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

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• List of contributors xiiiPreface xvAcknowledgment xviiPart I – Ageing of cells and organisms1 Human ageing a biological view 3Henrique Almeida and Liliana Matos1.1 Introduction 31.2 Human ageing and frailty 41.2.1 Mortality curves 41.2.2 Susceptibility to disease and mortality 51.2.3 Age-related and age-dependent diseases 61.3 Fundamental causes 71.4 Experimental approach to human ageing 81.4.1 Ageing models in dividing cells: Replicative senescence and telomere involvement 81.4.2 Stress-induced premature senescence 101.4.3 Ageing in organs and tissues 111.4.4 Lipofuscin deposition following organelle dysfunction and damage accumulation 121.4.5 Damage consequences: Dysfunctional organelles and cell functional decline. Cell loss 131.5 Involving genes in organism ageing and longevity 141.5.1 Longevous humans 141.5.2 Experimental approaches 151.5.2.1 The insulin/IGF-1 axis 171.5.2.2 IGF-1 signaling into FOXO proteins 181.5.2.3 Other pathways 201.6 Conclusions and prospects 21Acknowledgment 23References 232 To eat or not to eat – Anti-ageing effects of energy restriction 33Delminda Neves Maria João Martins Emanuel dos Passos and Inês TomadaPart 1 332.1 Energy restriction as more than a weight-loss strategy 332.2 Restriction of energy vs restriction of nutrients 342.2.1 Experimental models of energy restriction 352.2.2 Observational studies and the first human trial of energy restriction: CALERIE study 402.3 Effects of energy restriction on organisms 422.3.1 Increased longevity and health of energy-restricted organisms 432.3.2 Body composition temperature and resting metabolic rate 462.3.3 Metabolism and insulin sensitivity 482.3.4 Immune system and inflammatory modulation 492.3.5 Neuroendocrine axes and adipokines 502.3.6 Growth factors and cytoprotective effects 572.4 Cellular and molecular effects of energy restriction 572.4.1 Modulation of gene expression 582.4.2 Molecular mechanisms of sirtuins 602.4.2.1 Sirtuin 1 602.4.2.2 Sirtuin 6 632.4.2.3 Sirtuin 7 632.4.2.4 Sirtuin 3 632.4.2.5 Sirtuins 4 and 5 642.4.2.6 Sirtuin 2 642.4.3 AMPK 652.4.4 Oxidative stress and metabolic reprogramming 652.4.5 Autophagy and mTOR signaling 672.5 Energy restriction mimetics 712.5.1 Sirtuin activity stimulators 722.5.2 Antidiabetic drugs 732.5.3 Rapamycine 742.5.4 Polyamines 742.5.5 Antilipolytic drugs 75Part 2 762.6 Obesity and ageing 762.6.1 Obesity as a premature death inducer 762.6.2 Adipose tissue and metabolic dysregulation 792.6.2.1 Adipose tissue and disruption of endocrine secretion of adipokines 802.6.3 Mitochondrial dysfunction 802.6.4 Endoplasmic reticulum stress 812.6.4.1 Endoplasmic reticulum stress-induced unfolded protein response 822.6.4.2 Ageing-induced modification in unfolded protein response 832.6.4.3 Obesity-induced endoplasmic reticulum stress 852.6.5 Anti-obesity effects of natural compounds extracted from plants 882.6.5.1 Polyphenols 882.6.6 Anti-obesity effects of minerals (magnesium) 962.7 Conclusion 98Acknowledgment 98References 983 Nutrition epigenetics and ageing 133Jill Ann McKay and Luisa Anne Wakeling3.1 Introduction 1333.2 Epigenetics 1333.2.1 DNA methylation 1343.2.2 Histone modifications 1353.2.3 Noncoding RNAs 1353.2.4 The function of epigenetic mechanisms 1363.3 Epigenetics and ageing 1373.3.1 DNA methylation profiles and ageing 1373.3.2 Histone modifications and ageing 1373.3.3 MicroRNAs and ageing 1383.4 Influence of nutrition on epigenetic modifications 1383.4.1 Nutritional modulation of epigenetic enzyme activity 1393.4.2 Influence of nutrition on substrate availability for epigenetic modifications 1413.4.3 Critical windows and the developmental origins hypothesis 1423.5 Nutrition epigenetics and ageing 1443.5.1 Overview 1443.5.2 Specific dietary regimens and nutrients that influence epigenetics and ageing 