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 ......................................................... 353
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