Dr Delminda Neves is Associate Professor and Senior Researcher at the Department of Experimental Biology, Faculty of Medicine, University of Porto, Portugal

List of contributors xiii

Preface xv

Acknowledgment xvii

Part I – Ageing of cells and organisms

1 Human ageing a biological view 3
Henrique Almeida and Liliana Matos

1.1 Introduction 3

1.2 Human ageing and frailty 4

1.2.1 Mortality curves 4

1.2.2 Susceptibility to disease and mortality 5

1.2.3 Age-related and age-dependent diseases 6

1.3 Fundamental causes 7

1.4 Experimental approach to human ageing 8

1.4.1 Ageing models in dividing cells: Replicative senescence and telomere involvement 8

1.4.2 Stress-induced premature senescence 10

1.4.3 Ageing in organs and tissues 11

1.4.4 Lipofuscin deposition following organelle dysfunction and damage accumulation 12

1.4.5 Damage consequences: Dysfunctional organelles and cell functional decline. Cell loss 13

1.5 Involving genes in organism ageing and longevity 14

1.5.1 Longevous humans 14

1.5.2 Experimental approaches 15

1.5.2.1 The insulin/IGF-1 axis 17

1.5.2.2 IGF-1 signaling into FOXO proteins 18

1.5.2.3 Other pathways 20

1.6 Conclusions and prospects 21

Acknowledgment 23

References 23

2 To eat or not to eat – Anti-ageing effects of energy restriction 33
Delminda Neves Maria João Martins Emanuel dos Passos and Inês Tomada

