1;Contents;5 2;Contributors;7 3;Introduction;10 3.1;1.1 Ageing;10 3.2;2.1 Stem Cells;11 3.3;3.1 Cancer;12 3.4;4.1 Therapies;12 4;Telomere Shortening and Ageing;14 4.1;Cellular versus Organismal Aging;15 4.1.1;1 Cellular Aging: The Hayflick Limit;15 4.1.2;2 Cellular Aging: The End Replication Problem;16 4.1.3;3 Telomeres and Telomerase: A Brief Introduction;17 4.1.4;4 Telomere Shortening and Cellular Aging;19 4.1.5;5 Organismal Aging and Survival;21 4.1.5.1;5.1 Telomeres and Organismal Aging;21 4.1.5.2;5.2 Genome Integrity/DNA Damage Response in Postmitotic Aging;23 4.1.5.3;5.3 Genetic Pathways of Postmitotic Cell and Organismal Survival;24 4.1.6;6 Perspectives;29 4.1.7;References;29 4.2;Telomere-Induced Senescence of Primary Cells;35 4.2.1;1 Primary Human Cells and Replicative Senescence;36 4.2.2;2 The Telomere Hypothesis of Cell Aging and Immortalization;39 4.2.3;3 Validation of the Hypothesis;40 4.2.4;4 Exceptions to the Hypothesis;43 4.2.5;5 Mechanism of Telomere-Induced Senescence;45 4.2.6;6 Telomere-Induced Replicative Senescence and Organismal Aging;48 4.2.7;References;50 4.3;Telomeres, Senescence, Oxidative Stress, and Heterogeneity;55 4.3.1;1 Heterogeneity: The Hallmark of Ageing;55 4.3.2;2 Replicative Senescence and the Telomere Hypothesis;56 4.3.3;3 Heterogeneity in Senescence;57 4.3.4;4 Heterogeneity and Telomeres;58 4.3.5;5 Heterogeneity and Mitochondria;60 4.3.6;6 Mitochondrial Dysfunction Causes Telomere Dysfunction and Thus Heterogeneity in Replicative Senescence;61 4.3.7;7 Complexities Beyond;64 4.3.8;References;64 4.4;Initiation of Genomic Instability, Cellular Senescence, and Organismal Aging by Dysfunctional Telomeres;69 4.4.1;1 Telomeres and Telomerase;69 4.4.2;2 A Six-Protein Core Complex Mediates Telomere End Protection;71 4.4.3;3 Telomere Dysfunction Results in Genomic Instability;72 4.4.4;4 Telomere Dysfunction Initiates p53-Dependent Replicative Senescence;73 4.4.5;5 Consequences of Telomerase Loss In Vivo: The Telomerase Knockout Mouse;74 4.4.6;6 Telomere Shortening and Organismal Aging;76 4.4.7;7 The mTerc-/- Wrn-/- Compound Mutant Mouse as a Model of Human Werner Syndrome;78 4.4.8;8 Conclusions;81 4.4.9;References;82 4.5;Telomerase Mutations and Premature Ageing in Humans;88 4.5.1;1 Introduction;89 4.5.2;2 Telomerase and Ageing;89 4.5.3;3 Dyskeratosis Congenita as a Premature Ageing Syndrome;90 4.5.3.1;3.1 Clinical Presentation of Dyskeratosis Congenita;91 4.5.3.2;3.2 Similarities and Differences Between DC and Ageing;92 4.5.4;4 Dyskeratosis Congenita and Telomerase Mutations;93 4.5.4.1;4.1 X-linked DC and Mutations in DKC1;93 4.5.4.2;4.2 AD DC and Mutations in TERC and TERT;98 4.5.4.3;4.3 AR DC and Mutations in Other Components;107 4.5.5;5 Telomerase and Cancer;108 4.5.6;6 Conclusion;110 4.5.7;References;110 5;Telomerase, Telomeres, and Stem Cell Aging;119 5.1;Mechanisms of Stem Cell Ageing;120 5.1.1;1 Introduction;120 5.1.2;2 Cell Intrinsic Regulation of HSCs;121 5.1.2.1;2.1 HSC Cell Cycle Status;122 5.1.2.2;2.2 HSC Gene Expression Profiles: Transcription Factors and Epigenetic Modification;122 5.1.2.3;2.3 Maintaining the HSC Population: Stem Cells Make Life or Death Decisions;124 5.1.3;3 Cell-Intrinsic Mechanisms of Stem Cell Dysfunction ;125 5.1.3.1;3.1 Signaling Pathways Implicated in Cell-Intrinsic HSC Ageing;125 5.1.3.2;3.2 HSC-Intrinsic Mechanisms of Functional Decline Lead to Changes in Stem Cell Number with Age;126 5.1.4;4 Hematopoietic Stem Cell Niches - Extrinsic Regulation of HSCs;129 5.1.4.1;4.1 The Vascular Niche;129 5.1.4.2;4.2 The Endosteal Niche;129 5.1.4.3;4.3 Why Two Stem Cell Niches?;130 5.1.4.4;4.4 Molecular Interactions within the Niche;130 5.1.5;5 Evaluating Stem Cell-Microenvironment Interactions: Transplantation and Mobilization;133 5.1.5.1;5.1 Transplantation;134 5.1.5.2;5.2 Molecular Mechanisms of HSC Homing;134 5.1.5.3;5.3 Mechanisms of HSC Mobilization;135 5.1.6;6 Functional Changes with Age that Involve both HSCs and the Microenvironment ;136 5.1.6.1;6.1 Effects of Age