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AGING
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 AGING
Oxidative Stress and Dietary Antioxidants

SECOND EDITION
Edited by

VICTOR R. PREEDY
VINOOD B. PATEL
Academic Press is an imprint of Elsevier
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 Contents

Contributors xi Recent advances in cardiovascular disease, aging and

oxidative stress 30
Preface xv
Applications to other diseases and conditions 31
Summary points 32
1 References 32
Further reading 35
Oxidative stress and aging
4. Aging, oxidative stress, mitochondrial
dysfunction, and the liver
1. Oxidative stress and miR-200c
JANICE G. LOZADA-DELGADO, CARLOS A. TORRES-RAMOS,
ALESSANDRA MAGENTA, MARIA CRISTINA FLORIO, MARCO SYLVETTE AYALA-PEÑA
D’AGOSTINO, SARA SILENO
Introduction 37
Introduction 3
Evidence for age-associated morphological, structural,
miR-200c and oxidative stress 5 and functional changes in the liver 38
Applications to other diseases or conditions 8 Evidence for age-associated loss of mitochondrial
Summary points 9
bioenergetics in liver 38
References 9
Oxidative stress and antioxidant responses in liver
aging 39
2. Caloric restriction, reactive oxygen Oxidative damage to the nuclear and mitochondrial
species, and longevity genomes in liver aging 40
MIYUKI KOBARA, HIROE TOBA, TETSUO NAKATA Mitochondrial dysfunction and liver-associated disease 42
Conclusion 44
Introduction 11 Summary points 44
CR in animals 11 References 45
Mechanisms responsible for beneficial effects of CR
in animals 12 5. Culprit effect of oxidative stress in the development
CR in humans 13
of Parkinson’s disease: A conundrum of senescence
Trials on other modified CR and other modules mimicking
RAHUL SAXENA, GLADYS RAI
CR-induced beneficial signaling 15
Conclusions and future prospective questions 16
Introduction 47
Applications to other diseases or conditions 16
Aging and Parkinson disease: A mysterious convergence 48
Summary points 16 Treacherous role of oxygen and nitrogen molecule in PD 48
References 16 Neuroinflammation in PD 56
Further reading 18
Therapeutic interventions 57
Summary points 57
3. Cardiovascular disease in aging and References 58
the role of oxidative stress Further reading 59
LUCIE ORLIAGUET, VINOOD B. PATEL, VICTOR R. PREEDY,
FAWAZ ALZAID
6. Linking bone cells, aging, and oxidative stress:
Introduction 19 Osteoblasts, osteoclasts, osteocytes, and bone
Physiology of the aging cardiovascular system 21 marrow cells
The molecular basis of oxidative stress as applied to the JUAN A. ARDURA, LUIS ÁLVAREZ-CARRIÓN,
cardiovascular system 23 ARANCHA R. GORTÁZAR, VERÓNICA ALONSO
Longevity genes and the longevity network 24
Genes of the longevity network: SIR2, IGF-1, AMPK, Basic biology of bone 61
and mTOR 24 Aging and bone: Role of oxidative stress 62
The longevity network: SIR2, IGF1, AMPK, Molecular mechanisms that mediate oxidative stress
and mTOR 27 in aging bone cells 63
Other genes and pathways in oxidative stress and age-related Summary points 69
cardiovascular disease 27 References 69

v
vi Contents

7. Oxidative stress, senescence and Mediterranean Free radical theory of aging 115
diet effects on osteoarthritis Involvement of other biomolecules in senescence 115
Mechanisms of senescence in reproduction 117
SERGIO AMMENDOLA, ANNA SCOTTO D’ABUSCO
Evidence linking senescence, apoptosis, and oxidative
Introduction 73 stress in fertility 117
Chondrocytes in osteoarthritis 74 Senescence exacerbates apoptosis 118
Chondrocytes and senescence 74 Senescence alters endocrine system 119
Chondrocytes and oxidative stress 76 Senescence alters sex hormone levels 119
Chondrocytes and pro- and antioxidant agents 77 The impact of senescence on sexual organs 120
Mediterranean nutrients: Protective or risk factors? 78 Impact of senescence on female reproductive function 120
Conclusions 79 Senescence and ovarian function 120
Application to other diseases 79 Applications to other diseases 121
Summary points 80 Summary points 122
References 80 References 122

8. Arthritis as a disease of aging and 12. Antioxidant capacity and menopausal

changes in antioxidant status symptoms
RAHUL SAXENA, JYOTI BATRA GITY SOTOUDEH, MARYAM ABSHIRINI

Introduction 83 Introduction 125

The concept of oxygen toxicity and free radicals 84 Menopausal symptoms 125
Summary 92 Oxidative stress, blood antioxidant status, and menopausal
References 92 symptoms 126
Antioxidant-rich diets and menopausal symptoms 127
9. Oxidative stress and sarcopenia Antioxidants supplementation in menopausal symptoms
management 128
FRANCESCO BELLANTI, AURELIO LO BUGLIO,
GIANLUIGI VENDEMIALE
Antioxidants and minerals 129
Summary points 131
Introduction 95 References 131
The aging muscle and sarcopenia 95
Reactive species and redox signaling in aging 97 2
Redox signaling in skeletal muscle 98
Redox alterations and sarcopenia 99 Antioxidants and aging
Applications to other diseases or conditions 100
Summary points 101
References 101 13. Reference dietary requirements of antioxidant
vitamins in the older adults
10. Oxidative stress and hypertension in old age: MINA YAMAZAKI PRICE, VICTOR R. PREEDY
The role of physical exercise
Introduction 137
CLODOALDO ANTÔNIO DE SÁ, VANESSA CORRALO,
FRANCIELLE GARGHETTI BATTISTON, Oxidative stress 137
MARIA ISABEL GONÇALVES DA SILVA Reference dietary requirements 138
Vitamin A 138
Introduction 105 Vitamin C (ascorbic acid) 138
Aging, oxidative stress, and hypertension 106 Vitamin E 138
Physical exercise, oxidative stress, and blood Other vitamins 139
pressure control 106 Challenges in meeting reference dietary requirements
Conclusion 109 in older adults 143
Applications to other diseases or conditions 109 Applications to other diseases or conditions 143
Summary points 109 Summary points 143
References 109 References 144

11. Linking senescence, apoptosis, and oxidative 14. Oxidative stress and antioxidants in elderly
stress in fertility women
MATHIAS ABIODUN EMOKPAE, OSARETIN GODWIN IGHARO BRUNNA CRISTINA BREMER BOAVENTURA,
PATRICIA FARIA DI PIETRO, FRANCIELI CEMBRANEL
Introduction 113
Changing maternal age in some countries 114 Introduction 145
Senescence enhances free radical generation 114 Review 145
 Contents vii
Role of exercise on oxidative stress and antioxidant What happens during aging? 178
status of elderly women 150 Has diet any modulatory role in CoQ10 effect on bone
Applications to other diseases or conditions 151 health during aging? 180
Summary points 152 Summary points 181
References 152 References 181

15. Caffeine and its analogs, antioxidants 18. Coenzyme Q10 supplementation in aging
and applications GUILLERMO LÓPEZ-LLUCH, PLÁCIDO NAVAS
BEATA JASIEWICZ, ARLETA SIERAKOWSKA
Introduction 183
Introduction 155 Bioenergetics and antioxidant activity of CoQ10 184
Oxidative stress and reactive oxygen species 155 CoQ10 and longevity, the intriguing role of
Antioxidant properties of caffeine and its analogs 156 Clk-1/COQ7 184
Caffeine and its analogs as adenosine receptors CoQ10 levels and longevity in humans 186
antagonists 157 CoQ10 in age-related diseases 187
Caffeine and its analogs as monoamine oxidase CoQ1010 supplementation and longevity 187
inhibitors 158 Applications to other diseases or conditions 188
Caffeine and its analogs in neurodegenerative Summary points 189
disease 159 References 189
Anticancer properties of caffeine and its analogs 160
Antibacterial and antifungal activity of caffeine 19. Crocus sativus L. (saffron) extract antioxidant
analogs 162 potential and use in aging
Caffeine and its analogs in medicines, cosmetics, and SAEED SAMARGHANDIAN, TAHEREH FARKHONDEH,
dietary supplements 162 TAYEBEH ZEINALI
Summary points 162
References 162 Background 193
Antioxidant system 194
16. Coenzyme Q10 as an antioxidant in Mode of action of saffron 194
the elderly Chemical composition of saffron 194
Safety assessments of saffron and its main ingredients 195
ELENA M. YUBERO-SERRANO,
FRANCISCO M. GUTIERREZ-MARISCAL, ANTONIO GARCIA-RIOS,
Saffron and its main ingredients, oxidative stress,

JAVIER DELGADO-LISTA, PABLO PEREZ-MARTINEZ, and aging 196
ANTONIO CAMARGO, FRANCISCO PEREZ-JIMENEZ, References 199
JOSE LOPEZ-MIRANDA
20. Pharmacological profile of γ-oryzanol:
Aging 165
Coenzyme Q10 165 Its antioxidant mechanisms and its effects in
Coenzyme Q10 functions 166 age-related diseases
Levels and distribution of coenzyme Q10 in the WIRAMON RUNGRATANAWANICH, GIULIA ABATE,
human organism 166 DANIELA UBERTI
Biosynthesis and transport of CoQ10 167
Uptake and distribution of CoQ10 167 Introduction 201
CoQ10 and aging 168 Pharmacokinetics of γ-oryzanol 202
Therapeutic uses of CoQ10 in age-related diseases 168 Pharmacodynamics of γ-oryzanol 202
Conclusions 169 Antioxidant effects of γ-oryzanol in age-related
Summary points 170 diseases 204
References 170 Summary points 206
References 206
17. The role of coenzyme Q10 in the protection
21. Herbs including shell ginger, antioxidant profiles,
of bone health during aging
 L. QUILES, JOSE
 M. ROMERO-MÁRQUEZ, MARÍA D. NAVARRO-
aging, and longevity in Okinawa, Japan: A critical
JOSE
HORTAL, MAURIZIO BATTINO, ALFONSO VARELA-LÓPEZ analysis of current concepts
ROLF TESCHKE, TRAN DANG XUAN
Bone biology 173
Regulation of bone remodeling 174 Introduction 209
Reactive oxygen species (ROS) in bone remodeling 175 Literature search 210
Oxidative stress and bone health 175 Definitions 210
Aging at the bone 176 Specificities of plant use 211
Coenzyme Q10 (CoQ10), oxidative stress, and bone Shell ginger and selected plants with their antioxidant
metabolism 176 profiles and biological activities 212
viii Contents

Issue of plant antioxidants in aging or longevity and its 25. Murici (Byrsonima crassifolia (L.) Kunth):
evidence 214 Antioxidant effects and application to aging
Okinawa plants, their antioxidants and association with 
MARIANA SEFORA BEZERRA SOUSA,
longevity 215 DIEGO DE SOUZA BUARQUE
Longevity-specific bioactivities of A. zerumbet 216
Okinawa longevity 217 Introduction 259
Causality gap under discussion between antioxidant plants Mechanisms of free radical production 259
and longevity in Okinawa 219 Antioxidant defense system 260
Conclusions 220 Oxidative stress and aging 260
Summary points 220 Murici [Byrsonima crassifolia (L.) Kunth] 261
References 221 Conclusion 263
Summary points 263
22. Lycopene as an antioxidant in the References 264
prevention and treatment of postmenopausal
osteoporosis 26. Natural products in aging skin
L.G. RAO, E.S. MACKINNON, A.V. RAO MAHENDRAN SEKAR

Introduction 223 Introduction 267

Oxidative stress and antioxidants 223 Natural products in aging skin 268
Osteoporosis 224 Discussion 271
Studies on lycopene 225 Conclusion 272
Summary points 229 Summary points 272
Acknowledgments 229 References 272
References 230
27. Antioxidant properties and applications
23. Medicinal plants, antioxidant potential, and of Ophiopogon japonicus root for age-related disease
applications to aging YUMI KITAHIRO, MAKIO SHIBANO
WASEEM HASSAN, MEHREEN ZAFAR, JEAN PAUL KAMDEM
Introduction 275
Introduction 233 Features of cellular senescence 275
The free radical theory of aging 233 Ophiopogonis Radix 276
Free radical-induced damages 233 Antiinflammatory effects of Ophiopogonis Radix on
Antiaging effects of medicinal plants 235 senescent NHDFS 277
Some of the major antioxidant enzymes and nonenzymes Kampo, the traditional Japanese medicine 279
of medicinal plants and their proposed mechanism Conclusions 279
of action 237 Summary points 281
Some important points to be noted 238 References 282
Summary points 240
References 240 28. Passion fruit seed: Its antioxidative extracts
and potency in protection of skin aging
24. Antioxidant and antiinflammatory role of NATTAYA LOURITH, MAYUREE KANLAYAVATTANAKUL
melatonin in Alzheimer’s neurodegeneration
Introduction 283
SERGIO A. ROSALES-CORRAL, RUSSEL J. REITER, XIAOYAN LIU
Oxidative stress and skin aging 283
Introduction 243 Antioxidative passion fruit seed extract and its potency
How free radicals are formed 244 in skin protection 284
Some oxidative stress-related facts about the brain 246 Conclusion 285
Where do free radicals come from in the Alzheimer’s Applications to other diseases or conditions 287
disease brain? 247 Summary points 287
How does melatonin scavenge free radicals? 250 References 287
Melatonin stimulates antioxidant systems 252
Breaking the cycle neuroinflammation $ oxidative 29. Phaseolus vulgaris L. as a functional food
stress 252 for aging protection
Melatonin production decreases with age 253 EUNICE SANTOS, GUILHERMINA MARQUES, TERESA LINO-NETO
Conclusions 253
Applications to other diseases or conditions 254 Introduction 289
Summary points 254 Nutritional importance of common bean 289
References 254 Occurrence of bioactive compounds in common bean 290
 Contents ix
Polyphenols as important antioxidant compounds in 33. Resveratrol, SIRT1, oxidative stress, and
common bean 291 brain aging
Other antioxidants in common bean 292
FIORELLA SARUBBO, SILVIA TEJADA, SUSANA ESTEBAN,
Common bean and prevention of aging processes 292 MANUEL JIMENEZ-GARCÍA, DAVID MORANTA
Conclusions 293
Applications to other diseases or conditions 294 Brain aging: Role of oxidative stress and sirtuins 319
Summary points 294 Resveratrol: Their effect in brain aging through
Acknowledgments 294 SIRT1 321
References 294 Challenges on resveratrol application in the prevention of
neurodegeneration 323
30. Quercetin and resveratrol, aging and kidney Applications to other diseases or conditions 324
MINA HEMMATI, MARYAM MOOSSAVI Summary points 324
Acknowledgments 324
Introduction 297 References 324
Diabetes and renal cell aging 298
Transforming growth factor beta (TGF-β) 299 34. Antioxidants, vegetarian diets, and age-related
Tumor necrosis factor alpha (TNF-α) 299 disease
Advanced glycation end product (AGE) 299
ANDREW C. BULMER, SHAILENDRA ANOOPKUMAR-DUKIE,
NADPH oxidase 299 IRIS F.F. BENZIE
Endothelin-1 (ET-1) 299
Urotensin II 300 Introduction 327
Cannabinoid receptor (CB) 300 Human aging and its consequences 327
Beta-galactosidase as a marker of senescent cells 300 Oxidative stress and age-related disease 328
Summary points 301 Potential role of vegetarian diets for lowering
References 301 risk of disease and increasing health span 330
Some evidence 331
31. Rambutan fruits extract in aging skin Questions of molecular connections and research
MAHENDRAN SEKAR needs 333
Summary points 334
Introduction 303 References 334
Minerals in rambutan peel 303
Polyphenolic compounds in rambutan peel 304 35. Protective effect of vitamin D on oxidative
Role of polyphenolic compounds in antiaging 304 stress in elderly people
Relationship of antioxidants with antiaging
BRUNNA CRISTINA BREMER BOAVENTURA,
therapy 304 FRANCIELI CEMBRANEL
Antioxidant activity of various parts of rambutan
fruits 304 Introduction 337
Antiaging effect of rambutan fruits 305 Review 337
Conclusion 305 Applications to other diseases or conditions 342
Summary points 306 Summary points 342
References 306 References 342