1453.5.2.1 Dietary restriction 1453.5.2.2 Dietary polyphenols 1453.5.2.3 One-Carbon metabolism 1463.6 Conclusions and future perspective 147References 147Part II – Nutritional modulation of age-related organ functional decline4 Nutritional interventions in age-related genetic and epigenetic instability and cancer 157Thomas Prates Ong and Ana Paula de Melo Loureiro4.1 Cancer as an age-associated disease 1574.2 Genetic and epigenetic alterations as molecular mechanisms underlying carcinogenesis 1594.3 Diet nutrition and cancer 1654.4 Targeting age-related genomic and epigenomic alterations with nutritional interventions for cancer prevention 1674.4.1 Folate 1684.4.2 Energy restriction 1704.4.3 Bioactive food components 1724.5 Conclusions and perspectives 173Acknowledgment 174References 1745 Nutraceuticals in immunosenescence 183Thea Magrone and Emilio Jirillo5.1 Introduction 1835.2 The immune response in ageing 1845.2.1 Phagocytes 1845.2.2 Natural killer cells 1845.2.3 T cells 1855.2.4 B cells 1855.3 Micronutrients that modulate immunosenescence 1865.3.1 Zinc 1865.3.2 Copper 1875.3.3 Iron 1885.3.4 Selenium 1885.4 Probiotics and prebiotics 1895.4.1 Probiotics 1895.4.2 Prebiotics 1905.5 Dietary lipids 1915.6 Polyphenols 1925.7 Conclusion and future directions 195Acknowledgments 195References 1956 Cardiovascular ageing 203Carmen Brás Silva and Delminda Neves6.1 Age-related cardiac changes 2036.1.1 Heart changes 2036.1.1.1 Structural changes 2036.1.1.2 Functional changes 2046.1.1.3 Changes in cardioprotective and repair processes 2076.2 Age-related vascular changes 2076.2.1 Central arterial changes 2076.2.1.1 Arterial structural changes 2086.2.2 Peripheral arterial changes 2106.2.3 Arterial functional changes 2106.2.3.1 Blood pressure 2106.3 Changes in the interaction between heart and arterial system 2116.4 Endothelial dysfunction 2116.5 Erectile dysfunction as an early signal of cardiovascular disease 2136.5.1 The erection mechanism 2146.5.2 Contribution of ageing to erectile dysfunction onset 2146.5.2.1 Age-related structural and molecular modifications of erectile tissue 2156.6 Diet nutrition and cardiovascular ageing 2186.6.1 Obesity energy restriction and cardiovascular ageing 2186.6.2 Diet patterns and cardiovascular ageing 2206.6.2.1 Contribution of dietary pattern to erectile dysfunction onset 2216.7 Nutritional intervention for cardiovascular disease prevention or amelioration 2226.7.1 Nutritional pattern modulation 2236.7.2 Intervention of specific nutrients in cardiovascular disease protection 2256.7.2.1 Polyphenolic compounds 2256.7.2.2 l-Carnitine and l-arginine 2276.7.2.3 Fatty acids 2286.7.2.4 Vitamins 2286.7.2.5 Minerals 2306.7.2.6 Caffeine 2306.8 Conclusions 230References 2317 Bone and muscle ageing 247Joana Carvalho Elisa Marques and Pedro Moreira7.1 Introduction 2477.1.1 Determinants of bone loss in ageing 2487.1.2 Regulation of muscle atrophy in ageing 2497.2 Osteoporosis and fragility fractures in the elderly 2517.3 Nutritional mechanisms of age-related bone loss 2527.4 Calcium and vitamin D and the ageing skeleton: Efficacy in the treatment of osteoporosis 2547.5 Skeletal muscle age-related contributory mechanisms 2567.6 The role of nutrition in preventing ageing skeletal muscle atrophy 2597.6.1 Protein 2597.6.2 PUFA and inflammation 2607.6.3 Anti-oxidants and oxidative stress 2617.6.4 Vitamin D 2627.6.5 Food and dietary patterns 2627.7 Resistance exercise and nutrition: effective treatment strategy to counteract age-related muscle wasting and bone loss 2637.7.1 Protein and resistance exercise 2647.8 Concluding remarks 266References 2668 Nutrition and the ageing eye 277Ângela Carneiro8.1 The ageing eye 2778.1.1 The lens 2778.1.2 The retina 2788.2 Nutrients in the structure and physiology of the healthy human eye 2798.2.1 Vitamins 2798.2.2 Polyunsaturated fatty acids 2808.2.3 Zinc 2808.3 The human eye and the oxidative stress 2808.4 The anti-oxidant systems in the eye 2818.5 How can diet interfere with the ocular anti-oxidant system? 