The Molecular Genetics of Aging

Centenarians and the Genetics of Longevity.- 1 Introduction.- 2 Are Centenarians a New Phenomenon?.- 3 Centenarians Are the Fastest Growing Age Group.- 4 Are Centenarians Different?.- 5 The Centenarian Phenotype: Compressing Morbidity Towards the End of Life.- 6 Evidence from Centenarians Supporting a Strong Genetic Influence upon Longevity.- 7 Siblings of Centenarians Live Longer.- 8 Parents of Centenarians also Achieve Unusually Old Age.- 9 Four Families with Clustering for Extreme Longevity.- 9.1 Mathematical Analysis.- 10 Middle-Aged Mothers Live Longer: An Evolutionary Link Between Reproductive Success and Longevity-Enabling Genes.- 10.1 What Determines When a Woman Will Go Through Menopause?.- 10.2 Menopause: An Adaptive Response.- 10.3 Why Menopause Does Not Occur in Other Mammals?.- 10.4 Nonhuman Data Supporting the Association Between Delayed Reproductive Senescence and Increased Longevity.- 10.5 Alternative Explanations for Why Menopause Occurs.- 10.6 Why Is the Human Life Span 122 Years and What Is the Evolutionary Advantage for Living to Such an Age?.- 10.7 What If We Removed the Selective Force for Maximizing Life Span?.- 10.8 The Association Between Longevity-Enabling Genes and Genes Which Regulate Reproductive Health.- 11 In Our Near Future.- References.- Coordination of Metabolic Activity and Stress Resistance in Yeast Longevity.- 1 Introduction.- 2 Phenomenology of Yeast Aging.- 3 Genetics of Longevity.- 4 Physiological and Molecular Mechanisms of Aging.- 4.1 Genetic Instability and Gene Dysregulation.- 4.2 Metabolic Control.- 4.3 Stress Resistance.- 4.4 Coordination of Metabolic Activity and Resistance to Stress.- 4.5 Comparisons with Other Organisms.- 5 Primacy of Metabolic Control.- References.- Current Issues Concerning the Role of Oxidative Stress in Aging: A Perspective.- 1 Introduction.- 2 The Concept of Life Span: A Cautionary Note.- 3 Metabolic Rate, Stress Resistance and Antioxidative Defenses.- 4 Current Evidential Status of the Oxidative Stress Hypothesis of Aging.- 5 Longevity Studies in Transgenic Drosophila.- 6 Hazards of Life-Span Analysis in Drosophila.- 6.1 Compensation.- 6.2 Genetic Effects.- 6.3 Inducible Expression Systems.- 7 Conclusions.- References.- Regulation of Gene Expression During Aging.- 1 Importance of Examining Gene Expression During Aging.- 2 Drosophila as a Model System for Studying Gene Expression During Aging.- 3 Enhancer Trap and Reporter Gene Techniques Can Be Used to Study Gene Expression During Aging.- 4 The Level of Expression of Many Genes Is Dynamically Changing During Adult Life in Drosophila melanogaster.- 5 Gene Expression Is Carefully Regulated During Adult Life in Drosophila melanogaster.- 6 Some Genes Are Regulated by Mechanisms That Are Linked to Life Span and May Serve as Biomarkers of Aging.- 7 The Expression of Some Genes Is Not Changed by Environmental or Genetic Manipulations That Alter Life Span.- 8 Use of Temporal Patterns of Gene Expression as Biomarkers of Aging.- 9 The drop-dead Mutation May Be Used to Accelerate Screens for Long-Lived Mutations.- 10 Studies on Gene Expression Suggest That Not All Things Fall Apart During Aging.- 11 Conclusions.- References.- Crossroads of Aging in the Nematode Caenorhabditis elegans.- 1 Introduction.- 1.1 Life Span Versus Aging.- 1.2 The Worm.- 1.3 Three Paths of Longevity.- 2 Dormancy.- 2.1 The Dauer Larva.- 2.2 The Genetics of Dauer Formation.- 2.3 The Molecular Identities of the Dauer Genes.- 3 The Rate of Living.- 3.1 The Identification of clk Genes.- 3.2 The clk-1 Phenotype.- 3.3 Four clk Genes.- 3.4 The Molecular Identity of clk-1.- 3.5 clk-1 Mutant Mitochondria.- 3.6 Overexpression of CLK-1 Activity.- 3.7 Acceleration of the Rate of Aging.- 3.8 clk-1, Mitochondria and the Nucleus.- 4 Caloric Restriction.- 4.1 Hungry Rats.- 4.2 Hungry Worms.- 5 How Many Different Mechanisms?.- 5.1 An Answer from Genetic Interactions.- 5.2 Rate of Living and Dormancy.- 5.3 Dormancy and Caloric Restriction.- 5.4 Rate of Living and Caloric Restriction.- 5.5 Additivity of clk Genes.- 5.6 Common Grounds: Metabolic Rates and the Germline.- 6 A Unifying Hypothesis.- References.- Contributions of Cell Death to Aging in C. elegans.- 1 Introduction.- 2 C. elegans as Model for Analysis of Molecular Mechanisms of Aging.- 2.1 C. elegans as a Model System.- 2.2 Characterization of Aging Nematodes.- 2.3 Genetics of Life Span in C. elegans.- 3 Cell Death.- 3.1 Programmed Cell Death.- 3.1.1 Programmed Cell Death During Development in C. elegans.- 3.1.2 Relation of Programmed Cell Death (Apoptosis) to Aging in C. elegans.- 3.2 Degenerative Cell Death.