Part 1 33

2.1 Energy restriction as more than a weight-loss strategy 33

2.2 Restriction of energy vs restriction of nutrients 34

2.2.1 Experimental models of energy restriction 35

2.2.2 Observational studies and the first human trial of energy restriction: CALERIE study 40

2.3 Effects of energy restriction on organisms 42

2.3.1 Increased longevity and health of energy-restricted organisms 43

2.3.2 Body composition temperature and resting metabolic rate 46

2.3.3 Metabolism and insulin sensitivity 48

2.3.4 Immune system and inflammatory modulation 49

2.3.5 Neuroendocrine axes and adipokines 50

2.3.6 Growth factors and cytoprotective effects 57

2.4 Cellular and molecular effects of energy restriction 57

2.4.1 Modulation of gene expression 58

2.4.2 Molecular mechanisms of sirtuins 60

2.4.2.1 Sirtuin 1 60

2.4.2.2 Sirtuin 6 63

2.4.2.3 Sirtuin 7 63

2.4.2.4 Sirtuin 3 63

2.4.2.5 Sirtuins 4 and 5 64

2.4.2.6 Sirtuin 2 64

2.4.3 AMPK 65

2.4.4 Oxidative stress and metabolic reprogramming 65

2.4.5 Autophagy and mTOR signaling 67

2.5 Energy restriction mimetics 71

2.5.1 Sirtuin activity stimulators 72

2.5.2 Antidiabetic drugs 73

2.5.3 Rapamycine 74

2.5.4 Polyamines 74

2.5.5 Antilipolytic drugs 75

Part 2 76

2.6 Obesity and ageing 76

2.6.1 Obesity as a premature death inducer 76

2.6.2 Adipose tissue and metabolic dysregulation 79

2.6.2.1 Adipose tissue and disruption of endocrine secretion of adipokines 80

2.6.3 Mitochondrial dysfunction 80

2.6.4 Endoplasmic reticulum stress 81

2.6.4.1 Endoplasmic reticulum stress-induced unfolded protein response 82

2.6.4.2 Ageing-induced modification in unfolded protein response 83

2.6.4.3 Obesity-induced endoplasmic reticulum stress 85

2.6.5 Anti-obesity effects of natural compounds extracted from plants 88

2.6.5.1 Polyphenols 88

2.6.6 Anti-obesity effects of minerals (magnesium) 96

2.7 Conclusion 98

Acknowledgment 98

References 98

3 Nutrition epigenetics and ageing 133
Jill Ann McKay and Luisa Anne Wakeling

3.1 Introduction 133

3.2 Epigenetics 133

3.2.1 DNA methylation 134

3.2.2 Histone modifications 135

3.2.3 Noncoding RNAs 135

3.2.4 The function of epigenetic mechanisms 136

3.3 Epigenetics and ageing 137

3.3.1 DNA methylation profiles and ageing 137

3.3.2 Histone modifications and ageing 137

3.3.3 MicroRNAs and ageing 138

3.4 Influence of nutrition on epigenetic modifications 138

3.4.1 Nutritional modulation of epigenetic enzyme activity 139

3.4.2 Influence of nutrition on substrate availability for epigenetic modifications 141

3.4.3 Critical windows and the developmental origins hypothesis 142

3.5 Nutrition epigenetics and ageing 144

3.5.1 Overview 144

3.5.2 Specific dietary regimens and nutrients that influence epigenetics and ageing 145

3.5.2.1 Dietary restriction 145

3.5.2.2 Dietary polyphenols 145

3.5.2.3 One-Carbon metabolism 146

3.6 Conclusions and future perspective 147

References 147

Part II – Nutritional modulation of age-related organ functional decline

4 Nutritional interventions in age-related genetic and epigenetic instability and cancer 157
Thomas Prates Ong and Ana Paula de Melo Loureiro