2828.6 Nutritional intervention in age-associated eye diseases 2838.6.1 Cataract 2838.6.1.1 The blue mountains eye study 2848.6.1.2 The beaver dam eye study 2848.6.1.3 The india age-related eye disease study 2848.6.1.4 The spanish segment of european eye study (EUREYE) 2858.6.1.5 The physicians’ health study 2858.6.1.6 The women’s health study 2858.6.1.7 The age-related eye disease study (AREDS) 2858.6.1.8 The age-related eye disease study 2 (AREDS2) 2868.6.2 Age-related macular degeneration 2868.6.2.1 AREDS 2898.6.2.2 AREDS2 2908.7 Nutrigenomics 2918.8 Conclusions 291References 2929 Beauty from the inside: Nutrition and skin ageing 299Alessandra Marini and Jean Krutmann9.1 Introduction 2999.2 Vitamins 3029.2.1 Vitamin C (l-ascorbic acid) 3029.2.2 Vitamin E (tocopherol) 3039.2.3 Vitamin B6 3049.2.4 Carotenoids 3049.2.5 Vitamin D 3069.3 Polyphenols and flavonoids 3069.4 Polyunsaturated fatty acids 3089.5 Pre- and probiotics 3089.6 Conclusions 310References 31010 Retarding brain ageing and cognitive decline 315José Paulo Andrade10.1 Ageing and brain 31510.2 From “healthy ageing” to dementia 31610.3 Green tea as a functional food and source of nutraceuticals 31810.3.1 Bioavailability of the catechins of green tea 31910.3.2 Direct and indirect actions of catechins 32010.3.3 Action of catechins in brain 32110.3.4 Catechins and neurodegenerative diseases 32110.3.5 Other polyphenols 32310.4 Modulatory effect of diet pattern on age-associated cognitive decline 32310.5 Multidomain interventions 32610.6 Conclusions 327Acknowledgment 327References 327Part III – Evidence-based retardation of ageing11 Science-based anti-ageing nutritional recommendations 335Inês Tomada and José Paulo Andrade11.1 Introduction 33511.2 The relevance of nutraceuticals and functional nutrients in anti-ageing medicine 33611.3 Nutrition from food vs from supplements 34011.3.1 Food enrichment and fortification 34111.3.2 Nutritional supplements 34211.3.2.1 Nutritional compounds as drugs delivered via food 34311.3.3 Pills capsules powders and syrups 35111.3.4 Factors that affect the bioavailability of nutrients 35211.3.4.1 Food processing and cooking methods 35311.3.4.2 Competitive interactions between nutrients 35511.3.4.3 Drug–food and drug–nutrients interactions 35711.4 Favorable combinations of nutrients in food 36011.5 Lifestyle strategies for successful ageing 36311.5.1 The mediterranean and asian diets 36811.5.2 The french paradox 375Acknowledgment 378References 378Index 391

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

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• List of contributors xiiiPreface xvAcknowledgment xviiPart I – Ageing of cells and organisms1 Human ageing a biological view 3Henrique Almeida and Liliana Matos1.1 Introduction 31.2 Human ageing and frailty 41.2.1 Mortality curves 41.2.2 Susceptibility to disease and mortality 51.2.3 Age-related and age-dependent diseases 61.3 Fundamental causes 71.4 Experimental approach to human ageing 81.4.1 Ageing models in dividing cells: Replicative senescence and telomere involvement 81.4.2 Stress-induced premature senescence 101.4.3 Ageing in organs and tissues 111.4.4 Lipofuscin deposition following organelle dysfunction and damage accumulation 121.4.5 Damage consequences: Dysfunctional organelles and cell functional decline. Cell loss 131.5 Involving genes in organism ageing and longevity 141.5.1 Longevous humans 141.5.2 Experimental approaches 151.5.2.1 The insulin/IGF-1 axis 171.5.2.2 IGF-1 signaling into FOXO proteins 181.5.2.3 Other pathways 201.6 Conclusions and prospects 21Acknowledgment 23References 232 To eat or not to eat – Anti-ageing effects of energy restriction 33Delminda Neves Maria João Martins Emanuel dos Passos and Inês TomadaPart 1 332.1 Energy restriction as