32. Resveratrol, aging, and fatigue 36. Zinc, oxidative stress in the elderly,
LUANA TONIOLO, EMILIANA GIACOMELLO and implication for inflammation
ANANDA S. PRASAD, BIN BAO
Introduction 309
Skeletal muscle fatigue 309 Introduction 345
ROS and muscle fatigue 310 Discovery of zinc deficiency in humans 345
Sarcopenia and lifestyle 311 Clinical manifestations of zinc deficiency 346
Calorie restriction and aging 311 Zinc deficiency in the elderly subjects 347
Resveratrol is a potent antioxidant with multiple Effect of zinc supplementation in the elderly: Cell-mediated
functions 311 immunity and incidence of infection 348
Resveratrol and exercise in animal models 312 Effect of zinc supplementation on oxidative stress
Resveratrol and exercise in humans 313 and inflammatory cytokines in the elderly 352
Resveratrol and fatigue, the underlying mechanisms 313 Zinc trials in AMD 354
Conclusions 315 Zinc and NF-κB activation 355
Summary points 315 Proposed concept of mechanism of zinc action as an
References 315 antioxidant and antiinflammatory agent 355
x Contents

Mechanism of zinc action as an antioxidant 356 Production of oxidative stress in glutamatergic

Zinc as a molecular signal regulating oxidative stress neurotransmission 365
and chronic inflammation 357 Changes in antioxidant defense systems of SAM10 in
Metallothionein 358 aging 365
Summary points 359 Conclusion 366
References 359 Summary points 366
References 366
37. Oxidative stress and the senescence acceleration
in senescence-accelerated mouse P10 (SAMP10) 38. Recommended resources on aging: Oxidative
TAKESHI SAITO, MASAAKI KURASAKI stress and dietary antioxidants
RAJKUMAR RAJENDRAM, VINOOD B. PATEL, VICTOR R. PREEDY
Free radical theory of aging 363
Senescence-accelerated mouse: Animal model of
Introduction 369
aging 363
Resources 370
Oxidative stress and aging of SAMP10 364
Summary points 372
Production of reactive oxygen species (ROS) in
Acknowledgments 373
SAMP10 364
References 373
Production of ROS in mitochondria of SAMP10 mice
with aging 364
Production of neuronal NO by NO synthase 364 Index 375
 Contributors
Giulia Abate Department of Molecular and Translational
Medicine, University of Brescia, Brescia, Italy
Maryam Abshirini School of Health Sciences, College of
Health, Massey University, Palmerston North, New Zealand
Verónica Alonso Department of Basic Medical Sciences,
School of Medicine, San Pablo CEU University, CEU
Universities, Alcorcón, Madrid, Spain
Luis Álvarez-Carrión Bone Physiopathology Laboratory,
Applied Molecular Medicine Institute (IMMA), Universidad
San Pablo-CEU, CEU Universities, Alcorcón, Madrid,
Spain
Fawaz Alzaid Immunity and Metabolism of Diabetes Team,
INSERM Unit 1138, Cordeliers Research Centre, Paris,
France
Sergio Ammendola Ambiotec S.A.S., Cisterna di Latina, Italy
Shailendra Anoopkumar-Dukie School of Pharmacy &
Pharmacology, Griffith University, Gold Coast, QLD,
Australia
Juan A. Ardura Department of Basic Medical Sciences, School
of Medicine, San Pablo CEU University, CEU Universities,
Alcorcón, Madrid, Spain
Sylvette Ayala-Peña Department of Pharmacology and
Toxicology, University of Puerto Rico Medical Sciences
Campus, San Juan, PR, United States
Bin Bao Department of Oncology, Wayne State University
School of Medicine, and Barbara Ann Karmanos Cancer
Institute, Detroit, MI, United States
Jyoti Batra Dean Research & Professor, Department of
Biochemistry, Santosh Medical College and Hospital, Santosh
University, Ghaziabad, Uttar Pradesh, India
Maurizio Battino Nutrition and Food Science Group,
Department of Analytical and Food Chemistry, CITACA,
CACTI, University of Vigo, Vigo, Spain; Dipartimento di
Scienze Cliniche Specialistiche ed Odontostomatologiche
(DISCO)-Sez. Biochimica, Facoltà di Medicina, Università
Politecnica delle Marche, Ancona, Italy
Francielle Garghetti Battiston Postgraduate Program on
Health Sciences, Unochapecó University, Chapecó, Santa
Catarina, Brazil
Francesco Bellanti Department of Medical and Surgical
Sciences, University of Foggia, Foggia, Italy
Iris F.F. Benzie School of Pharmacy & Pharmacology, Griffith
University, Gold Coast, QLD, Australia
Brunna Cristina Bremer Boaventura Department of
Nutrition, Health Sciences Center, Federal University of Santa
Catarina, Florianópolis, SC, Brazil
xi
Aurelio Lo Buglio Department of Medical and Surgical
Sciences, University of Foggia, Foggia, Italy
Andrew C. Bulmer School of Medical Science, Griffith
University, Gold Coast, QLD, Australia
Antonio Camargo Lipid and Atherosclerosis Unit, IMIBIC/
Reina Sofia University Hospital, University of Cordoba,
Córdoba; CIBER Fisiopatologia Obesidad y Nutricion
(CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
Francieli Cembranel Department of Nutrition, Health
Sciences Center, Federal University of Santa Catarina,
Florianópolis, SC, Brazil
Vanessa Corralo Postgraduate Program on Health
Sciences, Unochapecó University, Chapecó, Santa
Catarina, Brazil
Marco D’Agostino Experimental Immunology
Laboratory, Dermopatic Institute of Immaculate-IDI-
IRCCS, Rome, Italy
Javier Delgado-Lista Lipid and Atherosclerosis Unit, IMIBIC/
Reina Sofia University Hospital, University of Cordoba,
Córdoba; CIBER Fisiopatologia Obesidad y Nutricion
(CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
Patricia Faria Di Pietro Department of Nutrition, Health
Sciences Center, Federal University of Santa Catarina,
Florianópolis, SC, Brazil
Mathias Abiodun Emokpae Department of Medical
Laboratory Science, School of Basic Medical Sciences, College
of Medical Sciences, University of Benin, Benin City, Nigeria
Susana Esteban Neurophysiology Group, Biology
Department, University of Balearic Islands, Palma, Balearic
Islands, Spain
Tahereh Farkhondeh Cardiovascular Diseases Research
Center, Birjand University of Medical Sciences, Birjand,
Iran
Maria Cristina Florio Laboratory of Cardiovascular Science,
National Institute on Aging, NIH, Biomedical Research
Center, Baltimore, MD, United States
Antonio Garcia-Rios Lipid and Atherosclerosis Unit,
IMIBIC/Reina Sofia University Hospital, University of
Cordoba, Córdoba; CIBER Fisiopatologia Obesidad y
Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid,
Spain
Emiliana Giacomello Department of Medical, Surgical and
Health Sciences, University of Trieste, Trieste, Italy
Maria Isabel Gonçalves da Silva Postgraduate Program on
Health Sciences, Unochapecó University, Chapecó, Santa
Catarina, Brazil
xii Contributors
Arancha R. Gortázar Department of Basic Medical Sciences,
School of Medicine, San Pablo CEU University, CEU
Universities, Alcorcón, Madrid, Spain
Francisco M. Gutierrez-Mariscal Lipid and Atherosclerosis
Unit, IMIBIC/Reina Sofia University Hospital, University of
Cordoba, Córdoba; CIBER Fisiopatologia Obesidad y
Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid,
Spain
Waseem Hassan Institute of Chemical Sciences, University of
Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan
Mina Hemmati Biochemistry Department, Faculty of
Medicine, Zanjan University of Medical Sciences, Zanjan,
Iran
Osaretin Godwin Igharo Department of Medical
Laboratory Science, School of Basic Medical Sciences,
College of Medical Sciences, University of Benin, Benin City,
Nigeria
Beata Jasiewicz Faculty of Chemistry, Adam Mickiewicz
University in Pozna
n, Uniwersytetu Pozna
nskiego, Pozna
n,
Poland
Manuel Jimenez-García Neurophysiology Group, Biology
Department, University of Balearic Islands, Palma, Balearic
Islands, Spain
Jean Paul Kamdem Department of Biological Sciences,
Regional University of Cariri, Crato, Ceara, Brazil
Mayuree Kanlayavattanakul School of Cosmetic Science;
Phytocosmetics and Cosmeceuticals Research Group, Mae
Fah Luang University, Chiang Rai, Thailand
Yumi Kitahiro Department of Natural Products Research,
Osaka University of Pharmaceutical Sciences, Takatsuki,
Japan
Miyuki Kobara Department of Clinical Pharmacology,
Division of Pathological Science, Kyoto Pharmaceutical
University, Kyoto, Japan
Masaaki Kurasaki Faculty of Environmental Earth Science,
Hokkaido University, Sapporo, Japan
Teresa Lino-Neto Biosystems & Integrative Sciences Institute
(BioISI), Plant Functional Biology Center (CBFP), University
of Minho, Braga, Portugal
Xiaoyan Liu School of Traditional Chinese Medicine, Beijing
University of Chinese Medicine, Beijing, China
Guillermo López-Lluch Centro Andaluz de Biología del
Desarrollo (CABD-CSIC-JA) (CIBERER), Instituto de Salud
Carlos III, Universidad Pablo de Olavide, Sevilla, Spain
Jose Lopez-Miranda Lipid and Atherosclerosis Unit,
IMIBIC/Reina Sofia University Hospital, University of
Cordoba, Córdoba; CIBER Fisiopatologia Obesidad y
Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid,
Spain
Nattaya Lourith School of Cosmetic Science; Phytocosmetics
and Cosmeceuticals Research Group, Mae Fah Luang
University, Chiang Rai, Thailand
Janice G. Lozada-Delgado Department of Pharmacology and
Toxicology, University of Puerto Rico Medical Sciences
Campus, San Juan, PR, United States
E.S. Mackinnon Department of Medicine, St. Michael’s
Hospital; University of Toronto, Toronto, ON, Canada
Alessandra Magenta Experimental Immunology
Laboratory, Dermopatic Institute of Immaculate-IDI-IRCCS,
Rome, Italy
Guilhermina Marques Centre for Research and Technology
of Agro-Environment and Biological Sciences (CITAB),
University of Trás-os-Montes and Alto Douro (UTAD), Vila
Real, Portugal
Maryam Moossavi Student Research Committee, Birjand
University of Medical Sciences, Birjand, Iran
David Moranta Neurophysiology Group, Biology
Department, University of Balearic Islands, Palma, Balearic
Islands, Spain
Tetsuo Nakata Department of Clinical Pharmacology,
Division of Pathological Science, Kyoto Pharmaceutical
University, Kyoto, Japan
María D. Navarro-Hortal Institute of Nutrition and Food
Technology “Jose Mataix Verdú,” Department of Physiology,
Biomedical Research Center, University of Granada,
Granada, Spain
Plácido Navas Centro Andaluz de Biología del Desarrollo
(CABD-CSIC-JA) (CIBERER), Instituto de Salud Carlos III,
Universidad Pablo de Olavide, Sevilla, Spain
Lucie Orliaguet Immunity and Metabolism of Diabetes
Team, INSERM Unit 1138, Cordeliers Research Centre,
Paris, France
Vinood B. Patel Department of Biomedical Sciences, School of
Life Sciences, University of Westminster, London,
United Kingdom
Francisco Perez-Jimenez Lipid and Atherosclerosis Unit,
IMIBIC/Reina Sofia University Hospital, University of
Cordoba, Córdoba; CIBER Fisiopatologia Obesidad y
Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid,
Spain
Pablo Perez-Martinez Lipid and Atherosclerosis Unit,
IMIBIC/Reina Sofia University Hospital, University of
Cordoba, Córdoba; CIBER Fisiopatologia Obesidad y
Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid,
Spain
Ananda S. Prasad Department of Oncology, Wayne State
University School of Medicine, and Barbara Ann Karmanos
Cancer Institute, Detroit, MI, United States
Victor R. Preedy Diabetes and Nutritional Sciences Research
Division, School of Medicine; Department of Nutritional
Sciences, School of Life Course Sciences, Faculty of Life
Sciences & Medicine, King’s College London, London, United
Kingdom
Mina Yamazaki Price Division of Critical Care, Medicine and
Surgery, Department of Therapies, Royal Free Hospital,
Royal Free London NHS Foundation Trust, London,
United Kingdom
e L. Quiles Institute of Nutrition and Food Technology
Jos
“Jose Mataix Verdú,” Department of Physiology, Biomedical
Research Center, University of Granada, Granada, Spain
 Contributors
Gladys Rai Department of Biochemistry, School of Medical
Sciences & Research, Sharda University, Greater Noida, Uttar
Pradesh, India
Rajkumar Rajendram College of Medicine, King Saud bin
Abdulaziz University for Health Sciences; Department of
Medicine, King Abdulaziz Medical City, Riyadh, Ministry of
National Guard Health Affairs, Riyadh, Saudi Arabia;
Diabetes and Nutritional Sciences Research Division, Faculty
of Life Science and Medicine, King’s College London,
London, United Kingdom
A.V. Rao Department of Nutritional Sciences, University of
Toronto, Toronto, ON, Canada
L.G. Rao Department of Medicine, St. Michael’s Hospital;
University of Toronto, Toronto, ON, Canada
Russel J. Reiter Department of Cellular and Structural
Biology, University of Texas Health Science Center at San
Antonio, San Antonio, TX, United States
Jose M. Romero-Márquez Institute of Nutrition and Food
Technology “Jose Mataix Verdú,” Department of Physiology,
Biomedical Research Center, University of Granada,
Granada, Spain
Sergio A. Rosales-Corral Western Biomedical Research
Center from the Mexican Institute of Social Security,
Guadalajara, Jalisco, Mexico
Wiramon Rungratanawanich Department of Molecular and
Translational Medicine, University of Brescia, Brescia, Italy
Clodoaldo Antônio De Sá Postgraduate Program on Health
Sciences, Unochapecó University, Chapecó, Santa Catarina,
Brazil
Takeshi Saito Faculty of Health Sciences, Hokkaido
University, Sapporo, Japan
Saeed Samarghandian Healthy Ageing Research Center,
Neyshabur University of Medical Sciences, Neyshabur, Iran
Eunice Santos Centre for Research and Technology of
Agro-Environment and Biological Sciences (CITAB),
University of Trás-os-Montes and Alto Douro (UTAD),
Vila Real; Biosystems & Integrative Sciences Institute (BioISI),
Plant Functional Biology Center (CBFP), University of Minho,
Braga, Portugal
Fiorella Sarubbo Neurophysiology Group, Biology
Department, University of Balearic Islands; Research Unit,
Hospital Universitario Son Llàtzer, Health Research Institute
of Balearic Islands (IdISBa), Palma, Balearic Islands, Spain
Rahul Saxena Department of Biochemistry, School of Allied
Health Sciences, Sharda University, Greater Noida, Uttar
Pradesh, India
Anna Scotto d’Abusco Department of Biochemical Sciences,
Sapienza University of Rome, Rome, Italy
Mahendran Sekar Department of Pharmaceutical Chemistry,
Faculty of Pharmacy and Health Sciences, Universiti
Kuala Lumpur, Royal College of Medicine Perak, Ipoh,
Malaysia
Makio Shibano Department of Natural Products Research,
Osaka University of Pharmaceutical Sciences, Takatsuki,
Japan
xiii
Arleta Sierakowska Faculty of Chemistry, Adam Mickiewicz
University in Pozna
n, Uniwersytetu Pozna
nskiego, Pozna
n,
Poland
Sara Sileno Experimental Immunology Laboratory,
Dermopatic Institute of Immaculate-IDI-IRCCS, Rome,
Italy
Gity Sotoudeh Department of Community Nutrition, School
of Nutritional Sciences and Dietetics, Tehran University of
Medical Sciences, Tehran, Iran
efora Bezerra Sousa Nutrition Department,
Mariana S
Federal Institute of Ceará (IFCE), Iguatu, Brazil
Diego de Souza Buarque Academic Unit of Serra Talhada
(UAST), Rural Federal University of Pernambuco (UFRPE),
Serra Talhada, Brazil
Silvia Tejada Neurophysiology Group, Biology Department;
Biology Department and CIBEROBN (Physiopathology of
Obesity and Nutrition), University of Balearic Islands, Palma,
Balearic Islands, Spain
Rolf Teschke Department of Internal Medicine, Division of
Gastroenterology and Hepatology, Klinikum Hanau, Hanau;
Academic Teaching Hospital of the Medical Faculty,
Goethe University Frankfurt/Main, Frankfurt/Main,
Germany
Hiroe Toba Department of Clinical Pharmacology, Division
of Pathological Science, Kyoto Pharmaceutical University,
Kyoto, Japan
Luana Toniolo Department of Biomedical Sciences,
University of Padova, Padova, Italy
Carlos A. Torres-Ramos Department of Physiology,
University of Puerto Rico Medical Sciences Campus, San
Juan, PR, United States
Daniela Uberti Department of Molecular and Translational
Medicine, University of Brescia, Brescia, Italy
Alfonso Varela-López Institute of Nutrition and Food
Technology “Jose Mataix Verdú,” Department of Physiology,
Biomedical Research Center, University of Granada,
Granada, Spain
Gianluigi Vendemiale Department of Medical and Surgical
Sciences, University of Foggia, Foggia, Italy
Tran Dang Xuan Division of Development Technology,
Graduate School for International Development and
Cooperation (IDEC), Hiroshima University, Higashi
Hiroshima, Japan
Elena M. Yubero-Serrano Lipid and Atherosclerosis Unit,
IMIBIC/Reina Sofia University Hospital, University of
Cordoba, Córdoba; CIBER Fisiopatologia Obesidad y
Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid,
Spain
Mehreen Zafar Institute of Chemical Sciences, University of
Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan
Tayebeh Zeinali Social Determinants of Health Research
Center, School of Health, Birjand University of Medical
Sciences, Birjand, Iran
This page intentionally left blank
 Preface
Here is this book Aging: Oxidative Stress and Dietary
Antioxidants, Second Edition that bridges the transdisci-
plinary divide and covers the science of oxidative stress
in aging and the therapeutic use of natural antioxidants
in the food matrix in a single volume.
The second edition covers new trials and investigations
used to determine the comprehensive properties of antiox-
idants, food items and extracts, and any adverse properties
they may have. It has been updated to include new clinical
human trials and studies dedicated to animal models of
aging. Throughout the book the processes within the
science of oxidative stress are described in concert with
other processes, such as apoptosis, cell signaling, and
receptor-mediated responses. This approach recognizes
that diseases are often multifactorial and oxidative stress
is a single component of this.
Here is this book Aging: Oxidative Stress and Dietary
Antioxidants, Second Edition that contains two sections:
xv
in Section 1, there is coverage of oxidative stress and
aging in cardiovascular disease, arthritis, the liver, ferti-
lity, sarcopenia, and calorie restriction. In Section 2
the focus is on antioxidants, covering recommended
amounts in the elderly, Coenzyme Q10 supplemen-
tation, antioxidants and vegetarian diets, and caffeine
analogues; natural antioxidants such as lycopene, zinc,
and ginger; and plant-derived products including,
Murici extract, Ophiopogonis radix root, passion fruit
seed, and saffron extract, where models of aging are
also discussed.
Thus this text is relevant to gerontologist, geriatricians,
nutritionists, dieticians, and nutrition researchers as aging
is a multifaceted process covering disease processes, clinical
research, and treatment.
Victor R. Preedy and Vinood B. Patel
This page intentionally left blank
 S E C T I O N 1

