Methods 288
Dietary Restriction 288
Animals and Diet 288
Quantitative Analysis of Synoptic Dynamic Morphology 288
Vitamin E Deficiency 289
Animals and Diet 289
Quantitative Analysis of Synaptic Dynamic Morphology 290
Quantitative Cytochemistry of Succinic Dehydrogenase (SDH) Activity in Purkinje Cell Mitochondria 290
Intracellular Ionic Content 291
Chronic Ethanol Administration 291
Animals and Diet 291
Quantitative Analysis of Synaptic Dynamic Morphology 291
lntracellular Ionic Content 292
Results 293
Dietary Restriction 293
Vitamin E Deficiency 294
Chronic Ethanol Administration 295
Discussion 296
Dietary Restriction 296
Synaptic Dynamic Morphology 296
Vitamin E Deficiency 298
Synaptic Dynamic Morphology 298
SDH Activity in Purkinje Cell Mitochondria 298
Intracellular Ionic Content 299
Chronic Ethanol Administration 299
Synaptic Dynamic Morphology 299
Intracellular Ionic Content 300
Conclusions 300
References 301
Ageing-Related Role of Nitric Oxide in the Brain 305
Abstract 305
Introduction 305
Nitric Oxide 306
No Synthase 306
Homeostasis of No System 307
Role of NO in the Brain 307
Ageing-Related Changes in the No Production 309
Endothelial NOS in the Brain during Ageing 310
Neuronal NO Synthase in the Brain during Ageing 310
Inducible NO Synthase in the Brain during Ageing 311
Concluding Remark 312
References 312
V. Links between One Global System and another Global System during the Ageing Process 315
Introduction: Links Between One Global System and Another Global System During the Ageing Process 317
Abstract 317
Ageing of One Part of Global System Involves another part of another Global System 317
DHEA and IL-6 317
Zinc, Hormones and Thymic Function 318
Glucocorticoids and Brain Function 318
Hormone Loss and Osteoporosis 318
Conclusions 318
References 319
Plasticity of Neuroendocrine-thymus Interactions During Ontogeny and Ageing: Role of Zinc 321
Abstract 321
Introduction 321
Neuroedocrine-Thymus Interactions: The Strategic Circuit in Ontogeny 325
Intrathymic T-cell Differentiation and Maturation 325
Paracrine Cycle of Cytokines on Thymic Microenviromental Cells 326
Cytokines as Immunotransmitters towards the HP Axis 327
Neuroendocrine Influence on Thymic Functions and Vice Versa 329
Neuroendocrine Influence on Thymic Functions 329
Thymic Influence on the Neuroendocine Sytem 330
The Role of Zinc 330
Neuroendocrine-Thymus Interactions during Ageing 332
Thymic Rejuvenation by Nutritional Approach: The Example of Zinc 333
Thymic Rejuvenation by Neuroendocrine Approacb 334
The Example of Growth Hormone 334
The Example of Melatonin 335
Is there a Unique Meditor for Hormone-Induced Thymic Rejuvenation? 336
Acknowledgments 337
References 337
Adverse Glucocorticoid Actions and their Relevance to Brain Ageing 345
Abstract 345
Introduction 345
GCS and Ageing 346
An Overview of the Adverse CNS Actions of Glucocorticoids 346
Necrotic Neurological Insults and "Endangerment" by Stress and/or Glucocorticoids 348
Mechanisms Mediating the GC Endangerment 349
Disruption of Neuronal Energetics [48] 349
Endangering GC Actions that are Independent of Energetic Effects 349
Disruption of Cellular Defenses 349
Triggering/worsening Apoptosis 350
Glucocorticoid Endangerment and a Seeming Paradox 350
CGS and the Immune System 350
GCs and Immunosenescence 351
GC Effects on CNS vs. Peripheral Inflammation 352
Stress and Ageing 353
Acknowledgements 353
References 353
Neuroendocrine Immune Aspects of Osteoporosis During the Ageing Process 361
Abstract 361
Introduction 361
The Bone Remodeling Process 362
Bone Formation/Resorption Coupling 362
Regulation of Osteoblast Differentiation and Activity 362
Regulation of Osteoclast Differentiation and Activity 362
Ageing of Bone: Alterations in Bone Cell Precursor Pool Sizes and Differentiation 363
Neuro/Endocrine/Immune Circuits in Control of Bone Turnover 364
Peripheral Effects of Neuropeptides on Bone Turnover 364
Calcitonin, CGRP, and VIP 364
NPY and Alpha-Melanocyte Stimulating Hormone (Alpha-MSH) 365
Central Nervous Control of Bone Turnover 365
Leptin, NPY and Ageing 366