more than a weight-loss strategy 332.2 Restriction of energy vs restriction of nutrients 342.2.1 Experimental models of energy restriction 352.2.2 Observational studies and the first human trial of energy restriction: CALERIE study 402.3 Effects of energy restriction on organisms 422.3.1 Increased longevity and health of energy-restricted organisms 432.3.2 Body composition temperature and resting metabolic rate 462.3.3 Metabolism and insulin sensitivity 482.3.4 Immune system and inflammatory modulation 492.3.5 Neuroendocrine axes and adipokines 502.3.6 Growth factors and cytoprotective effects 572.4 Cellular and molecular effects of energy restriction 572.4.1 Modulation of gene expression 582.4.2 Molecular mechanisms of sirtuins 602.4.2.1 Sirtuin 1 602.4.2.2 Sirtuin 6 632.4.2.3 Sirtuin 7 632.4.2.4 Sirtuin 3 632.4.2.5 Sirtuins 4 and 5 642.4.2.6 Sirtuin 2 642.4.3 AMPK 652.4.4 Oxidative stress and metabolic reprogramming 652.4.5 Autophagy and mTOR signaling 672.5 Energy restriction mimetics 712.5.1 Sirtuin activity stimulators 722.5.2 Antidiabetic drugs 732.5.3 Rapamycine 742.5.4 Polyamines 742.5.5 Antilipolytic drugs 75Part 2 762.6 Obesity and ageing 762.6.1 Obesity as a premature death inducer 762.6.2 Adipose tissue and metabolic dysregulation 792.6.2.1 Adipose tissue and disruption of endocrine secretion of adipokines 802.6.3 Mitochondrial dysfunction 802.6.4 Endoplasmic reticulum stress 812.6.4.1 Endoplasmic reticulum stress-induced unfolded protein response 822.6.4.2 Ageing-induced modification in unfolded protein response 832.6.4.3 Obesity-induced endoplasmic reticulum stress 852.6.5 Anti-obesity effects of natural compounds extracted from plants 882.6.5.1 Polyphenols 882.6.6 Anti-obesity effects of minerals (magnesium) 962.7 Conclusion 98Acknowledgment 98References 983 Nutrition epigenetics and ageing 133Jill Ann McKay and Luisa Anne Wakeling3.1 Introduction 1333.2 Epigenetics 1333.2.1 DNA methylation 1343.2.2 Histone modifications 1353.2.3 Noncoding RNAs 1353.2.4 The function of epigenetic mechanisms 1363.3 Epigenetics and ageing 1373.3.1 DNA methylation profiles and ageing 1373.3.2 Histone modifications and ageing 1373.3.3 MicroRNAs and ageing 1383.4 Influence of nutrition on epigenetic modifications 1383.4.1 Nutritional modulation of epigenetic enzyme activity 1393.4.2 Influence of nutrition on substrate availability for epigenetic modifications 1413.4.3 Critical windows and the developmental origins hypothesis 1423.5 Nutrition epigenetics and ageing 1443.5.1 Overview 1443.5.2 Specific dietary regimens and nutrients that influence epigenetics and ageing 1453.5.2.1 Dietary restriction 1453.5.2.2 Dietary polyphenols 1453.5.2.3 One-Carbon metabolism 1463.6 Conclusions and future perspective 147References 147Part II – Nutritional modulation of age-related organ functional decline4 Nutritional interventions in age-related genetic and epigenetic instability and cancer 157Thomas Prates Ong and Ana Paula de Melo Loureiro4.1 Cancer as an age-associated disease 1574.2 Genetic and epigenetic alterations as molecular mechanisms underlying carcinogenesis 1594.3 Diet nutrition and cancer 1654.4 Targeting age-related genomic and epigenomic alterations with nutritional interventions for cancer prevention 1674.4.1 Folate 1684.4.2 Energy restriction 1704.4.3 Bioactive food components 1724.5 Conclusions and perspectives 173Acknowledgment 174References 1745 Nutraceuticals in immunosenescence 183Thea Magrone and Emilio Jirillo5.1 Introduction 1835.2 The immune response in ageing 1845.2.1 Phagocytes 1845.2.2 Natural killer cells 1845.2.3 T cells 1855.2.4 B cells 1855.3 Micronutrients that modulate immunosenescence 1865.3.1 Zinc 1865.3.2 Copper 1875.3.3 Iron 1885.3.4 Selenium 1885.4 Probiotics and prebiotics 1895.4.1 Probiotics 1895.4.2 Prebiotics 1905.5 Dietary lipids 1915.6 Polyphenols 1925.7 Conclusion and future directions 195Acknowledgments 