Oxidative stress and aging

This page intentionally left blank
 C H A P T E R

1
Oxidative stress and miR-200c
Alessandra Magentaa, Maria Cristina Floriob, Marco D’Agostinoa,
Sara Silenoa
a
Experimental Immunology Laboratory, Dermopatic Institute of Immaculate-IDI-IRCCS, Rome, Italy
b
Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Biomedical Research Center, Baltimore, MD,
United States

List of abbreviations enzymes such as several oxidases, peroxidase, cyto-

chromes, mono- and dioxygenases, and uncoupled nitric
BCNU 1,3-bis(2 chloroethyl)-1-nitrosourea
CAT catalase oxide synthase (NOS).1 Enzymatic and nonenzymatic
ECs endothelial cells antioxidant defenses such as superoxide dismutases
EMT epithelial-mesenchymal transition (SODs), catalase (CAT), glutathione peroxidase (GPx),
eNOS endothelial nitric oxide synthase and glutathione finely modulate the amount of ROS
FOXO1 forkhead box O1 within the cell.2
GPx glutathione peroxidase
HEI-OC1 House Ear Institute-Organ of Corti 1 Insufficient scavenging or ROS production exacerba-
H2O2 hydrogen peroxide tion has been demonstrated to impair many biological
MAPK mitogen-activated protein kinase processes.
miRNA microRNA There is a close link between NOS activity and ROS
MnSOD manganese superoxide dismutase production, since uncoupling of NOS leads to the produc-
mRNA messenger RNA
NAC N-acetyl-L-cysteine
tion of superoxide anion, rather than NO.3,4 The cellular
NOS nitric oxide synthase transduction pathways induced by the increase in ROS
NOX NADPH oxidase are known to cause growth arrest and senescence, as well
p66Shc p66 isoform of ShcA protein as cell death, both by apoptosis and necrosis, based on the
ROS reactive oxygen species level of oxidative stress experienced by the cell and its
pRb retinoblastoma protein
RISC RNA-induced silencing complex genotype. A mechanism of induction of apoptosis from
SIRT1 sirtuin 1 oxidative stress involves the p53 tumor suppressor pro-
SOD superoxide dismutase tein; p53, in turn, regulates the intracellular redox state
TRBP TAR RNA-binding protein and induces apoptosis through a mechanism involving
t-BHP tert-butyl hydroperoxide ROS production.5
Xpo-5 exportin 5
ZEB1 zinc finger E-box-binding homeobox 1 A key role in ROS-induced apoptosis is also played by
the p66 isoform of the ShcA protein (p66Shc), a funda-
mental regulator of mitochondrial ROS production from
Introduction a variety of different stimuli.6
Different studies underlined the role of microRNAs
Physiological reactive oxygen species (ROS) levels (miRNAs) in cellular homeostasis and in the regulation
play an important role as second messengers within the of redox balance.
intracellular signaling.
ROS, which include superoxide anion, hydroxyl radi-
cals, and hydrogen peroxide (H2O2), are generated as
microRNA
consequence of aerobic metabolism and are produced
by several cellular sources. These include mitochondria, miRNAs are 21- to 23-nucleotide-long noncoding
plasma membrane NADPH oxidase (NOX), and different RNA molecules that modulate the stability and/or the

Aging 3 Copyright © 2020 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/B978-0-12-818698-5.00001-8
4 1. Oxidative stress and miR-200c

translational efficiency of target messenger RNAs miRNA-processing pathway without a Drosha-mediated

(mRNAs). miRNA genes can be expressed as polycis-
tronic transcripts containing multiple miRNAs, as inde-
pendent transcripts, or can be embedded in introns of
protein coding mRNAs. Commonly miRNAs act as neg-
ative regulators of gene expression, although few oppo-
site examples have been described.7
miRNA biogenesis (Fig. 1) starts with a primary tran-
script transcribed by RNA polymerase II, a generally
thousands of nucleotides long mRNA termed the pri-
miRNA; only few miRNAs are transcribed by RNA poly-
merase III. The pri-miRNA is a stem-loop structure
containing the active miRNA. This hairpin undergoes
nuclear cleavage by the ribonuclease III Drosha, com-
plexed to the RNA-binding protein DGCR8/Pasha, to
generate a 70–100 nucleotides pre-miRNA. Notably, most
intronic miRNAs can be processed from unspliced intro-
nic regions before splicing catalysis; only a subset of
intronic miRNAs, named mirtrons, enters in the
cleavage. Afterward the pre-miRNA is transported to the
cytoplasm by the nuclear export factor exportin 5 (Xpo-5)
and then processed by the ribonuclease III Dicer, com-
plexed to TRBP (TAR RNA-binding protein), to form
the mature 22-nt miRNA: miRNA* duplex. The mature
single-stranded form is incorporated into the RNA-
induced silencing complex (RISC), while the complemen-
tary strand miRNA* is typically degraded.
Besides few exceptions, mammalian miRNAs base
pair imperfectly with their mRNA targets and induce
translational inhibition. Mature miRNAs loaded into
the RISC mediate translational inhibition of target
mRNAs through several different mechanisms. More-
over, RISC-miRNA complexes can shuttle mRNAs to spe-
cialized cytoplasmic compartments, the “P-bodies,” that
are enriched in mRNA-catabolizing enzymes. Conse-
quently, miRNAs also have an important effect on
mRNA degradation. Since each miRNA can target

FIG. 1 miRNA biogenesis. RNA polymerase II transcribes miRNA genes to generate the primary transcripts (pri-miRNAs). The cleavage is medi-
ated by the Drosha-DGCR8 complex, located in the nucleus. The
70-nucleotide-long product of the nuclear processing is a pre-miRNA, which
shows a short stem plus
2-nucleotide 30 overhang. This structure is the signature motif, recognized by exportin 5 (Exp5), a nuclear export factor.
Pre-miRNA constitutes a transport complex with Exp5 and its cofactor Ran. Ribonuclease III Dicer drives the second processing step (dicing) to
produce miRNA duplexes in the cytoplasm. The duplex is then separated, and either of the strands is stably associated with RNA-induced silenced
complex (RISC). The mature miRNA can inhibit the target genes by promoting translational repression and/or mRNA degradation.