4.1 Cancer as an age-associated disease 157

4.2 Genetic and epigenetic alterations as molecular mechanisms underlying carcinogenesis 159

4.3 Diet nutrition and cancer 165

4.4 Targeting age-related genomic and epigenomic alterations with nutritional interventions for cancer prevention 167

4.4.1 Folate 168

4.4.2 Energy restriction 170

4.4.3 Bioactive food components 172

4.5 Conclusions and perspectives 173

Acknowledgment 174

References 174

5 Nutraceuticals in immunosenescence 183
Thea Magrone and Emilio Jirillo

5.1 Introduction 183

5.2 The immune response in ageing 184

5.2.1 Phagocytes 184

5.2.2 Natural killer cells 184

5.2.3 T cells 185

5.2.4 B cells 185

5.3 Micronutrients that modulate immunosenescence 186

5.3.1 Zinc 186

5.3.2 Copper 187

5.3.3 Iron 188

5.3.4 Selenium 188

5.4 Probiotics and prebiotics 189

5.4.1 Probiotics 189

5.4.2 Prebiotics 190

5.5 Dietary lipids 191

5.6 Polyphenols 192

5.7 Conclusion and future directions 195

Acknowledgments 195

References 195

6 Cardiovascular ageing 203
Carmen Brás Silva and Delminda Neves

6.1 Age-related cardiac changes 203

6.1.1 Heart changes 203

6.1.1.1 Structural changes 203

6.1.1.2 Functional changes 204

6.1.1.3 Changes in cardioprotective and repair processes 207

6.2 Age-related vascular changes 207

6.2.1 Central arterial changes 207

6.2.1.1 Arterial structural changes 208

6.2.2 Peripheral arterial changes 210

6.2.3 Arterial functional changes 210

6.2.3.1 Blood pressure 210

6.3 Changes in the interaction between heart and arterial system 211

6.4 Endothelial dysfunction 211

6.5 Erectile dysfunction as an early signal of cardiovascular disease 213

6.5.1 The erection mechanism 214

6.5.2 Contribution of ageing to erectile dysfunction onset 214

6.5.2.1 Age-related structural and molecular modifications of erectile tissue 215

6.6 Diet nutrition and cardiovascular ageing 218

6.6.1 Obesity energy restriction and cardiovascular ageing 218

6.6.2 Diet patterns and cardiovascular ageing 220

6.6.2.1 Contribution of dietary pattern to erectile dysfunction onset 221

6.7 Nutritional intervention for cardiovascular disease prevention or amelioration 222

6.7.1 Nutritional pattern modulation 223

6.7.2 Intervention of specific nutrients in cardiovascular disease protection 225

6.7.2.1 Polyphenolic compounds 225

6.7.2.2 l-Carnitine and l-arginine 227

6.7.2.3 Fatty acids 228

6.7.2.4 Vitamins 228

6.7.2.5 Minerals 230

6.7.2.6 Caffeine 230

6.8 Conclusions 230

References 231

7 Bone and muscle ageing 247
Joana Carvalho Elisa Marques and Pedro Moreira

7.1 Introduction 247

7.1.1 Determinants of bone loss in ageing 248

7.1.2 Regulation of muscle atrophy in ageing 249

7.2 Osteoporosis and fragility fractures in the elderly 251

7.3 Nutritional mechanisms of age-related bone loss 252

7.4 Calcium and vitamin D and the ageing skeleton: Efficacy in the treatment of osteoporosis 254

7.5 Skeletal muscle age-related contributory mechanisms 256

7.6 The role of nutrition in preventing ageing skeletal muscle atrophy 259

7.6.1 Protein 259

7.6.2 PUFA and inflammation 260

7.6.3 Anti-oxidants and oxidative stress 261

7.6.4 Vitamin D 262

7.6.5 Food and dietary patterns 262

7.7 Resistance exercise and nutrition: effective treatment strategy to counteract age-related muscle wasting and bone loss 263

7.7.1 Protein and resistance exercise 264

7.8 Concluding remarks 266

References 266

8 Nutrition and the ageing eye 277
Ângela Carneiro

8.1 The ageing eye 277

8.1.1 The lens 277

8.1.2 The retina 278

8.2 Nutrients in the structure and physiology of the healthy human eye 279

8.2.1 Vitamins 279

8.2.2 Polyunsaturated fatty acids 280

8.2.3 Zinc 280

8.3 The human eye and the oxidative stress 280

8.4 The anti-oxidant systems in the eye 281

8.5 How can diet interfere with the ocular anti-oxidant system? 282

8.6 Nutritional intervention in age-associated eye diseases 283

8.6.1 Cataract 283

8.6.1.1 The blue mountains eye study 284

8.6.1.2 The beaver dam eye study 284

8.6.1.3 The india age-related eye disease study 284

8.6.1.4 The spanish segment of european eye study (EUREYE) 285

8.6.1.5 The physicians’ health study 285

8.6.1.6 The women’s health study 285

8.6.1.7 The age-related eye disease study (AREDS) 285

8.6.1.8 The age-related eye disease study 2 (AREDS2) 286

8.6.2 Age-related macular degeneration 286

8.6.2.1 AREDS 289

8.6.2.2 AREDS2 290

8.7 Nutrigenomics 291

8.8 Conclusions 291

References 292

9 Beauty from the inside: Nutrition and skin ageing 299
Alessandra Marini and Jean Krutmann

9.1 Introduction 299

9.2 Vitamins 302

9.2.1 Vitamin C (l-ascorbic acid) 302

9.2.2 Vitamin E (tocopherol) 303

9.2.3 Vitamin B6 304

9.2.4 Carotenoids 304

9.2.5 Vitamin D 306

9.3 Polyphenols and flavonoids 306

9.4 Polyunsaturated fatty acids 308

9.5 Pre- and probiotics 308

9.6 Conclusions 310

References 310

10 Retarding brain ageing and cognitive decline 315
José Paulo Andrade

10.1 Ageing and brain 315

10.2 From “healthy ageing” to dementia 316

10.3 Green tea as a functional food and source of nutraceuticals 318

10.3.1 Bioavailability of the catechins of green tea 319

10.3.2 Direct and indirect actions of catechins 320

10.3.3 Action of catechins in brain 321

10.3.4 Catechins and neurodegenerative diseases 321

10.3.5 Other polyphenols 323

10.4 Modulatory effect of diet pattern on age-associated cognitive decline 323

10.5 Multidomain interventions 326

10.6 Conclusions 327

Acknowledgment 327

References 327

Part III – Evidence-based retardation of ageing

11 Science-based anti-ageing nutritional recommendations 335
Inês Tomada and José Paulo Andrade

11.1 Introduction 335

11.2 The relevance of nutraceuticals and functional nutrients in anti-ageing medicine 336

11.3 Nutrition from food vs from supplements 340

11.3.1 Food enrichment and fortification 341

11.3.2 Nutritional supplements 342

11.3.2.1 Nutritional compounds as drugs delivered via food 343

11.3.3 Pills capsules powders and syrups 351

11.3.4 Factors that affect the bioavailability of nutrients 352

11.3.4.1 Food processing and cooking methods 353

11.3.4.2 Competitive interactions between nutrients 355

11.3.4.3 Drug–food and drug–nutrients interactions 357

11.4 Favorable combinations of nutrients in food 360

11.5 Lifestyle strategies for successful ageing 363

11.5.1 The mediterranean and asian diets 368

11.5.2 The french paradox 375

Acknowledgment 378

References 378

Index 391

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