195References 1956 Cardiovascular ageing 203Carmen Brás Silva and Delminda Neves6.1 Age-related cardiac changes 2036.1.1 Heart changes 2036.1.1.1 Structural changes 2036.1.1.2 Functional changes 2046.1.1.3 Changes in cardioprotective and repair processes 2076.2 Age-related vascular changes 2076.2.1 Central arterial changes 2076.2.1.1 Arterial structural changes 2086.2.2 Peripheral arterial changes 2106.2.3 Arterial functional changes 2106.2.3.1 Blood pressure 2106.3 Changes in the interaction between heart and arterial system 2116.4 Endothelial dysfunction 2116.5 Erectile dysfunction as an early signal of cardiovascular disease 2136.5.1 The erection mechanism 2146.5.2 Contribution of ageing to erectile dysfunction onset 2146.5.2.1 Age-related structural and molecular modifications of erectile tissue 2156.6 Diet nutrition and cardiovascular ageing 2186.6.1 Obesity energy restriction and cardiovascular ageing 2186.6.2 Diet patterns and cardiovascular ageing 2206.6.2.1 Contribution of dietary pattern to erectile dysfunction onset 2216.7 Nutritional intervention for cardiovascular disease prevention or amelioration 2226.7.1 Nutritional pattern modulation 2236.7.2 Intervention of specific nutrients in cardiovascular disease protection 2256.7.2.1 Polyphenolic compounds 2256.7.2.2 l-Carnitine and l-arginine 2276.7.2.3 Fatty acids 2286.7.2.4 Vitamins 2286.7.2.5 Minerals 2306.7.2.6 Caffeine 2306.8 Conclusions 230References 2317 Bone and muscle ageing 247Joana Carvalho Elisa Marques and Pedro Moreira7.1 Introduction 2477.1.1 Determinants of bone loss in ageing 2487.1.2 Regulation of muscle atrophy in ageing 2497.2 Osteoporosis and fragility fractures in the elderly 2517.3 Nutritional mechanisms of age-related bone loss 2527.4 Calcium and vitamin D and the ageing skeleton: Efficacy in the treatment of osteoporosis 2547.5 Skeletal muscle age-related contributory mechanisms 2567.6 The role of nutrition in preventing ageing skeletal muscle atrophy 2597.6.1 Protein 2597.6.2 PUFA and inflammation 2607.6.3 Anti-oxidants and oxidative stress 2617.6.4 Vitamin D 2627.6.5 Food and dietary patterns 2627.7 Resistance exercise and nutrition: effective treatment strategy to counteract age-related muscle wasting and bone loss 2637.7.1 Protein and resistance exercise 2647.8 Concluding remarks 266References 2668 Nutrition and the ageing eye 277Ângela Carneiro8.1 The ageing eye 2778.1.1 The lens 2778.1.2 The retina 2788.2 Nutrients in the structure and physiology of the healthy human eye 2798.2.1 Vitamins 2798.2.2 Polyunsaturated fatty acids 2808.2.3 Zinc 2808.3 The human eye and the oxidative stress 2808.4 The anti-oxidant systems in the eye 2818.5 How can diet interfere with the ocular anti-oxidant system? 2828.6 Nutritional intervention in age-associated eye diseases 2838.6.1 Cataract 2838.6.1.1 The blue mountains eye study 2848.6.1.2 The beaver dam eye study 2848.6.1.3 The india age-related eye disease study 2848.6.1.4 The spanish segment of european eye study (EUREYE) 2858.6.1.5 The physicians’ health study 2858.6.1.6 The women’s health study 2858.6.1.7 The age-related eye disease study (AREDS) 2858.6.1.8 The age-related eye disease study 2 (AREDS2) 2868.6.2 Age-related macular degeneration 2868.6.2.1 AREDS 2898.6.2.2 AREDS2 2908.7 Nutrigenomics 2918.8 Conclusions 291References 2929 Beauty from the inside: Nutrition and skin ageing 299Alessandra Marini and Jean Krutmann9.1 Introduction 2999.2 Vitamins 3029.2.1 Vitamin C (l-ascorbic acid) 3029.2.2 Vitamin E (tocopherol) 3039.2.3 Vitamin B6 3049.2.4 Carotenoids 3049.2.5 Vitamin D 3069.3 Polyphenols and flavonoids 3069.4 Polyunsaturated fatty acids 3089.5 Pre- and probiotics 3089.6 Conclusions 310References 31010 Retarding brain ageing and cognitive decline 315José Paulo Andrade10.1 Ageing and brain 31510.2 From “healthy ageing” to dementia 31610.3 Green tea as a functional food and source of nutraceuticals 31810.3.1 