1. Oxidative stress and aging

 miR-200c and oxidative stress
multiple transcripts and individual transcripts may be
subject to multiple miRNA regulation, it may prove dif-
ficult to find a biological process or function that is not, at
least in part, under the influence of miRNAs.
The identification of miRNA targets is crucial to eluci-
date the role played by each miRNA in a biological func-
tion. The rules that guide miRNA/mRNA interactions are
complex and still incompletely understood.8 The current
paradigm states that a complete pairing between the
30 UTR region of the mRNA target and the “seed sequence”
of the miRNA, a region centered on nucleotides 2–7, is
required for miRNA-mRNA-mediated inhibition. Thus
seed pairing is a necessary requirement for most target
prediction algorithms. However, recent studies have dem-
onstrated that also noncanonical miRNA binding can con-
fer target regulation.9 Specifically, some mRNAs are
targeted by miRNAs through recognition of 50 UTR or cod-
ing sequences. Moreover, “seedless” miRNA/mRNA
interactions have been also demonstrated.10,11
The dysregulation of miRNAs has been linked to dif-
ferent conditions, including oxidative stress increase; in
most cases the miRNA transcription is deregulated. In
this respect, recent investigations demonstrated that epi-
genetic modifications such as histone acetylation or DNA
methylation can play an important role.12
miR-200c and oxidative stress
In a miRNA screening of ECs exposed to H2O2, the
entire miR-200 family was induced by oxidative stress.13
The miR-200 family is composed of five members (miR-
200c, miR-141, miR-200a, miR-200b, and miR-429); in
humans, miR-200c and miR-141 are clustered on chromo-
some 12, whereas miR-200a, miR-200b, and miR-429
are clustered on chromosome 1. They can also be
TABLE 1 miR-200 family upregulation by different sources of ROS.
ROS
miRNA source Tissue/organ
miR-200c, miR-141, H2O2 Endothelium, myoblasts,
miR-200a, miR-200b, fibroblasts
miR-429
miR-200c BCNU Endothelium
miR-200c, miR-141, H2O2 Colon carcinoma, melanoma cells,
miR-200a, miR-200b, breast adenocarcinoma and
miR-429 ovarian
miR-200c H2O2 Primary hippocampal neurons
miR-200c chronic Trabecular meshwork cells
H2O2
treatment
miR-200c, miR-141 t-BHP Auditory cells
1. Oxidative stress and aging
5
classified on the basis of the seed sequences: miR-200c,
miR-200b, and miR-429 share the same seed sequence,
whereas miR-200a and miR-141 show a different one.
miR-200c is the most expressed family member and the
most induced by oxidative stress in ECs; in fact, its
expression increases nearly 30-fold upon 16 h treatment
of H2O2, which is a very high upregulation for a micro-
RNA; in fact, miRNAs are usually modulated around
two- or threefolds.13 miR-141 also is highly induced, sim-
ilarly to the cotranscribed miR-200c, and the other mem-
bers are all induced albeit to a lower level (around two- to
eightfold maximum). miR-200c upregulation upon H2O2
occurs also in murine myoblast, myotubes and in human
fibroblast.13 Other interventions causing redox imbal-
ance, such as the alkylating agent 1,3-bis(2 chloroethyl)-
1-nitrosourea (BCNU), a glutathione reductase inhibitor
that blocks the conversion of oxidized to reduced gluta-
thione, is also able to increase miR-200c expression. More-
over, BCNU-induced miR-200c increase is inhibited by
the free-radical scavenger N-acetyl-L-cysteine (NAC),
confirming the oxidative stress dependence of miR-200c
upregulation.13
The upregulation of miR-200 family is also observed in
different context and with different sources of oxidative
stress summarized in Table 1; therefore it seems to be a
conserved mechanism.
miR-200c is upregulated by chronic oxidative stress-
induced senescence in human fibroblasts and in human
trabecular meshwork cells.14 miR-200c and miR-141
upregulation is observed in a cell model of oxidative
stress by treatment of House Ear Institute-Organ of Corti
1 (HEI-OC1) cells with different concentrations of tert-
butyl hydroperoxide (t-BHP).15 miR-200 family induction
following H2O2 exposure has been confirmed also in
different cell lines, that is, mouse primary hippocampal
neurons,16 human and mouse immortalized fibroblasts,
Source Target Functions References
Human ZEB1 Apoptosis/senescence 13
Human ZEB1 Apoptosis/senescence 13
Human p38 ROS accumulation; 17
improved response to
chemotherapy
Mouse Unknown Unknown 16
Human Unknown Senescence 14
Mouse Unknown Unknown 15
6 1. Oxidative stress and miR-200c

colon carcinoma, mammary gland epithelial cells and
human cell lines, melanoma cells, kidney cells, breast ade-
nocarcinoma, and ovarian adenocarcinoma.17 miR-141
and miR-200a, which display the same seed sequence,
target p38α mitogen-activated protein kinase (MAPK).
p38α is a signaling molecule that modulates cellular
responses to stress18 and is involved in proliferation
and survival control of many cell types.19 Indeed, p38α
redox-sensing function is essential in the control of tumor
development.20 Therefore enhanced expression of miR-
200 family miRNAs not only mimics p38α deficiency
and increases tumor growth in mouse models but also
improves the response to chemotherapeutic agents.
In keeping the modulation of miR-200c and other
miR-200 family expression has been exploited to sensitize
different tumors to therapy.21–24
miR-200c induces apoptosis and senescence via
ZEB1 inhibition
The transcriptional factor zinc finger E-box-binding
homeobox 1 (ZEB1) is a direct target of the entire
miR-200 family and inhibits the transcription miR-200
family in a negative feedback loop.25 This loop has been
investigated in the epithelial-mesenchymal transition
(EMT) of many tumors, where miR-200 family expression
levels decrease by determining the increase of their target
protein ZEB1, which is an inhibitor of the adhesion mol-
ecule E-cadherin. Therefore the decrease of miR-200
determines the lack of cell adhesion causing metastasis.25
The increase of miR-200c caused by oxidative stress in
ECs downregulates ZEB1 that in nontumor cells elicits
apoptosis and senescence, a state of permanent cell growth
arrest in response to oxidative stress, recapitulating the
oxidative stress-induced phenotype.13 Indeed the forced
expression of ZEB1 in ECs overexpressing miR-200c
partially rescued this phenotypes.13
The molecular mechanisms elicited by oxidative stress
in ECs are depicted in Fig. 2.
miR-200c upregulation by oxidative stress in ECs
occurs at the transcriptional level, since H2O2 upregulates
also the pre-miR-200c and this upregulation requires the
tumor suppressors protein p53 and the retinoblastoma
protein (pRb).13 Furthermore, ZEB1 transcription is
under the control of pRb/E2F.26 In ECs, H2O2 induces
a rapid pRb dephosphorylation via a serine-threonine
phosphatase named PP2A27,28; this allows pRb binding
and inhibition of the E2F transcriptional activity factor
on ZEB1 gene.26 Therefore, upon oxidative stress, the
upregulation of miR-200c inhibits ZEB1 protein transla-
tion and induces ZEB1 mRNA degradation; in addition,
ZEB1 mRNA decreases because of a pRb/E2F-dependent
mechanism. ZEB1 demise induces a further upregulation
of miR-200c, since it is a transcriptional inhibitor of miR-
200c,25 reinforcing the upregulation of miR-200c.13

FIG. 2 miR-200c upregulation in ECs occurs via p53- and pRb-dependent mechanisms. H2O2 induces a rapid dephosphorylation of pRb via a
serine-threonine phosphatase (PP2A)-dependent mechanism, repressing transcription factor E2F activity. ZEB1 is under pRb/E2F control. Therefore
H2O2 dephosphorylating pRb causes ZEB1 mRNA and protein level downregulation. ZEB1 is a transcriptional inhibitor of miR-200c; consequently,
its decrease provokes miR-200c upregulation. miR-200c transcriptional upregulation is also induced by p53, which is induced by oxidative stress. p53
in turn induces p21, which sustains pRb dephosphorylation, further decreasing ZEB1. ZEB1 downregulation induces p21 transcription, being ZEB1 a
transcriptional inhibitor of p21. Finally, ZEB1 demise provokes growth arrest, senescence, and apoptosis.

1. Oxidative stress and aging

 miR-200c and oxidative stress 7
Finally, oxidative stress induces p53 activity that is
known to induce the cyclin-dependent kinase inhibitor
p21Waf1/Cip1/Sdi1 (p21) transcription that reinforce pRb
dephosphorylation.29 Additionally, p53 induces apopto-
sis and miR-200c transcription, enhancing miR-200c
increase. Finally, ZEB1 is a transcriptional inhibitor of
p2130; therefore its downregulation further increases
p21. This molecular circuitry induces growth arrest, apo-
ptosis, and senescence, which are all the effects induced
by oxidative stress (Fig. 2).

miR-200c oxidative stress and endothelial

dysfunction
A fundamental molecular circuit for vascular homeo-
stasis is the one existing among sirtuin 1 (SIRT1), endo-
thelial nitric oxide synthase (eNOS), and forkhead box
O1 (FOXO1) proteins. These proteins play a key role in
endothelial function, since they are involved in oxidative
stress resistance (Fig. 3). SIRT1 plays an important role in
cell senescence, having an antiinflammatory and antiox-
idant role.31 Indeed, it is known that ROS and aging cause
a reduction in the expression of SIRT1, causing senes-
cence and endothelial dysfunction, and the activation
of SIRT1 improves the response to oxidative stress.32 Fur-
thermore, SIRT1 promotes mitochondrial biogenesis and
NO production released by eNOS.31,32
In turn, NO increases the stability of mRNA and SIRT1
protein, confirming the existence of a positive circuit
between eNOS activity and SIRT1 expression levels.32
In the molecular circuit existing between eNOS and
SIRT1, the transcription of FOXO1 plays a very
important role.
In fact, FOXO1 is a direct target of SIRT1 deacetylation;
deacetylation of FOXO1 induces its transcriptional activ-
ity on the promoter of SIRT1 and of CAT and manganese
superoxide dismutase (MnSOD) antioxidant enzymes.32
The correct functioning of the SIRT1/eNOS/FOXO1
molecular circuit plays a fundamental role in endothelial
survival and in vasodilation (Fig. 3).
An important player in oxidative stress response and
modulation is the p66 isoform of ShcA protein
(p66Shc), a key regulator of mitochondrial ROS produc-
tion by a variety of different stimuli.33 Oxidative stress
induces the phosphorylation of p66Shc protein in serine
36 residue (Fig. 3), which causes an increase in ROS in
three cellular districts:
- in the nucleus, where it inhibits FOXO134;
- in the mitochondria, where it binds to cytochrome c,
acting as an oxidoreductase enzyme that generates
ROS35;
- in the plasma membrane, where it activates NADPH
oxidase.36
FIG. 3 miR-200c disrupts the regulatory loop existing among eNOS/
SIRT1/FOXO1. miR-200c inhibits situin1 (SIRT1)/endothelial nitric
oxide synthase (eNOS)/forkhead box O1 (FOXO1) regulatory loop,
by targeting directly all of them. This loop controls different cell func-
tions. Specifically, miR-200c increases ROS production by two mecha-
nisms: (i) it decreases ROS scavengers by targeting peroxiredoxin 2
(PRDX2) and forkhead box O1 (FOXO1), a transcription factor required
for catalase (CAT) and manganese superoxide dismutase (MnSOD)
expression; (ii) it sustains ROS production via p66Shc phosphorylation
in serine 36. miR-200c decreases NO production by targeting eNOS.
miR-200c induces senescence targeting SIRT1 deacetylase that causes
the following: (i) eNOS acetylation increase further reducing the bio-
availability of NO that is a molecule that stabilizes SIRT1 mRNA and
protein, thus provoking a further SIRT1 decrease, and (ii) acetylation
of FOXO1 increase causing FOXO1 transcriptional activity inhibition.
In addition, miR-200c targets FOXO1 both directly and indirectly via
a p66Shc phosphorylation-dependent mechanism that inhibits FOXO1
transcriptional activity, decreasing CAT and MnSOD expression, fur-
ther sustaining ROS production. In conclusion, ROS-induced miR-
200c disrupts SIRT1/FOXO1/eNOS loop promoting cell senescence
and activating a complex molecular pathway that sustains oxidative
stress and miR-200c upregulation.
miR-200c has been shown to target directly SIRT1, eNOS,
and FOXO137; ROS-upregulated miR-200c decreases NO
and increases the acetylation of SIRT1 protein targets, such
as FOXO1 and p53. p53 acetylation increases its transcrip-
tional activity on miR-200c and also its ability to induce
senescence and apoptosis. FOXO1 acetylation inhibits its
transcriptional activity, decreasing the expression of antiox-
idant enzymes such as CAT and MnSOD, therefore increas-
ing ROS production. Consequently, miR-200c increases
ROS and induces the phosphorylation of p66Shc protein
in Ser-36, which in turn inhibits the transcriptional activity
of FOXO1, reinforcing this molecular circuit (Fig. 3).

1. Oxidative stress and aging

8 1. Oxidative stress and miR-200c

Moreover, miR-200c has been demonstrated to target
directly also peroxiredoxin 2,38 a selective scavenger for
H2O2,39 further inducing oxidative stress.
Aging is a process of functional deterioration of an
organism that can occur at different levels (cellular, tis-
sue, and organelle), bringing life to end. One of the
most relevant players in the aging process and age-
related disorders is cellular senescence. In humans
and in many animal models, an age-dependent increase
in oxidative stress has been demonstrated, showing
that increased ROS can be both a consequence and a
cause of aging.
In keeping, the in vitro results obtained in ECs are also
recapitulated in different in vivo oxidative stress models,
namely, in human skin fibroblasts from elderly donors,
femoral arteries of old mice, and in a mouse model of ische-
mia of the hind limbs.37 In all cases, miR-200c was higher
than the control, and its targets, that is, SIRT1, eNOS, and
FOXO1, were decreased. In the mouse model of hind limb
ischemia, treatment with anti-miR-200c restored the
expression of these proteins and limb perfusion.37
Aging increases miR-200c expression also in other tis-
sues different from the aforementioned described and all
summarized in Table 2. These include skeletal muscle
from rhesus monkeys40 and human liver.41
TABLE 2 miR-200c upregulation in aged tissues.
Tissue/organ Source References
Skeletal muscle Monkey 40
Liver Human 41
Skin fibroblast Human 37
Femoral artery Mouse 37
Applications to other diseases or conditions
miR-200c is increased in different pathological condi-
tions associated to an increase of oxidative stress (sum-
marized in Table 3) such as acute hind limb ischemia in
skeletal muscle,13,37 ischemia and ischemia/reperfusion
in the brain,42 in different tissues in diabetes,43–47 high
glucose-induced cardiac hypertrophy,48 nonalcoholic
steatohepatitis,49 and Duchenne muscle dystrophy.50
Moreover, miR-200c and the entire miRNA family are
deregulated in many different types of cancers, since they
are deeply involved in the EMT of tumor cells.51
In many of the previously described disease conditions,
the inhibition of miR-200c was able to recover most of
thedeleterious effects caused by miR-200c increase.37,48–50
miR-200c expression is also increased in cardiotoxicity
induced by anthracyclines, such as doxorubicin (DOX)
treatment in mice and in human cardiac mesenchymal
progenitor cells.52
Furthermore, circulating miR-200c levels are increased
in children with familial hypercholesterolemia53 and in
adult patients with carotid artery plaques,54 both condi-
tions associated with enhanced ROS.
Moreover, miR-200c increases also in atherosclerotic
carotid plaques in human patients, and it is more
enhanced in unstable than stable plaques.54
In conclusion, miR-200c increases in an age-dependent
manner and in different pathological conditions that dis-
play an increase of ROS. miR-200c upregulation causes a
decrease of antioxidants, an increase of ROS, and a
decrease of NO, all features associated with aging.
Therefore the comprehension of miR-200c roles and
targets may support the analysis of new therapeutic strat-
egies to delay and treat age-related modifications and
aging signs.

