Table Of ContentSIRTUIN BIOLOGY IN MEDICINE
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SIRTUIN BIOLOGY IN
MEDICINE
Targeting New Avenues of Care in
Development, Aging, and Disease
Edited by
K M
ENNETH AIESE
BiotechnologyandVentureCapitalDevelopment,OfficeofTranslationalAlliancesandCoordination,
NationalHeart,Lung,andBloodInstitute;CellularandMolecularSignaling,NewYork,NY,UnitedStates
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Dedication
To the readers and the students who live inside all of us, inspire our curiosity, and excite our desire to break
newboundariesfortherapeuticstrategiesthatimpacttheextensionofhumanlifespanandtheunderlyingbiology
ofhumandisease.
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Contents
List of contributors xi 2.4 Roles ofsirtuins in aging 26
2.5 NAD1 as a principle regulator of
About the editor xiii
sirtuin activity 28
Preface xv
2.6 Therapeutic activationofsirtuinsby
Acknowledgment xvii raisingNAD1 levels 29
2.7 Conclusion 31
Section I References 31
Sirtuins, neurodegenerative disease, lifespan
3. Sirtuins and life span extension
extension, and aging
SHIN-HAELEEANDKYUNG-JINMIN
3.1 Sirtuins—a family ofattractive antiaging
1. Novel treatment strategies for neurodegenerative molecules 37
disease with sirtuins 3.2 Lifespan extensioneffectofsirtuins 37
KENNETHMAIESE 3.3 Activators ofsirtuin inlife span extension effect 40
3.4 Conclusion andperspectives 43
Abbreviations 3 References 43
1.1 Increased life expectancy andneurodegenerative
disease 4
1.2 Noncommunicable diseases andneurodegenerative 4. Sirtuins and aging
disease 4
BRIANJ.MORRIS
1.3 Innovative avenuesfor the treatment of
neurodegenerative disease 5 Abbreviations 49
1.4 Silent mating type information regulation2 4.1 Introduction 51
homolog1 (Saccharomyces cerevisiae)and 4.2 Overview ofsirtuins 51
neurodegenerative disease 6 4.3 Functions of each sirtuin 54
1.5 SIRT1 and forkhead transcription factors 7 4.4 Molecular genetics 65
1.6 SIRT1 and the mechanistic target ofrapamycin 9 4.5 Sirtuins as biomarkers ofaging 66
1.7 SIRT1 and the circadian clock genes 10 4.6 Sirtuin-activating compounds 66
1.8 SIRT1 and noncoding RNAs 11 4.7 Epigenetics 68
1.9 Futureconsiderations 11 4.8 Conclusions 68
Acknowledgments 13 References 68
References 13
5. Sirtuins in the biology of aging
2. NAD1: a crucial regulator of sirtuin
MATEUSZWa˛TROBAANDDARIUSZSZUKIEWICZ
activity in aging
5.1 Introduction 79
NADYBRAIDYANDMARIAVILLALVA(D.)
5.2 Mechanisms of sirtuin activation bycaloric
2.1 Introduction 23 restriction 79
2.2 NAD1 consumption—a key cause ofNAD1 5.3 Functions of individual sirtuins in mammals,
decline 24 including humans 80
2.3 The sirtuin reaction 25 References 86
vii
viii
Contents
6. Sirtuins as regulators and the regulated 9. Sirtuins, melatonin, and the relevance
molecules of exosomes of circadian oscillators
QINGHAN,YIRUICHENGANDWEILIANGXIA RU¨DIGERHARDELAND
6.1 Introduction 91 9.1 Introduction 137
6.2 The dual characters ofexosomes 92 9.2 Sirtuins andthe circadian system 138
6.3 Sirtuinsregulate exosome secretion 93 9.3 Melatonin and the circadian system 139
6.4 Exosomes regulatesirtuin activity in 9.4 Sirtuins andmelatonin inthe context of
recipient cells 95 metabolic sensing 140
6.5 Sirtuinsreleased byexosomes 97 9.5 Mitochondrial relevance ofmelatoninand
6.6 Conclusion 97 sirtuins 141
Acknowledgment 98 9.6 Effectsof melatonin on sirtuin expressionin
References 98 nontumor cells 142
9.7 Contrasting findingsof melatonin on SIRT1
expression intumor cells 143
7. Sirtuins in aging, age-related pathologies
9.8 Secondary signaling ofmelatoninvia SIRT1 144
and their association with circadian rhythm
9.9 Conclusion 145
SANKARATHIBALAIYA References 146
7.1 Sirtuin function andlocalization 103
7.2 Sirtuinsandcalorierestriction 104 10. Epigenetic role of sirtuins in
7.3 Sirtuinsandaging 105
neurodegenerative brain disorders
7.4 Sirtuinsin eye 106