Bioavailability of the catechins of green tea 31910.3.2 Direct and indirect actions of catechins 32010.3.3 Action of catechins in brain 32110.3.4 Catechins and neurodegenerative diseases 32110.3.5 Other polyphenols 32310.4 Modulatory effect of diet pattern on age-associated cognitive decline 32310.5 Multidomain interventions 32610.6 Conclusions 327Acknowledgment 327References 327Part III – Evidence-based retardation of ageing11 Science-based anti-ageing nutritional recommendations 335Inês Tomada and José Paulo Andrade11.1 Introduction 33511.2 The relevance of nutraceuticals and functional nutrients in anti-ageing medicine 33611.3 Nutrition from food vs from supplements 34011.3.1 Food enrichment and fortification 34111.3.2 Nutritional supplements 34211.3.2.1 Nutritional compounds as drugs delivered via food 34311.3.3 Pills capsules powders and syrups 35111.3.4 Factors that affect the bioavailability of nutrients 35211.3.4.1 Food processing and cooking methods 35311.3.4.2 Competitive interactions between nutrients 35511.3.4.3 Drug–food and drug–nutrients interactions 35711.4 Favorable combinations of nutrients in food 36011.5 Lifestyle strategies for successful ageing 36311.5.1 The mediterranean and asian diets 36811.5.2 The french paradox 375Acknowledgment 378References 378Index 391

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

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• List of contributors xiiiPreface xvAcknowledgment xviiPart I – Ageing of cells and organisms1 Human ageing a biological view 3Henrique Almeida and Liliana Matos1.1 Introduction 31.2 Human ageing and frailty 41.2.1 Mortality curves 41.2.2 Susceptibility to disease and mortality 51.2.3 Age-related and age-dependent diseases 61.3 Fundamental causes 71.4 Experimental approach to human ageing 81.4.1 Ageing models in dividing cells: Replicative senescence and telomere involvement 81.4.2 Stress-induced premature senescence 101.4.3 Ageing in organs and tissues 111.4.4 Lipofuscin deposition following organelle dysfunction and damage accumulation 121.4.5 Damage consequences: Dysfunctional organelles and cell functional decline. Cell loss 131.5 Involving genes in organism ageing and longevity 141.5.1 Longevous humans 141.5.2 Experimental approaches 151.5.2.1 The insulin/IGF-1 axis 171.5.2.2 IGF-1 signaling into FOXO proteins 181.5.2.3 Other pathways 201.6 Conclusions and prospects 21Acknowledgment 23References 232 To eat or not to eat – Anti-ageing effects of energy restriction 33Delminda Neves Maria João Martins Emanuel dos Passos and Inês TomadaPart 1 332.1 Energy restriction as more than a weight-loss strategy 332.2 Restriction of energy vs restriction of nutrients 342.2.1 Experimental models of energy restriction 352.2.2 Observational studies and the first human trial of energy restriction: CALERIE study 402.3 Effects of energy restriction on organisms 422.3.1 Increased longevity and health of energy-restricted organisms 432.3.2 Body composition temperature and resting metabolic rate 462.3.3 Metabolism and insulin sensitivity 482.3.4 Immune system and inflammatory modulation 492.3.5 Neuroendocrine axes and adipokines 502.3.6 Growth factors and cytoprotective effects 572.4 Cellular and molecular effects of energy restriction 572.4.1 Modulation of gene expression 582.4.2 Molecular mechanisms of sirtuins 602.4.2.1 Sirtuin 1 602.4.2.2 Sirtuin 6 632.4.2.3 Sirtuin 7 632.4.2.4 Sirtuin 3 632.4.2.5 Sirtuins 4 and 5 642.4.2.6 Sirtuin 2 642.4.3 AMPK 652.4.4 Oxidative stress and metabolic reprogramming 652.4.5 Autophagy and mTOR signaling 672.5 Energy restriction mimetics 712.5.1 Sirtuin activity stimulators 722.5.2 Antidiabetic drugs 732.5.3 Rapamycine 742.5.4 Polyamines 742.5.5 Antilipolytic drugs 75Part 2 762.6 Obesity and ageing 762.6.1 Obesity as a premature death inducer 762.6.2 Adipose tissue and metabolic dysregulation 792.6.2.1 Adipose tissue and disruption