TABLE 3 miR-200c modulation in diseases.

Disease Regulation Tissue/organ Source References

Cancer Down/up Different tissues/organs Human 51

Ischemia Up Skeletal muscles Mouse 13,37
Ischemia/reperfusion Up Brain Mouse 42
Cardiac hypertrophy Up Cardiomyocytes Rat 48
Nonalcoholic steatohepatitis Up Liver Human 49
Duchenne muscle dystrophy Up Different muscles, myoblasts Mouse, Human 50

Familial hypercholesterolemia Up Plasma Human 53

Atherosclerosis Up Carotid arteries, plasma Human 54
Diabetes Up Heart, VSMC, pancreatic beta cells, renal arteries Mouse/human 43–47

1. Oxidative stress and aging

 References
Summary points
• ROS play a causative pathological role in different
cellular processes implicated in growth arrest,
senescence, and cell death.
The cells have developed a series of enzymatic and
nonenzymatic antioxidant defenses to maintain the
intracellular redox state homeostasis.
miRNAs are short noncoding RNAs that modulate
the stability and/or the translational efficiency of
target messenger.
Each miRNA can regulate multiple mRNAs, and
each mRNA can be regulated by many miRNAs.
miRNAs can act as key regulators in cell
proliferation and cell death, early development,
apoptosis, metabolism, and cell differentiation.
Dysregulation of miRNAs has been associated with
different diseases.
• miR-200 family is induced by different sources of
oxidative stress and in many different nontumor and
tumor cells.
miR-200 family is composed of five members: miR-
200a, miR-200b, miR-200c, miR-141, and miR-429.
miR-200c is the most upregulated family member in
ECs upon H2O2 treatment.
miR-200c upregulation by H2O2 in ECs is
transcriptional and involves p53 and pRb.
ZEB1 is a direct target of the entire miR-200 family
and inhibits the transcription of miR-200 family in a
negative feedback loop.
ZEB1 plays important functions in the tumor
progression process and in metastatic diffusion
inhibiting E-cadherin.
ZEB1 demise induced by oxidative stress in ECs is
caused by miR-200c- and pRb/E2F-dependent
mechanisms.
ZEB1 downregulation in nontumor cells is
responsible for cell growth arrest, apoptosis, and
senescence induction.
• The loop existing among SIRT1, eNOS, and FOXO1 is a
molecular regulatory circuit involved in the
maintenance of vascular homeostasis.
These proteins are involved in resistance to
oxidative stress and play fundamental roles in EC
survival and vasodilation.
miR-200c destroys the loop existing between SIRT1,
eNOS, and FOXO1 targeting all of them.
miR-200c disrupting this loop increases ROS and
decreases NO, causing endothelial dysfunction.
Moreover, miR-200c enhances oxidative stress
inducing p66Shc protein phosphorylation in Ser36 that
sustains ROS increase.
miR-200c is upregulated in different
pathophysiological conditions associated with an
increase of ROS including, aging, diabetes,
nonalcoholic steatohepatitis, diabetic cardiac
1. Oxidative stress and aging
9
hypertrophy, hind limb ischemia, brain ischemia
reperfusion, Duchenne muscle dystrophy, familial
hypercholesterolemia, and atherosclerosis.
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 C H A P T E R

2
Caloric restriction, reactive oxygen species,
and longevity
Miyuki Kobara, Hiroe Toba,Tetsuo Nakata
Department of Clinical Pharmacology, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan

List of abbreviations Adequate CR extends healthy life span, whereas exces-

sive CR with malnutrition is harmful. Therefore, CR to an
AMPK adenosine 30 ,50 -monophosphate-dependent protein kinase
CR caloric restriction appropriate extent and for a sufficient duration to maxi-
FoxO forkhead transcription factor O mize healthy life span is important. Treatment costs for
GPx glutathione peroxidase age-related diseases are now markedly increasing in
hsCRP high-sensitivity C-reactive protein the aging society, and thus the cost-effective prevention
IGF-1 insulin growth factor 1
of age-related diseases is desired. CR has favorable cost
IL-1β interleukin-1β
NFkβ nuclear factor kappa β
benefits. In this chapter, we summarize the effects of
PGC1-α peroxisome proliferator-activated receptor-γ coactivator 1-α CR in a number of organisms and describe the main pro-
ROS reactive oxygen species posed signaling pathways for the beneficial effects of CR,
SIRT1 silent information regulator 1 with a focus on oxidative stress.
SOD superoxide dismutase
TNF-α tumor necrosis factor α
TOR target of rapamycin
CR in animals

Introduction CR was initially reported by McCay in 1935, who

Aging is inevitable and progressive phenomena in all
living organisms. The accumulation of damage leads to
functional decline and structural deterioration in organs
in association with increases in susceptibility to diseases,
ultimately resulting in death as the final stage. Age-
related diseases, such as cancer, cardiovascular diseases,
stroke, and neurally degenerative diseases, are now the
leading causes of mortality worldwide.1 In antiaging
research conducted to date, numerous interventions to
retard the aging process have been examined. Among
antiaging interventions, caloric restriction (CR), a reduc-
tion in caloric intake without malnutrition, is a powerful
nongenetic intervention that prolongs maximum and
mean life spans and suppresses age-related diseases.2–4
These favorable phenomena are conserved in many spe-
cies from yeast to mammals.2–5 Therefore, elucidation of
the mechanism responsible for the beneficial effects of CR
may reveal targets for age-related disease retardation and
healthy life span elongation.
showed that a reduced food intake extended the life span
of rats.6 Subsequent studies in this field confirmed favor-
able life span elongation by CR in many organisms from
worms to nonhuman primates.2 CR also retarded age-
related cancers, cardiovascular diseases, stroke, diabetes,
dyslipidemia, and neural degenerative diseases in these
short-lived organisms.7 These age-related diseases are
major causes of mortality, and neural disorders decrease
the quality of life and shorten the health span of the
elderly.
As a bridge from these short-lived animals to humans,
prospective examinations on the effects of CR in rhesus
monkeys were initiated by two independent associations
in the United States from the late 1980s: the Wisconsin
National Primate Research Center based at the University
of Wisconsin-Madison (WNPRC) study and the National
Institute on Aging (NIA) study. In the WNPRC study,
30% CR in adult rhesus monkeys significantly delayed
age-associated pathological conditions and improved
all-cause mortality.8 On the other hand, in the NIA study,

Aging 11 Copyright © 2020 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/B978-0-12-818698-5.00002-X
12 2. Caloric restriction and longevity
all-cause mortality did not improve in CR monkeys even
though similar CR was conducted; however, measure-
ments on the metabolic health index and overall function
showed that old-onset CR exerted beneficial effects.9
Although the impact of CR on mortality differs, compar-
isons of important evidence from these long-term studies
demonstrated that CR resulted in a favorable lipid profile
and reduced susceptibility to cancer, type 2 diabetes, and
cardiovascular diseases.10
Mechanisms responsible for beneficial effects of
CR in animals
Oxidative stress and inflammation
In the aging process, tissue and cellular damage
induced by oxidative stress and inflammation accumu-
late.11 Oxidative stress also enhances the progression of
age-related diseases, including cancer, neurodegenera-
tion, cardiovascular diseases, and diabetes.12 CR studies
using animal models and humans demonstrated that CR
reduced the production of ROS, resulting in decreases in
lipid peroxidation, protein carbonylation, and DNA/
RNA oxidation, and also increased the antioxidant capac-
ity, including glutathione peroxidase (GPx), superoxide
dismutase (SOD), and catalase.7,12–16 CR was shown to
suppress the age-related and oxidative stress-related dis-
eases of cancer, neurodegeneration, and cardiovascular
diseases.12 It also inhibited inflammation and reduced
the levels of inflammatory cytokines, such as tumor
necrosis factor α (TNF-α) and interleukin-1β (IL-1β).2
Among several sources of ROS production in the aging
process, damaged mitochondria are important.17
Mitochondrial ROS were shown to induce mitochondrial
DNA mutations, leading to an impaired mitochondrial
respiratory chain, while a deficiency in mtDNA polymer-
ase promoted premature aging in mammals.18 Previous
studies found that CR attenuated mitochondrial ROS
production from the respiratory chain and preserved its
function.7,19,20 Therefore, life span elongation by CR
may be due to, at least in part, antioxidant activities
and the preservation of mitochondrial function.19 How-
ever, the importance of antioxidants for CR-induced life
span elongation remains controversial. One of the rea-
sons for this is the absence of an effect of the deletion
of NF-E2-related factor 2, a well-known transcription fac-
tor of antioxidant enzymes, on CR-induced life span
elongation.21
Moreover, Wang et al. reported that CR-induced mild
oxidative stress by mitochondria plays positive and inte-
grative roles as adaptive phenomena, which are beneficial
rather than detrimental in the aging process.17 Previous
studies reported that CR-induced ROS also slowed aging
1. Oxidative stress and aging
and prevented the progression of cancer.22 Therefore, the
roles of ROS in the effects of CR may be beneficial and det-
rimental depending on their source and volumes.
Insulin/IGF-1 pathway
During nutrient restriction, growth signaling by the
insulin/IGF-1 pathway is suppressed as an adaptation,2
and animal models of the genetic suppression of the
insulin/IGF-1 pathway showed an extended life span.2,23
The CR-induced suppression of the insulin/IGF-1 signal-
ing activates the forkhead family of transcription factors
(FoxO) through phosphatidylinositol-3-kinase (PI3K) and
Akt inhibition.24,25 Since FoxO3 is a transcription factor
of several antioxidant genes,26 this signaling pathway con-
tributes to the CR-induced inhibition of oxidative stress.
However, the contribution of this signaling pathway to
CR-induced life span elongation has not been fully clari-
fied, because CR could elongate life span in genetic knock-
out animals of IGF-1 signaling.2 Therefore, the insulin/
IGF-1 signaling pathway is enhanced during CR and con-
tributes to its beneficial effects; however, the dependency
of CR-induced life span elongation on this signaling path-
way is limited.
The TOR pathway and autophagy
The TOR signaling pathway is another nutrient sensor
that is suppressed by CR.27 As another candidate path-
way for CR-induced longevity, the suppression of TOR
signaling has been confirmed, and its deletion has been
shown to extend the life span of many organisms.2,27
TOR suppression under nutrient starvation conditions
enhanced autophagy, which removes damaged mito-
chondria, a major source of ROS production, and pre-
serves their function.28,29
The AMPK pathway
AMPK is an energy sensor of nutritional starvation.
CR activates AMPK in association with declines in the
AMP/ATP ratio in many organisms, and the deletion
of AMPK blunts CR-induced life span elongation.30
AMPK regulates many intracellular signaling pathways,
including the activation of FoxO,30 SIRT1, peroxisome
proliferator-activated receptor-γ coactivator 1-α (PGC1-
α), and the suppression of TOR.4 These factors collaborate
with the suppression of oxidative stress. Another path-
way for AMPK-mediated ROS reductions is the preserva-
tion of NADPH levels through the suppression of acetyl
CoA carboxylases.31
Another random document with
no related content on Scribd:
dezer namen. Van sommige vleinamen zijn verkleinnamen afgeleid
in alle of schier alle boven vermelde verkleinvormen. Van den
vleinaam H a y o , bij voorbeeld, zijn afgeleid de verkleinnamen
H a e i s e , H a e i t e , H a e i t s e , H a e i k e en H a e i t s j e (in
Nederlandsche spelling H a a i s e , enz.); van B o a y e (B o y e )
komen B o a i t e , B o a i t s e , B o a i k e , B o a i t s j e (volgens
Nederlandsche spelwijze B o i t e , enz.); van J e l l e zijn afgeleid
J e l s e , J e l t e , J e l t s e , J e l k e , J e l t s j e , enz.

