Aging of the Genome - the Dual Role of DNA in Life and Death

Aging of the Genome - the Dual Role of DNA in Life and Death

■ CONTENTS
Preface v
1 Introduction: the coming of age of the genome 1
1.1 The age of biology 2
1.2 From genetics to genomics 12
1.3 A return to function 17
1.4 The causes of aging: a random affair 23
2 The logic of aging 27
2.1 Aging genes 28
2.2 Pleiotropy in aging 36
2.3 Interrupting the pathways of aging 39
2.4 Longevity-assurance genes 47
2.5 Somatic damage and the aging genome 52
3 Genome structure and function 57
3.1 DNA primary structure 58
3.2 Higher-order DNA structure 71
3.3 Nuclear architecture 77
3.4 Transcription regulation 81
3.5 Conclusions 89
4 Genome maintenance 91
4.1 Why genome maintenance? 93
4.2 DNA-damage signaling and cellular responses 98
4.3 DNA-repair mechanisms 105
4.4 Genome maintenance and aging 140
5 Genome instability and accerated aging 151
5.1 Premature aging 152
5.2 Validity of accelerated-aging phenotypes 155
5.3 Genome maintenance and accelerated aging in mice 160
5.4 Conclusions 177

6 The aging genome 181
6.1 DNA damage 183
6.2 DNA-sequence changes 198
6.3 Changes in DNA modification and conformation 223
6.4 Summary and conclusions: a DNA damage report of aging 229
7 From genome to phenome 233
7.1 The causes of cancer 239
7.2 Genome instability and tissue dysfunction 247
7.3 Testing the role of genome instability in aging 278
8 A genomic limit to life? 289
8.1 Aiming for immortality 289
8.2 SENS, and does it make sense? 293
EPILOGUE 299
GLOSSARY 301
REFERENCES 309
INDEX



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