of endocrine secretion of adipokines 802.6.3 Mitochondrial dysfunction 802.6.4 Endoplasmic reticulum stress 812.6.4.1 Endoplasmic reticulum stress-induced unfolded protein response 822.6.4.2 Ageing-induced modification in unfolded protein response 832.6.4.3 Obesity-induced endoplasmic reticulum stress 852.6.5 Anti-obesity effects of natural compounds extracted from plants 882.6.5.1 Polyphenols 882.6.6 Anti-obesity effects of minerals (magnesium) 962.7 Conclusion 98Acknowledgment 98References 983 Nutrition epigenetics and ageing 133Jill Ann McKay and Luisa Anne Wakeling3.1 Introduction 1333.2 Epigenetics 1333.2.1 DNA methylation 1343.2.2 Histone modifications 1353.2.3 Noncoding RNAs 1353.2.4 The function of epigenetic mechanisms 1363.3 Epigenetics and ageing 1373.3.1 DNA methylation profiles and ageing 1373.3.2 Histone modifications and ageing 1373.3.3 MicroRNAs and ageing 1383.4 Influence of nutrition on epigenetic modifications 1383.4.1 Nutritional modulation of epigenetic enzyme activity 1393.4.2 Influence of nutrition on substrate availability for epigenetic modifications 1413.4.3 Critical windows and the developmental origins hypothesis 1423.5 Nutrition epigenetics and ageing 1443.5.1 Overview 1443.5.2 Specific dietary regimens and nutrients that influence epigenetics and ageing 1453.5.2.1 Dietary restriction 1453.5.2.2 Dietary polyphenols 1453.5.2.3 One-Carbon metabolism 1463.6 Conclusions and future perspective 147References 147Part II – Nutritional modulation of age-related organ functional decline4 Nutritional interventions in age-related genetic and epigenetic instability and cancer 157Thomas Prates Ong and Ana Paula de Melo Loureiro4.1 Cancer as an age-associated disease 1574.2 Genetic and epigenetic alterations as molecular mechanisms underlying carcinogenesis 1594.3 Diet nutrition and cancer 1654.4 Targeting age-related genomic and epigenomic alterations with nutritional interventions for cancer prevention 1674.4.1 Folate 1684.4.2 Energy restriction 1704.4.3 Bioactive food components 1724.5 Conclusions and perspectives 173Acknowledgment 174References 1745 Nutraceuticals in immunosenescence 183Thea Magrone and Emilio Jirillo5.1 Introduction 1835.2 The immune response in ageing 1845.2.1 Phagocytes 1845.2.2 Natural killer cells 1845.2.3 T cells 1855.2.4 B cells 1855.3 Micronutrients that modulate immunosenescence 1865.3.1 Zinc 1865.3.2 Copper 1875.3.3 Iron 1885.3.4 Selenium 1885.4 Probiotics and prebiotics 1895.4.1 Probiotics 1895.4.2 Prebiotics 1905.5 Dietary lipids 1915.6 Polyphenols 1925.7 Conclusion and future directions 195Acknowledgments 195References 1956 Cardiovascular ageing 203Carmen Brás Silva and Delminda Neves6.1 Age-related cardiac changes 2036.1.1 Heart changes 2036.1.1.1 Structural changes 2036.1.1.2 Functional changes 2046.1.1.3 Changes in cardioprotective and repair processes 2076.2 Age-related vascular changes 2076.2.1 Central arterial changes 2076.2.1.1 Arterial structural changes 2086.2.2 Peripheral arterial changes 2106.2.3 Arterial functional changes 2106.2.3.1 Blood pressure 2106.3 Changes in the interaction between heart and arterial system 2116.4 Endothelial dysfunction 2116.5 Erectile dysfunction as an early signal of cardiovascular disease 2136.5.1 The erection mechanism 2146.5.2 Contribution of ageing to erectile dysfunction onset 2146.5.2.1 Age-related structural and molecular modifications of erectile tissue 2156.6 Diet nutrition and cardiovascular ageing 2186.6.1 Obesity energy restriction and cardiovascular ageing 2186.6.2 Diet patterns and cardiovascular ageing 2206.6.2.1 Contribution of dietary pattern to erectile dysfunction onset 2216.7 Nutritional intervention for cardiovascular disease prevention or amelioration 2226.7.1 Nutritional pattern modulation 2236.7.2 Intervention of specific nutrients in cardiovascular disease protection 2256.7.2.1 Polyphenolic compounds 2256.7.2.2 l-Carnitine