Nog een andere naamsvorm is van de vleinamen afgeleid; te weten:

de patronymicale vorm op ing eindigende. Deze vorm, het echte, het
ware Oud-Germaansche patronymicum aanduidende, kan dus van
oorsprongswegen geene eigenlijke mansvóórnamen in ’t leven
roepen; hij duidt veeleer een maagschapsnaam aan, en is dan ook,
als inga, ink of ing, veelvuldig bij de Friesche, de Sassische en de
Frankische volksstammen, die gezamenlijk het Nederlandsche volk
uitmaken, als uitgang van maagschaps- of geslachtsnamen in
gebruik. Niettemin, sommigen van deze patronymicale, op ing
eindigende namen zijn heden ten dage, als bij misverstand (’t welk in
dezen zin ook bij andere Germaansche volken voorkomt), nog bij de
Friezen als mansvóórnamen in volle geijkt gebruik. Als zoodanigen
mogen hier vermeld worden: A l i n g , A m e l i n g , A s i n g en
A s i n g a , B a l i n g , B a l l i n g , B o a y i n g (B o o y i n g ),
Ebbing, Eling, Haring, Hemsing, Henning,
N a n n i n g , Ts j a l l i n g (T j a l l i n g ), W a l i n g en nog enkele
anderen. [217]

De hedendaagsche Friezen hebben de gewoonte hunner

voorouders om de mans- en vrouwenvóórnamen te verminken en te
vervormen door vleivormen en verkleiningsvormen (overigens
geenszins eene navolgenswaardige gewoonte), getrouwelijk
aangehouden. Zij breiden dit gebruik zelfs nog meer uit. Niet enkel
dat zij die verkorte en verknoeide namen hunner voorvaders trouw in
gebruik houden, als of die wannamen heel wat eigens en bijzonders
waren, maar zij blijven ook nog steeds voortgaan met dit verknoeien
hunner namen in vlei- en verkleinvormen. Vele reeds zeer verkorte
en verdraaide namen, vooral vrouwennamen, mishandelen zij rustig
verder, zoo dat die namen ten langen leste gansch onkenbaar
worden. Van de volledige namen C a t h a r i n a en M a r g a r e t h a ,
beiden van Griekschen oorsprong en beiden van schoone
beteekenis (te weten: „de reine” en „de perel”), was bij de Friezen in
den loop der eeuwen reeds T r y n t s j e en G r y t s j e (T r ij n t j e en
G r i e t j e ) geworden. Maar het schijnt als of voor de
hedendaagsche Friezen die namen nog niet genoeg verkort en
verbasterd waren. Immers maken zij in het dagelijksche leven de
wannamen T i n e of T y n k e en N i n e of N y n k e van T r y n t s j e
of C a t h a r i n a , en K i k e van G r y t s j e of M a r g a r e t h a . Even
zoo verknoeit men D i r k of D u r k (voluit D i e d e r i k ) wel tot
D u y e , de vrouwennamen D i r k j e (beter D i e d e r i k a ) tot
D u k k e , S i b b e l t s j e tot P i b b e , J e l l e wel tot J e y e ,
J e l t s j e tot J e i of J e i k e , A e l t s j e (A a l t j e ) en B a u k j e tot
A e y e en B a e y e , A u k j e en B a r t e l t s j e tot A k k e en
B a k k e , H y l k j e en H i l t s j e tot H i k e en H i k k e , E e l k j e tot
E k e ; Ts j e a r d t s j e (T j e e r d t j e ) tot K e k k e , L u t s k e tot
L u k k e of L o k k e , J i t s k e tot J i k k e , R o m k j e tot P o m m e ,
F r o u k j e tot P o i , (S j o e r d t s j e ) tot S j u t t e , enz., enz. Deze
nieuwerwetsche en leelijke naamsmisvormingen van den laatsten
tijd worden thans in den regel niet meer in de schrijftaal opgenomen,
ofschoon A k k e , B a e y e (B a a y e ) en J e i k e ook al een enkele
maal in de boeken van den burgerlijken stand vermeld staan.
Intusschen—ware ’t honderd of twee-honderd jaren vroeger
opgekomen om R o m k j e te mismaken tot P o m m e en
S i b b e l t s j e tot P i b b e , licht hadden wij thans ook Friezinnen die
als P o m m e en P i b b e in het kerkelijke doopregister en bij den
burgerlijken stand te boek stonden. En [218]de geleerden, die
honderd jaren na ons zullen leven, zouden zich dan mogen
inspannen zoo veel ze wilden en navorschen wat ze wilden, de
oorsprong en de beteekenis van de namen P o m m e en P i b b e en
P o i , dan zekerlijk als zeer eigenaardig Friesch vermeld, zoude hun
een raadsel moeten blijven.

Nemen wij als een enkel voorbeeld om aan te toonen hoe zeer de
oude, volledige namen heden ten dage in Friesland verbasterd zijn,
den naam E k e in behandeling. E k e , zoo heeten eenige mij
bekende Friezinnen, althans zoo worden zij in het dagelijksche leven
genoemd. Eene enkele staat ook werkelijk in de kerk en ten
gemeentehuize als E k e geboekt. In den regel echter, die E k e
genoemd worden, staan als E e l k j e te boek. E k e ! korter kan het
niet! Want dat ke is slechts een aanhangsel dat den verkleinvorm
maakt; lam of laem, bij voorbeeld, wordt lamke, lammetje, in het
Friesch. Neemt men dat aangehangene ke weg, dan blijft er van den
naam E k e anders niet over als eene enkele E. Is dat nu een naam,
een eigene Friesche naam? Wel neen! E k e is een vleivorm, een
poppenamme van E e l k j e , dat weet men nog. En de naam
E e l k j e is op zijn beurt weêr een verkleinvorm, door achtervoeging
van het aanhangsel je, van den mansnaam E e l k e . Zoo maakt
men, door ze den verkleinvorm te geven, vrouwennamen van
mansnamen: P y t t s j e , (P i e t j e ) van P i e t (P i e t e r , P e t r u s ),
B a u k j e van B a u k e (B a v o ), enz. Met E e l k e zijn wij
intusschen nog lang niet waar wij wezen moeten. Immers de
mansnaam E e l k e is op zich zelven ook weêr een verkleinvorm,
door achtervoeging van ke gemaakt. De Friezen toch, hierin
onderscheiden van andere Germaansche volken, die slechts hunnen
knapen, zoo lang ze nog kleine kinderkens zijn, met verkleinnamen
noemen—de Friezen hielden en houden die namen in
verkleinvormen ook in gebruik als de kinderen tot knapen en
jongelingen, zelfs tot mannen zijn opgegroeid. Nevens E e l k e staat
E e l t j e , het eerste met den Frieschen, het laatste met den
Hollandschen verkleinvorm; beide mansnamen beteekenen het
zelfde, beiden zijn het verkleiningsvormen van E l e . In der daad
worden zij, die E e l k e of E e l t j e heeten, in den dagelijkschen
omgang dan ook wel E l e , genoemd. Maar met E l e zijn wij [219]ook
nog niet tot den oorspronkelijken vorm des naams gekomen. Ook
E l e is weêr een verkorte, een versletene vorm. E l e staat in de
plaats van E d e l e , en is door zeer gewone uitslijting van de d (de)
ontstaan. Ook in het Hollandsch zegt men wel eêl voor edel,
vereêlen voor veredelen, vooral in dichterlijken stijl. E d e l e is de
volle vorm van dezen naam, die onder ons nog in zoo menigen
verschillenden verklein- en vleivorm voorkomt. E d e l e is een naam
die eene beteekenis heeft, die eenen zin te kennen geeft. Immers de
naam E d e l of E d e l e beteekent in der daad de edele, de edele
man. E d e l of E d e l e is de nieuwere vorm van den Oud-Frieschen
mansnaam A t h a l , dat is A d e l . Zoo heette, volgens de
overlevering, de tweede Prins van Friesland, de zoon van den
eersten, van F r i s o , en hij leefde 245 jaren voor Christus’ geboorte.
En A t h a l of A d e l , dien naam hebben vele oude Friezen
gedragen. Ook is de naam van het roemruchtige Oud-Friesche
geslacht A d e l e n er van afgeleid, en niets als een patronymikum
van A d e l . 6 De vrouwelijke vorm van A t h a l of A d e l is A t h a l a
of A d e l a , en dezen naam hebben zekerlijk vele Friezinnen in den
ouden tijd gedragen. Welke vader gaf niet gaarne zulken schoonen
naam, schoon in beteekenis en schoon in klank, aan zijn dochterke?
Ook was deze naam niet alleen bij de Friezen, maar bij alle Oud-
Germaansche volken in gebruik. Ook bij de oude Franken, die
gedeeltelijk de Germaansche voorouders der hedendaags geheel
verwaalschte Franschen geweest zijn. De naam A d e l a der
Frankische vrouwen is nog als Adèle bij de hedendaagsche
Fransche dames in gebruik. Andere volken, niet het minst ook de
Hollanders, hebben ook hier in, als in zoo menige andere zaak, de
Franschen nagevolgd, en zoo is nu Adèle vrij wel een
kosmopolitische naam geworden.

De Friezen echter, trouw gehecht aan hunnen Germaanschen

volksaard, hebben zich steeds te edel geacht om zulke en
[220]andere Fransche en verfranschte namen en naamsvormen te
dragen. Zij hebben ze steeds, met betamelijke minachting, van zich
gewezen. Maar zoo er nu eene Friezin is, wier verknoeide naam
E k e haar verdriet, of zoo er eene Friesche moeder of grootmoeder
is, die er iets op tegen heeft dat haar kind of kleinkind E e l k e of
E e l t j e zal heeten zoo het een knaap is, of E e l k j e als het een
meiske is—wel nu—met die, en met honderden andere soortgelijke
verkorte en verknoeide namen staat of valt haar Friesdom niet. Dat
men dan de volle, onverbasterde, oude en schoone namen A d e l
en A d e l a , vol beteekenis, weêr in gebruik neme en in eere
herstelle! Bij dien vrouwennaam hoede men zich echter wel dat men
er geen Fransche Adèle van make! Men late, bij ’t uitspreken, den
klemtoon of de stemsate rusten op de eerste en op de derde
lettergreep, op A en a. Zoo draagt men eenen echten Frieschen
naam, in volledigen, schoonen vorm.

Bij ’t verknoeien en verbasteren van de oude, oorspronkelijke

Friesche mans- en vrouwennamen spelen de verkleinvormen eene
zeer groote rol. Wij hebben boven reeds gezien dat de namen
E e l k e en E e l t j e , E e l k j e en E k e alle vier verkleinvormen
vertoonen door de aanhangsels ke, tje, en je, en deze vormen
vinden wij terug in een zeer groot aantal hedendaagsche namen,
zoo wel van mannen als van vrouwen. Bij voorbeeld in A u k e en
B a u k e , in E p k e , H a r k e en Y k e , in W i l k e en U u l k e
(U i l k e ), in F o l k e en Ts j e p k e (T j e p k e ), in S i p k e en
W o p k e ; dan in H a e n t s j e (H a a n t j e ) en H a n t s j e , in
J e n t s j e en Y n t s j e , in L u u t s j e , R i n t s j e en W i l t s j e ,
(H a n t j e , enz.) allen mansnamen. En in A u k j e en B a u k j e ,
Y m k j e en S j o u k j e , F r o u k j e en H o u k j e , F e i k j e ,
F o e k j e en F o k j e , H i s k j e en L i s k j e , H y l k j e en
L i e u w k j e , L o l k j e en N a m k j e met O f k e en O e d s k e ,
M a e i k e en M i n k e , R i e m k e en R i n s k e , S y t s k e en
W y t s k e , S a e p k e (S a a p k e ) en S w o b k j e , Te a t s k e en
Y f k e , allen vrouwennamen. Deze en soortgelijke namen erkent
nog iedereen als verkleinvormen, omdat de aanhangsels ke, tje en je
nog heden zoowel in de schrijf- als in de spreektaal in volle gebruik
zijn. Anders is het met de Friesche namen die uitgaan op
verkleinende aanhangsels welke in de hedendaagsche spreek- en
[221]schrijftaal niet meer voorkomen. Slechts de man die de Oud-
Friesche taalkunde in het bijzonder heeft beoefend, verstaat dat er
verkleinvormen schuilen in de namen A t s e en W a t s e , S y t s e
en W y t s e , R e i t s e , W e i t s e en S w e i t s e , D o a i t s e en
H o a i t s e , H o a t s e en H a i t s e , F e t s e en J e t s e , T j i t s e
en R i t s e , in R i e n t s , B i e n t s en G r a e t s , in U u l t s e n en
L u u t s e n , in Y t s e n en M o n t s e n , in D o u w t s e n , J e l t s e n
en M a r t s e n ; verder in A b e l e en H e a b e l e , A n d e l e en
B a r t e l e , E a b e l e en D o e k e l e , L y k l e en R y k l e ,
S e a k e l e en S i b b l e , J a k k e l e , N a m m e l e en O e b e l e .
En toch is dit het geval. Het aanhangsel tse (ts, tsen) is een Oud-
Friesche verkleinvorm, en le eveneens. Dit blijkt ook hier uit dat
velen dezer namen nog heden ook in onverkleinde vormen bij ons in
gebruik zijn. Bij voorbeeld: A t t e (de vrouwelijke verkleinvorm
A t s j e is vooral niet zeldzaam), F e i t e , H a i t e en H o a i t e ,
T j i t t e of T i e t e , M o n t e , A b e , E a b e , B a r t , D o e k e ,
N a m m e n (uit den verkleinvorm N a m m e l e is de n van den
oorspronkelijken vorm N a m m e n gesleten, omdat de n en de l te
veel op elkanderen stooten), O e b e (O b b e of U b b o ), enz. Het
Oud-Friesche verkleinende aanhangsel ts is volkomen een en het
zelfde als het Nieuw-Friesche aanhangsel ke. Immers zijn k en ts of
tsj wisselletters in het Friesch. De ts of tsj neemt in het Friesch en
Engelsch dikwijls de plaats in van de k in de verwante Germaansche
talen. Men denke aan tsjerke en church tegenover kerk en kirche,
aan tsjiis en cheese tegenover kaas en käse.

De hedendaagsche Friesche uitspraak van het Hollandsche

verkleinende aanhangsel tje als tsje, bij voorbeeld bytsje voor beetje,
potsje voor potje, Pytsje voor Pietje, enz. is eigenlijk en
oorspronkelijk tjse, tse, of ke. Zoo dat men eigenlijk byttsje (byt-tsje
= bytke) moest schrijven, met Pyttsje, pottsje, enz. Immers de
woorden byt, pot, Pyt eindigen uit zich zelven reeds op t, en ’t
aanhangsel tje of tse of tjse begint er mede. Even eens moest men
A t t s e (At-tse = At-ke = At-tje = de kleine A t t o ) schrijven, met
Ts j i t t s e , L u u t t s e n , enz., in plaats van A t s e , Ts j i t s e ,
L u u t s e n . Die aangaande deze ts = k, en tse of tjse = ke als
verkleinend aanhangsel iets naders weten wil, leze eene zeer
belangrijke aanteekening van onzen taalgeleerde J. H. Halbertsma,
bij zijn verhaal De treemter fen it Sint-Antoni-Gasthuws. [222]

Ook een zeer oud verkleinend aanhangsel is le, dat achter namen
als E a b e l e , D o e k e l e , N a m m e l e geplaatst is.
Oorspronkelijk is het volkomen een en het zelfde als het
verkleinende achtervoegsel lyn bij de oude Hollanders en
Vlamingen, als lein bij de hedendaagsche Hoogduitschers, in de
woorden maegdelyn, oogelyn, vogellyn (niet vogelijn), en blümlein,
röslein, äuglein.

Achter den verkleinvorm ke eischt de Oud-Hollandsche, alsook de

Hoogduitsche uitspraak eene n (b.v. roosken, meisken, en röschen,
mädchen), waar de Friesche uitspraak die n achterwege laat:
roaske, fanke. En zoo is het ook met den uitgang lyn of lein, die in
het Friesch, zonder n, als le luidt. Zoo als de oude Friezen in deze
zaak deden, spreken nog heden de Zwaben in Opper-Duitschland,
die rösle, mädle zeggen; terwijl de Zwitsers in hun röseli, maidli de i
nog laten hooren, maar de n ook niet.