ARCHITAKHANNA,ANAMIKAAND
7.5 Sirtuinsandage-related diseases 106
SURENDRAKUMARTRIGUN
7.6 Obesity 108
7.7 Sirtuinsandage-related neuronaldiseases 108 Abbreviations 153
7.8 Sirtuinsandcardiac diseases 109 10.1 Introduction 154
7.9 Sirtuinsandcircadianrhythm 110 10.2 Regulation ofSIRT1: posttranslational
7.10 Conclusion 111 modificationsversus subcellular
References 111 translocation and activity 158
10.3 Sirtuins as epigenetic regulators 158
10.4 SIRT1 andSIRT3 inneurodegenerative
8. Sirtuins, mitochondria, and the melatonergic
brain disorder 162
pathway in Alzheimer’s disease
10.5 Concluding remarks 167
G.ANDERSONANDM.MAES Acknowledgment 168
Authordeclaration 168
Abbreviations 117
References 168
8.1 Introduction 118
8.2 The sirtuins 119
8.3 Gut, sirtuins,and Alzheimer’sdisease 120 11. Sirtuins and stem cell maintenance,
8.4 Circadian dysregulation: mitochondria, proliferation, and differentiation
butyrate, andceramide 125
RYANA.DENUANDPEIMANHEMATTI
8.5 Integrating sirtuins into Alzheimer’sdisease
pathophysiology 126 Abbreviations 175
8.6 Futureresearch directions 127 11.1 Introduction 176
8.7 Treatment implications 127 11.2 Mesenchymal stromal/stem cells 177
8.8 Conclusion 129 11.3 Hematopoieticstem cells 180
Acknowledgment 129 11.4 Embryonic and induced pluripotent
Conflicts ofinterest 129 stemcells 182
References 129 11.5 Conclusions 185
Further reading 135 References 185
ix
Contents
12. Sirtuins in mechanistic target of rapamycin Section II
complex 1 signaling
Sirtuins, cardiovascular disease and
J.BURILLO,P.MARQUE´S,B.JIME´NEZ,C.GONZA´LEZ-BLANCO,
M.BENITOANDC.GUILLE´N end-organ disease
12.1 Introduction 191
12.2 The roleofsirtuinsin type 2 diabetes
15. Scope to develop sirtuins modulators as
mellitus 194
a therapy to attenuate cardiac complications
12.3 The roleofsirtuinsin aging 195
12.4 The roleofsirtuinsin thermogenesis 197 BUGGAPARAMESHAANDSANJAYK.BANERJEE
12.5 The roleofsirtuinsin neurodegeneration 199
Abbreviations 241
12.6 Sirtuinsin cancer 203
15.1 Introduction tosirtuins 242
References 205
15.2 Role ofsirtuins incardiac diseases 243
15.3 Role ofsirtuins incardiac hypertrophy 243
15.4 Sirtuins andischemia/reperfusion injury 247
13. Free-radical redox timer, sirtuins and aging:
15.5 Sirtuins incardiacfunctionand heart failure 248
from chemistry of free radicals to systems
15.6 Sirtuinsinoxidativestressandcardiacdiseases 251
theory of reliability
15.7 Sirtuin inautophagy 252
VITALYK.KOLTOVERANDTATJANAA.SKIPA 15.8 Sirtuins incardiometabolic diseases 253
15.9 Clinical studies ofsirtuins-activating
13.1 Introduction: ahistorical synopsis 213
compounds incardiac diseases 253
13.2 Reliability engineering andbiological
15.10 Clinical studies with nicotinamide adenine
robustness: basic terms andideas 214
dinucleotideboosters inthe context of
13.3 Free radical malfunctions inoxidative
cardiovascular diseases 254
metabolism 215
15.11 Conclusion and future perspective 255
13.4 Preset reliability as the backgroundof
Acknowledgment 255
limited life span 215
References 255
13.5 Free radical timer of aging: quantitative
aspects 217
13.6 Free radical timer of aging: the 16. Role of sirtuins in cardiovascular diseases
sirtuin way 217 VENKATRAMANRAVI,SNEHAMISHRAAND
13.7 Sirtuinsas mediators in the antioxidant NAGALINGAMRAVISUNDARESAN
biomedicine 220
16.1 Introduction 262
13.8 Conclusions 221
16.2 SIRT1 264
Acknowledgments 222
16.3 SIRT2 269
References 222
16.4 SIRT3 270
16.5 SIRT4 272
16.6 SIRT5 273
14. Sirtuins, mitochondria, and exercise in
16.7 SIRT6 274
health and disease
16.8 SIRT7 278
ANIBHM.DASANDPARTHADABKE 16.9 Conclusion 279
References 279
Abbreviations 225
14.1 Introduction 226
14.2 Regulatory elements ofenergy 17. Targeting sirtuins to modulate energy
production 227 metabolism in heart disease
14.3 Sirtuinsandexercise: impact on
TSUNEHISAYAMAMOTOANDKENSHINMURA
agingand disease 230
14.4 Conclusion 233 17.1 Introduction 285
References 234 17.2 Conclusions 290