and l-arginine 2276.7.2.3 Fatty acids 2286.7.2.4 Vitamins 2286.7.2.5 Minerals 2306.7.2.6 Caffeine 2306.8 Conclusions 230References 2317 Bone and muscle ageing 247Joana Carvalho Elisa Marques and Pedro Moreira7.1 Introduction 2477.1.1 Determinants of bone loss in ageing 2487.1.2 Regulation of muscle atrophy in ageing 2497.2 Osteoporosis and fragility fractures in the elderly 2517.3 Nutritional mechanisms of age-related bone loss 2527.4 Calcium and vitamin D and the ageing skeleton: Efficacy in the treatment of osteoporosis 2547.5 Skeletal muscle age-related contributory mechanisms 2567.6 The role of nutrition in preventing ageing skeletal muscle atrophy 2597.6.1 Protein 2597.6.2 PUFA and inflammation 2607.6.3 Anti-oxidants and oxidative stress 2617.6.4 Vitamin D 2627.6.5 Food and dietary patterns 2627.7 Resistance exercise and nutrition: effective treatment strategy to counteract age-related muscle wasting and bone loss 2637.7.1 Protein and resistance exercise 2647.8 Concluding remarks 266References 2668 Nutrition and the ageing eye 277Ângela Carneiro8.1 The ageing eye 2778.1.1 The lens 2778.1.2 The retina 2788.2 Nutrients in the structure and physiology of the healthy human eye 2798.2.1 Vitamins 2798.2.2 Polyunsaturated fatty acids 2808.2.3 Zinc 2808.3 The human eye and the oxidative stress 2808.4 The anti-oxidant systems in the eye 2818.5 How can diet interfere with the ocular anti-oxidant system? 2828.6 Nutritional intervention in age-associated eye diseases 2838.6.1 Cataract 2838.6.1.1 The blue mountains eye study 2848.6.1.2 The beaver dam eye study 2848.6.1.3 The india age-related eye disease study 2848.6.1.4 The spanish segment of european eye study (EUREYE) 2858.6.1.5 The physicians’ health study 2858.6.1.6 The women’s health study 2858.6.1.7 The age-related eye disease study (AREDS) 2858.6.1.8 The age-related eye disease study 2 (AREDS2) 2868.6.2 Age-related macular degeneration 2868.6.2.1 AREDS 2898.6.2.2 AREDS2 2908.7 Nutrigenomics 2918.8 Conclusions 291References 2929 Beauty from the inside: Nutrition and skin ageing 299Alessandra Marini and Jean Krutmann9.1 Introduction 2999.2 Vitamins 3029.2.1 Vitamin C (l-ascorbic acid) 3029.2.2 Vitamin E (tocopherol) 3039.2.3 Vitamin B6 3049.2.4 Carotenoids 3049.2.5 Vitamin D 3069.3 Polyphenols and flavonoids 3069.4 Polyunsaturated fatty acids 3089.5 Pre- and probiotics 3089.6 Conclusions 310References 31010 Retarding brain ageing and cognitive decline 315José Paulo Andrade10.1 Ageing and brain 31510.2 From “healthy ageing” to dementia 31610.3 Green tea as a functional food and source of nutraceuticals 31810.3.1 Bioavailability of the catechins of green tea 31910.3.2 Direct and indirect actions of catechins 32010.3.3 Action of catechins in brain 32110.3.4 Catechins and neurodegenerative diseases 32110.3.5 Other polyphenols 32310.4 Modulatory effect of diet pattern on age-associated cognitive decline 32310.5 Multidomain interventions 32610.6 Conclusions 327Acknowledgment 327References 327Part III – Evidence-based retardation of ageing11 Science-based anti-ageing nutritional recommendations 335Inês Tomada and José Paulo Andrade11.1 Introduction 33511.2 The relevance of nutraceuticals and functional nutrients in anti-ageing medicine 33611.3 Nutrition from food vs from supplements 34011.3.1 Food enrichment and fortification 34111.3.2 Nutritional supplements 34211.3.2.1 Nutritional compounds as drugs delivered via food 34311.3.3 Pills capsules powders and syrups 35111.3.4 Factors that affect the bioavailability of nutrients 35211.3.4.1 Food processing and cooking methods 35311.3.4.2 Competitive interactions between nutrients 35511.3.4.3 Drug–food and drug–nutrients interactions 35711.4 Favorable combinations of nutrients in food 36011.5 Lifestyle strategies for successful ageing 36311.5.1 The mediterranean and asian diets 36811.5.2 The french paradox 375Acknowledgment 378References 378Index 391