Eene bijzondere oorzaak van het verval der Friesche namen is

gelegen in het onverstand van allerlei vreemde, onfriesche
predikanten en pastoors, schoolmeesters, notarissen, ambtenaren
van den burgerlijken stand, enz. in Friesland. Van ouds schreven de
Friezen natuurlijk hunne Friesche namen volgens de Friesche
spelling en niet volgens de Hollandsche of eene andere. Trouwens,
eene andere schrijfwijze is ook niet mogelijk, ten zij men er niet om
geve zoo men onzin voor den dag brengt. Die Friesche spelling van
Friesche namen en woorden is de eenig goede, en is door alle
Friezen, die slechts een weinig gevoel voor taalzuiverheid, slechts
een weinig kennis van spelling en letterwaarde hebben, dan ook
steeds gevolgd tot in deze eeuw. Sedert de helft dezer eeuw zijn er
al meer en meer vreemde, onfriesche, meest Hollandsche
onderwijzers, predikanten, pastoors en ambtenaren in de Friesche
gewesten aangesteld geworden. Sommigen van deze
vreemdelingen, ja bijna allen, geven den Friesche taal geenszins de
eere die haar toekomt, waardeeren haar niet of minachten haar,
omdat zij haar niet kennen, omdat zij haar dwazelijk uit der hoogte
aanzien voor een verbasterd en leelijk volksdialect. Anderen zelfs
haten haar, haten de Friesche taal omdat zij hun moeielijkheden in
den weg legt in hun verkeer met het Friesche volk, haten haar omdat
de Friesche taal hen dwingt zich in te spannen en nog wat te leeren
—een zware eisch voor waanwijze [223]betweters. Die willen dan wel
het Friesch schoeien op de Hollandsche leest, het Friesch dwingen
in het Hollandsche spoor, met andere woorden: zij willen Friesche
namen en woorden schrijven volgens Hollandsche spelregels en—
begaan dan domheden, waar mede zij den waren Friezen ergeren.
Deze schadelijke invloed van vreemdelingen op de Friesche taal,
waartegen de Stand-Friezen dienen te waken en zich krachtig te
verzetten, blijkt ook uit de dwaze spelling waarin heden ten dage
sommige Friesche namen in nieuwsbladen en andere openbare
geschriften voor ’t licht komen. Daar vindt men wel S i e t s c h e en
W i e t s c h e , J e t s c h e en V e t j e met V o k e l t j e en
V r o u w k j e , Z w o p k j e en Z w e i t s e , R i n z e en B i n z e ,
Ta e k e en Ta e t s c h e , Z ij t z e en V o l k e r t geschreven, in
plaats van S y t s k e en W y t s k e , J e t s k e en F e t s j e (F e t j e ),
F o k e l t s j e (F o k e l t j e ) en F r o u k j e , S w o b k j e ,
S w e i t s e , R i n s e , B i n s e , Te a k e , Te a t s k e , S y t s e en
Folkert.

Die tweeklank ie in plaats van den enkelen klank dien de Friezen

met y afbeelden, die ie waarmede de Hollanders meenen de
Friesche zuivere, lange i (y of î) te kunnen weêrgeven, is in namen
als S i e t s e en W i e b r e n in het geheel niet op zijne plaats. De ie
is in het Friesch immers duidelijk een tweeklank, gelijk zij
oorspronkelijk in het Hollandsch ook was, en nog heet. De Friezen
laten in hunne uitspraak dan ook zeer te recht nog duidelijk hooren
dat de ie een tweeklank is, in tegenoverstelling met de Hollanders
die deze oude en zuivere uitspraak verloren hebben, en geen
onderscheid meer kennen tusschen ie en i of y. Immers in het woord
wiet (nat) laten de Friezen eenen gants anderen klank hooren als in
W y t (s k e ), een onderscheid dat het verstompte gehoor der
Hollanders niet meer schijnt te kunnen vatten.—De sch in woorden
als school, schoen, schip, visch, wasschen wordt in het Friesch,
even als in de Noordsche talen, als sk uitgesproken: skoale, skoe,
skip, fisk, waskje. Door deze Friesche uitspraak in de war gebracht,
meenen sommige waanwijze vreemdelingen ook de sk in de namen
W y t s k e , G e l s k e , A n s k e , enz. als sche te moeten
verhollandschen, en er W i e t s c h e , G e l s c h e , A u s c h e van
te moeten maken. Intusschen, de sk in W y t s k e , G e l s k e ,
A n s k e komt geenszins overeen met de Hollandsche sch. O neen!
Immers in deze en soortgelijke [224]namen is sk slechts eene
toevallige samenvoeging van letters. Hier staan de s en de k slechts
bij toeval naast elkanderen, en vormen geenszins eene bijzondere
letterverbinding. Hier behoort de s aan de lettergrepen W y t s ,
G e l s en A n s (A n s o ), en de k is de eerste letter van het
verkleinende aanhangsel ke. Dus W y t s - k e (W y t s - k e , de kleine
—of vrouwelijke—W y t s e ), en niet Wyt-ske, Wyt-sche of Wiet-sche.
—De Friesche taal kent geen letter ij, zooals de Hollandsche tongval
en het hedendaagsche geijkte Nederlandsch. Men kan, of liever mag
dus niet W ij t s e , S ij t s e , W ij b r e n , S ij b o u t schrijven.
W y t s e , S y t s e , W y b r e n , S y b o u t of S i b o u t moet het
wezen. Ook kent de Friesche taal niet de letters v en z. Die halve,
verloopene, vloeiende en suizende medeklinkers zijn te flauw en te
zwevende voor de Friesche tonge; zij worden in het Friesch door f
en s vervangen. Dat men dus niet Z ij t z e , B i n z e , Z w e i t z e en
Z w o p k j e , noch ook V e t j e , V r a n k , V e d d e , V o l k e r t of
V o l m e r schrijve, maar F e t s j e (F e t j e ), F r a n k , F e d d e ,
F o l k e r t , F o l m e r met S y t s e , B i n s e , S w e i t s e en
S w o b k j e . Even min schrijve men de bijzondere Friesche en
Engelsche tweeklank ea (in de woorden brea of bread, dea of dead),
waar deze klank in Friesche persoonsnamen voorkomt, als ae, als of
het een Oud-Hollandsche lange a ware. Dus niet A e b e , Ta e k e ,
Ta e t s c h e , A e d e , P a e z e n s gelijk men heden ten dage wel
doet, maar E a b e , Te a k e , Te a t s k e , E a d e (of Æ b e ,
Æ d e ) en P e a s e n s .

Mogen zulke misvormde namen nooit meer worden geschreven! Dat

de Friezen zich niet door allerlei vreemdelingen allerlei knollen voor
citroenen in de handen laten stoppen. Maar dat zij zuiver Friesch
mogen blijven, ook in de goede Friesche spelling hunner Friesche
namen! Immers, men kan geen Friesche woorden en namen, geen
Friesche klanken met Hollandsche letterteekens afbeelden. Die dit
nochtans doet, die W i e t s c h e schrijft en Z ij t z e , Ta e k e en
V e t j e , handelt even dwaas als de man die Engelsche, Duitsche en
Fransche namen met Hollandsche klanken en letterverbindingen
afbeeldt—die dus Dzjeems, Loedwieg en Zjaak, of Swensie,
Karrelsroe en Bordo schrijven zoude, in stede van J a m e s ,
L u d w i g , J a c q u e s , S w a n s e a , K a r l s r u h e en
B o r d e a u x . [225]

Alles wisselt, verandert, verslijt, teert uit, sterft af, in ’t

ondermaansche. Alles! Ook de bijzonderheden in zeden, taal en
kleeding der Friezen, al hoe trouw anders de Friezen in den regel
ook gehecht zijn aan de eigenaardigheden, door hunne edele en
roemrijke voorouders hen overgeleverd. In deze zaken toch zijn de
hedendaagsche Friezen geenszins meer de zelfden, die ze van ouds
geweest zijn, die ze nog voor honderd en voor vijftig jaren waren.
Zelfs kan de opmerkzame veel korter tijdsbestek noemen, om
veranderingen aan te toonen. Ook in de Friesche mans- en
vrouwennamen doet zich deze wisseling en verslijting, dit afsterven
of buiten gebruik raken bemerken—al is dit ook betrekkelijk gering
en weinig, veel minder dan bij onze stamverwante volken met hunne
volkseigene namen geschiedt. Maar toch droeg deze en gene onder
onze voorouders in de middeleeuwen en later eenen naam die thans
onder ons niet meer gehoord wordt. Ja zelfs in de vorige eeuw nog
kwamen onder de Friezen sommige namen, goed Oud-Friesche
namen voor, die men thans slechts uiterst zeldzaam of in het geheel
niet meer aan kinderen geeft, ’t en zij dan in veranderden vorm, als
R i c h j e voor R i x t a , L u t s k e voor L u x t a , J e l t s j e voor
J i l d o u , R e i n t s j e voor R e i n o u . Ook in deze zaak heerscht —
— de mode! Sedert de helft dezer eeuw vooral schijnt het alsof de
Friesche namen sommigen ontaarden Friezen niet meer goed
genoeg zijn. Die verbasterden en verbijsterden tooien hun kroost,
dwaas genoeg! liever met de romantische namen van allerlei
vreemde lui, vooral liefst met Fransche en Engelsche namen, dan
met de eenvoudige en eerlijke namen der eigene voorouders. Hier
en daar is er onder ons eene ijdele moeder en een zwakke vader die
aan zoontje of dochterke niet den Frieschen naam geven van
hunnen eigenen vader, van hunne eigene moeder, gelijk de Friesche
zede dit van ouds eischt, maar eenen vreemden, eenen
zoogenoemd mooien naam. Daartoe wordt dan de Friesche naam,
die het kind rechtmatig toekomt, verknoeid en verdraaid,
zoogenoemd verfraaid, maar in der daad misvormd en onkenbaar
gemaakt. Of wel—men bedenkt maar eenen geheel vreemden
naam, hoe vreemder en romantischer, hoe mooier; bij voorbeeld:
A u r e l i a voor A u k j e ; E l l a voor J e l t s j e ; H e n r i voor
H a r k e ; G e o r g voor G o s s e ; T i t u s voor T i e t e of Ts j i t t e ,
enz. [226]Dwaas, die zoo handelen! Onwaardig, onfriesch, die zoo
doen! Zal men den kinderen de oude en eervolle namen der eigene
ouders en voorouders onthouden, die kenmerken hunner Friesche
afstamming, de edelste onder de Germanen? Zal men ze tooien (?)
met de soms verachtelijke namen van vreemde schurken en
schelmen, hoeren en snoeren misschien? Neen immers! Geen ware
Fries, geen Stand-Fries zal aldus zijn kroost ontadelen.

Behalve deze dwaze en treurige gezindheid, die het vreemde,

opgesmukte, opzichtige, gekunstelde in alle opzichten verkiest
boven het eigene, eenvoudig-schoone, degelijke,—eene gezindheid
die gelukkiger wijze onder de Friezen nog weinig voorkomt, minder
dan bij eenig ander volk—is daar nog eene andere reden die het
uitsterven en verbasteren van Friesche namen ten gevolge heeft.
Die reden is gelegen in de meening welke niet weinigen, overigens
goed Frieschen Friezen eigen is, dat de Friesche namen leelijk zijn,
leelijk klinken, dat het slechts zinlooze klanken zijn, en dat zij den
dragers van die namen iets onbeschaafds, iets weinig
gedistingueerds (basterd-woorden passen bij verbasterde
gezindheden) zouden verleenen. En fijn beschaafd en gepolitoerd
(op zijn Fransch, God betere ’t!), ook gedistingueerd (al is het dan
ook valsch) willen er heden ten dage zoo velen zijn!
Nu—ik wil hier ook niet ten eenen male ontkennen dat sommige
Friesche namen, zoo wel van mannen als van vrouwen, in der daad
niet schoon van klank en vorm zijn. Ik kan mij zeer wel voorstellen
dat deze of gene, met een fijn ontwikkeld gehoor en met goeden
smaak begaafd, namen als S j e r p , N a m m e l e , O e g e ,
Oebele, Goaitsen, Durk, Harm, Freark, Olfert,
H o a t s e , J i s k , G o u k e , G u r b e , W o p k e , namen als
Eke, Baeye, Akke, Wobbeltsje, Gatske,
Jisseltsje, Nammentsje, Murkje, Jaeike,
S j o e r d t s j e , leelijk, zeer leelijk, op den duur ondragelijk vindt.
Maar aan deze, in zich zelven reeds misvormde, verkorte namen is
men immers ook niet gebonden! Men kan die namen in hunnen
oorspronkelijken, volledigen, onverbasterden vorm herstellen. Dan
zijn ze niet leelijk, noch zonder zin. Hier boven hebben wij dit reeds
aangetoond bij ’t behandelen der namen E k e of E e l k j e , E e l k e
of E e l t s j e met S j o e r d en S j o e r d t s j e , F r e a r k en S i e r k
enz. Als eene kleine proeve, hoe men in deze zaak te handelen
[227]hebbe, wil ik aan het einde van deze verhandeling een lijstje
geven van eenige hedendaagsche, verbasterde en verkorte Friesche
namen, met hunne Oud-Friesche, volledige vormen daar achter.