- 3.2.1 Necrotic-Like Cell Death in C. elegans.- 3.2.2 Neuropathology of mec-4(d)-Induced Degeneration.- 3.2.3 A Link Between Necrotic-Like Cell Death and Aging?.- 4 Roles of Cell Death in C. elegans Aging, Future Directions..- References.- Stress Response and Aging in Caenorhabditis elegans.- 1 Introduction.- 2 C. elegans Life History — Life in a Stressful Environment.- 3 Longevity (Age) Mutations.- 4 Aging and Stress Response.- 4.1 Is Aging a Stress?.- 4.2 Oxidative Stress and Worm Aging,.- 4.3 Thermotolerance and the Age Mutants.- 4.4 UV Resistance and Aging.- 5 Stress and Life-Span Determination.- References.- Oxidative Stress and Aging in Caenorhabditis elegans.- 1 Introduction.- 2 Genetics and Environment Causes of Aging.- 3 Isolation of Mutants.- 4 Fecundity.- 5 Life Span.- 5.1 mev-1.- 5.2 rad-8.- 6 Aging Markers.- 6.1 Fluorescent Materials.- 6.2 Protein Carbonyls.- 7 Superoxide Dismutase (SOD) Activity.- 8 Molecular Cloning of mev-1.- 9 Enzyme Activity of Cytochrome b560.- 10 Mutagenesis.- 11 Apoptosis in mev-1 and rad-8 Mutants.- 12 Mechanism of Cell Damage by the mev-1 Mitochondrial Abnormality.- 13 Other C. elegans Life-Span Mutants Show Abnormal Responses to Oxidative Stress.- 14 Closing Comments.- References.- Mutation Accumulation In Vivo and the Importance of Genome Stability in Aging and Cancer.- 1 Introduction.- 2 In Vivo Model Systems for Measuring Mutations.- 3 The lacZ-Plasmid Mouse Model for Mutation Detection.- 4 Monitoring Mutation Accumulation in Mice with Defects in Genome Stability Pathways.- 4.1 The TP53 Gene.- 4.2 The XPA Nucleotide Excision Repair Gene.- 5 Summary and General Discussion.- References.- Delayed Aging in Ames Dwarf Mice. Relationships to Endocrine Function and Body Size.- 1 Introduction.- 2 Ames Dwarf Mice.- 3 Snell Dwarf Mice.- 4 Development and Longevity of Dwarf Mice.- 5 Longevity of Snell Dwarf Mice and the Issues of Husbandry.- 6 Possible Mechanisms of Delayed Aging in Dwarf Mice.- 6.1 Reduced Blood Glucose and Increased Sensitivity to Insulin.- 6.2 Hypothyroidism.- 6.3 Reduced Body Temperature and Metabolic Rate.- 6.4 Improved Capacity to Remove Reactive Oxygen Species.- 6.5 Hypogonadism.- 6.6 Deficiency of GH and IGF-I.- 6.7 GH-IGF-I Axis, Body Size, and Aging.- 7 General Conclusions and Future Directions.- References.- Stem Cells and Genetics in the Study of Development, Aging, and Longevity.- 1 Introduction.- 1.1 Definitions.- 1.2 Cancer as a Disease of Both Development and Aging.- 1.3 Stem Cells Are Life-Sustaining Vestiges of Organismal Development.- 1.4 Interrelatedness of Development and Aging — Chapter Outline.- 2 Development as a Reversible Restriction of Developmental Potential.- 2.1 What Is the Mechanism?.- 2.2 Developmental Choices Are Not Necessarily Immutable.- 3 Stem Cell Populations Drive Developmental Systems.- 3.1 Models of Stem Cell Differentiation.- 3.1.1 Clonal Succession.- 3.1.2 Flexibility in Types of Daughter Cells Produced by Stem Cell Division.- 3.1.3 Stem Cell Populations Reflect Physiological Need While Developmental Choices at the Individual Stem Cell Level May Be Stochastic.- 3.2 Why Are Stem Cells Difficult to Study?.- 3.3 Renewal of Stem Cells as Revealed by Transplantation.- 3.4 Stem Cell Kinetics in Steady-State Animals May Be Different.- 3.5 Steady-State Stem Cells Enter and Leave Cell Cycle Regularly.- 3.6 Are Large Animals Fundamentally Different?.- 3.7 What Role for Apoptosis in a Continuously Renewing Stem Cell System?.- 4 Stem Cell Populations as Critical Targets of Damage During Aging.- 4.1 Cancer and Congenital Diseases.- 4.2 Hematologic Malignancies.- 4.3 All Reactive Oxygen Species Are Not Bad.- 5 Hematopoietic Stem Cells as a Model Population for Studies of Aging.- 5.1 Availability and Ease of Study.- 5.2 Contradictory Data.- 5.3 Stem Cell Populations Age.- 5.4 Genetic Influences.- 6 Telomeres.- 6.1 Relationship to Replicative Senescence.- 6.2 Telomeres and Stem Cells.- 6.2.1 Telomere Changes After Stem Cell Transplantation.- 6.3 Telomeres and Aging.- 6.4 Telomeres and Cancer.- 7 A Link Between Stem Cell Replication and Organismal Life Span in the Mouse.- 7.1 Study of Embryo-Aggregated Chimeric Mice.- 7.2 Reversibility of Stem Cell Activation and Quiescence.- 7.3 Genetic Studies.- 7.3.1 In Vitro Assay for Stem Cells.- 7.3.2 Average Life Span Correlates with Cell Cycle Kinetics.- 7.3.3 Mapping Studies in Recombinant Inbred Mouse Strains.- 7.3.4 Quantitative Trait Loci Affecting Life Span and Cell Cycle Kinetics Map to the Same Genomic Locations.- 7.3.5 Mapping of a Locus Determining Variation in Mouse Life Span.- 8 Conclusions and Final Thoughts.- References.