Neuroendocrine Regulation of Cytokine Expression: Relevance for Bone Turnover 366
The Hypothalamic/Pituitary/Endocrine Gland Axis in Control of Bone Remodeling: Influence of Ageing 367
References 368
VI. The Ageing Process and Chronic Inflammatory diseases 375
Neuroendocrine Immune Mechanisms of Accelerated Ageing in Patients with Chronic Inflammatory Diseases 377
Abstract 377
Systemic Inflammation in Chronic Inflammatory Diseases 377
Changes of the Endocrine System 378
ACTH, Cortisol, and Adrenal Androgens 378
Gonadal Hormones 378
Changes of the Metabolic System 379
Homocysteine and Zinc 379
Lipids and Lipoproteins 379
Advanced Glycosylation Products 379
Changes of the Nervous System 380
Neuronal Innervation 380
Autonomic Nervous Reflexes 380
Brain Functions 380
The Sequence of Events of Accelerated Ageing 382
Are there Therapeutic Consequences? 382
References 382
Thyroid Autoimmunity and Ageing 389
Abstract 389
Introduction 389
The Relevance of Thyroid and Thyroid Autoimmune Disease in the Ageing Process 390
Thyroid Autoimmunity and Ageing: Animal Models 390
Thyroid Autoimmunity and Ageing: the Lesson of Centenarians 391
Relevance of Thyroid Abnormalities in the Ageing Process and in Ageing-Associated Diseases 391
Abnormalities of Thyroid Function 391
Autoimmunity 393
Conclusions 393
References 394
The Clinical Importance of Proinflammatory Cytokines in Elderly Populations 397
Abstract 397
Introduction 397
The Inflammatory Response 398
Chronic Elevations of Circulating Cytokines in Elderly Populations 398
Cytokines, Morbidity and Mortality in the Oldest Old 399
TNF-Alpha is Associated with Dementia and Atherosclerosis in Centenarians 399
TNF-Alpha is a Prognostic Risk Marker in Centenarians 401
TNF-Alpha is a Possible Candidate to be a Marker of the Frailty Syndrome 401
The Clinical Significance of other Inflammatory Medicators in Centenarians 401
The Clinical Significance of Cytokines and the Role of IL-6 in Younger Elderly 402
Triggering Signals of Low-Grade Inflammation in Elderly Populations 403
Is Ageing Associated with a Dysregulated Cytokine Response? 404
Concluding Remarks 405
Acknowledgements 406
References 406
VII. Conclusions 411
Possible New Anti-Ageing Strategies Related to Neuroendocrine- Immune Interactions 413
Abstract 413
Introduction 413
L-Deprenyl 414
Ghrelin and Leptin 415
Carnosine 416
No-Donors 416
Conclusions 417
References 418
Concluding Remarks and Future Directions 423
Abstract 423
Introduction 423
Ageing of the Immune System 424
Immunosenescence 424
Metallothioneins as Potential Biological Markers of Immunosenescence 424
Neutrophil Ageing and Immunosenescence 425
Apoptosis and Ageing 425
MHC-Unrestricted Cytotoxity in Ageing 425
MHC Polymorphism and Ageing 426
Ageing of the Endorine System 426
Neuroplasticity in the Human Hypothalamus during Ageing 426
The Role of Growth Hormone Signaling in the Control of Ageing 426
Ageing and the Adrenal Cortex 427
Hormonal Changes in Ageing Men 427
Ageing of the Neuroendocrine Circadian System 428
Melatonin Rhythms, Melatonin Supplementation and Sleep in Old Age 428
Ageing of the Nervous System 429
Age-Related Changes of the Human Autonomic Nervous System 429
Age-Related Alterations in Autonomic Nervous Innervation 429
Ageing and the Neuroendocrine System of the Gut 429
Nutrition and Brain Ageing 430
Ageing-Related Role of Nitric Oxide in the Brain 430
Links between One Global System and Another Global System during the Ageing Process 431
Plasticity of Neuro-Endocrine-Thymus Interactions during the Ontogeny of Ageing: the Role of Zinc 431
Adverse Glucocorticoid Actions and their Relevance to Brain Ageing 431
Neuroendocrine Immune Aspects of Osteoporosis during the Ageing Process 432
The Ageing Process and Chronic Inflammatory Disease 432
Neuroendocrine Immune Mechanisms of Accelerated Ageing in Patients with Chronic Inflammatory Diseases 432
Thyroid Autoimmunity and Ageing 432
The Clinical Importance of Proinflammatory Cytokines in Elderly Populations 433
Conclusions 433
New Anti Ageing Strategies Related to Neuroendocrine Immune Interactions 433
The Future 434
References 434
Index 443