Al geef ik toe dat eenige, zelfs vele hedendaagsch Friesche namen

leelijke, wanklinkende, onbehagelijke vormen vertoonen, dit is toch
geenszins bij allen het geval. De mansnamen A l l e r t , E d s a r d of
I d s e r t , A l e f , A l g e r , A y o l t (meest in Groningerland in
gebruik), B r u c h t , F r a n k , J i l d e r t , W y b r a n d , S y b r a n d
en G e r b r a n d , O n n o , G e r l o f , Ts j a l l i n g , H a y o ,
Hillebrand, Hubert, Hero, Ivo, Meinert,
R e i n d e r t , Ta c o , H a r t g e r , en de vrouwennamen
B r e c h t j e , Y m k j e , S i b r i c h en W i b r i c h , A u k j e ,
M i n k e , W y t s k e en S y t s k e , W y p k j e , R i n s k e , E l s k e ,
G e e s k e zijn namen die, al zijn het ten deele ook slechts
verdraaide en verkorte namen, toch geenszins leelijk van klank en
vorm zijn te noemen. Deze en vele soortgelijke namen hebben in de
mansnamen iets krachtigs, edels, manhaftigs, in de vrouwennamen
iets liefelijks, ongekunstelds, dat Fries en uitman behaagt. Maar, het
zij dat men nu deze namen in deze vormen aanhoude of afschaffe,
het zij men ze tot hunne oorspronkelijke zuivere vormen terug
brenge, men wachte zich wel die namen nog meer te verdraaien, in
de meening ze te verfraaien. Ware misbaksels en monsters van
namen zijn er al, door dat zoogenoemde „mooier maken”, door
weinig belezene en weinig beschaafde, door smakelooze menschen
tot stand gebracht. Die R o m k j e tot R o m e l i a , W o b k j e tot
W o b b i n a , G e e s k e tot G e z i e n a , E l s k e tot E l z i e n a ,
A a l t j e tot A l i d a , J e l t j e tot J e l l i n a , S j o e r d t j e tot
S j o e r d i n a , F o k e l t j e tot F o k e l i n a , of D o e d e tot
D o e d e r u s , S i b b l e tot S y b i l l u s , A n n e tot A n n e e ,
F e d d e tot F e d d e r u s , E a b e l e tot A b e l i u s , T i m e n tot
T i m o t h e u s , B a r t e l e tot B a r t h o l o m e u s , J e n t j e tot
G e n t i u s , H e s s e l tot H e s s e l i u s , J i l l e r t tot J i l l a r d u s
maakt, geeft daar door een bewijs van onverstand en wansmaak.
Gelukkig is deze dwaasheid bij ons Friesche volk tusschen Flie en
Lauwers, dus bij de kern des geheelen Frieschen volks, veel minder
in zwang dan bij de andere Friesche stammen, vooral bij
Groningerlanders en Oost-Friezen. Dezen maken van R o e l f k e ,
S w a a n t j e , G e r k j e , G e e r t j e , L a m m e c h i e n en
L u b b e c h i e n (in ’t [228]eigenlijke Friesland L a m k j e en
L u b k j e ), van F r o u k j e , enz. R o e l f i n a , S w a a n t i n a ,
G e r c o l i n a , G e e r t j e d i n a , L a m m e c h i e n a en
L u b b e c h i e n a , F r o u k e l i n a , enz.; de Oost-Friezen van
H a i k e (de vrouwelijke vorm van H a y o ), H a y o n e t t a en
H a y o l i n a , van G e e s k e , H i l k e en L u b k e wel G e e s k e a ,
H i l k e a en L u b k e a . Dit zijn ware monsters van namen,
wannamen, die hoe eer hoe liever buiten gebruik moeten gesteld
worden, en die geen waarlijk beschaafd man zijnen kinderen geven
zal. Dan nog maar liever geheel vreemde namen, zoo als zij doen
die eenen knaap, welke naar zijnen grootvader H e t t e of T i e t e
moest heeten, H e c t o r of T i t u s noemen, of een meiske dat den
naam van hare grootmoeder A u k j e of H e i l t j e toekwam,
A u r e l i a of H e l e n a noemen—al geeft zulke handelwijze dan ook
getuigenis van onfriesche gezindheid, van weinig gevoel voor de
eere van ’t eigene volk, van de eigene voorouders. Dat men echter
oorspronkelijk onfriesche namen als K l a a s , T h ij s , P i e r , J a n
en K e e s , als N e e l t j e , L e e n t j e , T r ij n t j e , G r i e t j e ,
A n g e n i e t j e , M a r t j e , enz., die grootendeels ook bij de
Hollanders en andere Nederlanders in deze vormen voorkomen,
terug brengt tot de oude volle vormen N i c o l a a s , M a t t h e u s ,
Petrus, Johannes, Cornelis, Cornelia,
M a g d a l e n a , C a t h a r i n a , M a r g a r e t h a , A g n e s en
M a r t h a , daar kan niemand wat op tegen hebben. Dat druischt niet
in tegen den goeden smaak. In tegendeel, die volle namen zijn verre
weg te verkiezen boven de hier vermelde verdraaide en ingekorte
verbasteringen daar van.

Reeds in de vorige eeuw is men begonnen sommige Frieschen

mansnamen, die op eene toonlooze e eindigen (H o b b e , Y n t e ,
H a r k e ), welluidender, aannemelijker te maken door die e met eene
o te verwisselen, en dus van bovengenoemde namen H o b b o ,
I n t o , H a r c o te maken. Deze namen, op o eindigende, vertoonen
in der daad, volkomen of ten naasten bij, de Oud-Friesche vormen,
waarvan de namen op toonlooze e slechts verbasteringen,
afslijtingen uitmaken. Men handelt dus zeer redelijk zoo men die
oorspronkelijke o weêr in zijn recht herstelt. Ook zijn deze
naamsvormen, op o uitgaande, eigenlijk nooit geheel buiten gebruik
geweest, ook in de zestiende en zeventiende eeuw niet. [229]In
sommige aanzienlijke maagschappen hield men dien vorm op o
steeds in gebruik, al was het dat bij boeren, burgers en geringe
lieden de toonlooze e in plaats van die o getreden was. In Oost-
Friesland en Groningerland is deze o nooit zoo algemeen door de e
verdrongen geweest, als in Friesland bewesten Lauwers. Ook heden
nog treft men in die gewesten meer Friesche namen in hunnen
oorspronkelijk op o uitgaanden vorm aan, dan in ’t eigenlijke
Friesland. Men kan veilig de namen, op toonlooze e eindigende, in
beteren vorm herstellen door eene o de plaats van die e te doen
innemen; door bij voorbeeld van A i s e en van S i b e , van H a l b e
en van W y t s e , van R i n s e en van M i n n e , van A t s e en van
L y k e l e te maken A i s o en S i b o , H a l b o en W y t s o , R i n s o
en M i n n o of M e n n o , A t s o en L y k l o . Maar men doet beter,
men handelt in taalkundig opzicht wetenschappelijker, men bereikt in
den regel ook beter zijn doel (te weten het herstellen der namen in
zuiverder en welluidender vormen), zoo men die namen welke op tse
en le uitgaan (A t s e , F e t s e , S e a k e l e , L y k e l e , O e b e l e )
en die, gelijk op bl. 213 en vervolgens reeds is aangetoond, eigenlijk
slechts verkleinvormen zijn—eerst herstelle in den oorspronkelijken,
onverkleinden vorm, en er dan de o achter plaatse. Zoo men dus
van A t s e en F e t s e (A t - t s e en F e d - t s e , de kleine A t t e en
de kleine F e d d e ) maakt A t t o en F e d d o ; van S e a k e l e en
O e b e l e , S a c o en U b o (men spreke O e b o ). Zie hier, als
verdere voorbeelden, eenige Friesche mansnamen in den
hedendaags meest gebruikelijken, versletenen vorm, met den
oorspronkelijken Oud-Frieschen vorm er achter.

A b b e —A b b o .
A b e , A b e l e , E a b e , E a b e l e —A b o .
A d d e —A d d o .
A d e , E a d e , E d e —A d o , E d o .
A g e —A g o .
A g g e , E g g e —A g g o , E g g o .
A i k e —A i c o .
A i l k e —A i l c o .
A i s e , E i s e —A i s o , E i s o .
A l e , A l l e —A l o , A l l o .
E p p e , E p k e —E p p o , E p c o .
A t e , A t t e —A t o , A t t o .
A u k e —A u c o , A v o .
B a u w e , B a u k e —B a v o .
B o u w e , B o u k e —B u v o .
B o t e —B o t h o .
B r u i n —B r u n o .
D o e d e —D o d o .
D o e k e , D o e k e l e —D u c o , [230]in zuiverder, onverkleinden
vorm echter D o d o .
E d e —E d o .
E e l k e , E e l t j e —E e l c o ; in zuiverder, onverkleinden vorm
echter A d e l .
F e y e , F e i k e —F e y o , F e i c o .
F o k k e , F o e k e —F o c c o , F u c c o .
F o l k e —F u l c o .
H a y e , H a i k e , H a i t e , H a i t s e —H a y o , H a i c o ; de
laatste vorm is niet te verkiezen.
H e r e , H e e r e , H e a r e , H j e r r e —H e r o .
O e d s —O d o , U d o (spreek O e d o ).
O e n e —O n n o , U n o (spreek O e n o ).
P o p p e , P o p k e —P o p p o , P o p c o ; de laatste vorm is
niet te verkiezen.
S a k e , S a k e l e , S e k e l e , S e a k e l e —S a c o .
Ta k e , Te a k e , Te k e , Te k e l e , Te a k e l e —Ta c o .
S c h e l t e —S c e l t o .
S o l k e —S o l c o .
Ta d e , Te a d e —Ta d o .
T i e d e , T i e t e , T j i t t e , T j i t s e —T h i e d o of T h e o d o .
S i b e , S i b b e , S i p p e , S i p k e , S i b b e l e —S i b o ,
Sibbo.
 W i b e —W i b o .
U i l k e , U i l t j e , U i l t z e n —U l o .
W i t e , W i t t e , W y t s e —W i t o .
W o b b e , W o p , W o p k e —W u b b o .

Van deze soort van eenvoudige, zoogenoemde stamnamen zijn

H a y o , H u g o , O n n o , O t t o , M e n n o , B e n n o , enz.
steeds in gebruik geweest, ook bij de andere volksstammen in de
Nederlanden en Duitschland.

Geheel in overeenstemming met de bovengenoemde mansnamen

kan men de toonlooze e, waarop vele hedendaagsch Friesche
vrouwennamen eindigen, veranderen in eene a. Die namen
herkrijgen daar door veelal hunnen ouden, oorspronkelijken vorm, en
worden tevens welluidender en aannemelijker. Zoo kan men van
Te t , Te t t e of Te t s j e maken Te t t a , van A t h of A t s j e A t t a ,
en M i n n a van M i n k e of M i n t s j e .

De Friesche vrouwennamen komen heden ten dage meest in

verkleinvormen voor; gaan dus veelal op je, tje, kje, ke uit. Zoo men
deze onnoodige, meestal leelijke verkleinvormen eerst van de
namen afneemt, en dan eene a voegt achter den overblijvenden
[231]naamsstam, dan verkrijgt men in den regel den oorspronkelijken
vorm van den naam. Zoo men dus van Y t s j e of I t s j e (eigenlijk
I d - t j e of Y d - t j e ) den verkleinvorm tje wegneemt, en achter den
overblijvenden naamsstam I d of Y d eene a voegt, is de naam in
zijnen oorspronkelijken en schoonen vorm I d a hersteld.

Zie hier, als verdere voorbeelden, eenige Friesche vrouwennamen in

den hedendaags meest gebruikelijken vorm, met den
oorspronkelijken Oud-Frieschen vorm daar achter.
D e t j e —D e d d a .
E l s k e , E l s j e —E l s a .
F r o u k j e —F r o u w a , F r o w a ; de laatste is de beste vorm.
H e i l t j e —H e i l a .
H i l t j e , H i k k e , H y l t j e , H y l k j e , H i k e —H i l d a .
H o u k j e , H o l k j e —H o l d a .
Y n s k j e —I n a .
J e l t j e , J e i k e —J e l l a .
B o n t j e —B o n n a .
B o t j e —B o t h a .
M e i n t j e —M e i n a ; in den alleroudsten vorm M e g i n a of
Magina.
F e t j e , (F e d - t j e )—F e d d a .
F o k j e , F o e k j e , F o k e l t j e —F o c c a , F u c c a , F o c a .
Y m k j e , I m k j e , E m k j e —I m a , I m m a , E m m a .
E a d s k e , A t j e —A d a .
R e i n t j e —R e i n a ; in den alleroudsten vorm R e g i n a of
R a g i n a , waarbij men echter niet aan het Latijnsche woord
regina (koningin) te denken hebbe.
G e e s j e , G e e s k e —G e s a . De meer bijzonder Oud-
Duitsche vorm G i s e l a (ook een verkleinvorm), kan ook zeer
wel in de plaats van G e e s k e genomen worden.
E p k j e , E p j e —E p p a .
A a f k e —A v a .
D o e t j e (d.i. D o e d - t j e ), D o e k j e , D o e k e l t j e —D o d a .
D o u t j e , D o u w t s e n —D u v a .
D i e u w k e , D i e u w e r t j e —D i u v a , D i e t w a r a ,
Thiadware.
H a i t s k e , H a i k j e , H a i t j e —H a y a .
G e e l t j e , G e a l t j e —G e l a .
H i t j e (H i d - t j e )—H i d d a .
T i e t j e —T h i e d a of T h e o d a .
De namen A d a , E m m a , I d a zijn van ouds her ook bij andere
Germaansche volken buiten Friesland in gebruik gebleven. De
meeste overigen hebben alleen de Friezen behouden. [232]

Ten slotte nog geef ik hier eene lijst van Friesche persoonsnamen in
hunnen hedendaagschen, verbasterden en verkleinden vorm, met
de oude, oorspronkelijke, volle vormen daar achter. De letters m en v
achter de namen duiden aan of zij mans- of vrouwennamen zijn.

A a r t , A r e n t , A a n m.—A r n of ook A r n o l d .
A l g e r . m.—A d e l g a r .
A l l e r t . m.—A d e l h a r t .
A n d e l e . m.—A n d o .
A a f j e , A a f k e . v.—A v a of ook A b a .
A a l t j e . v.—A d e l a .
A n s k e . m.—A n s o .
A u k e . m.—A u d o , A u c o of A v o .
A u k j e . v.—A u d a of A v a .
B e a n , B a a r t , B e e r t , B e r e n d , B a r e n d , m.—
Bernhard.
B a a r t j e , B a a t j e , B e r e n d j e (B e r e n d i n a ). v.—
Bernharda.
B a u w e . m.—B a v o .
B a u k j e , B a a i e . v.—B a v a .
B a r t e l e , B a r t l e . m.—B a r t of B r e c h t en B a r t h o l d .
B a r t e l t j e , B a r t j e , B r e c h t j e , v.—B a r t h a of
B e r t h a , of B r e c h t a en B a r t h o l d a .
B o u w e . m.—B u v o .
B o u k j e . v.—B u v a .
B i n n e , B i n s e , B e n t e , m.—B e n n o .
Bentje, Benskje, Bints, Binke, Bintje,
B i n t s k e , v.—B e n n a .
B e n n e r t , B i n n e r t . m.—B e r n h a r d .