Main description:

The molecular genetics of aging or life-span determination is an expanding field. One reason is because many people would consider it desirable if hu man life span could be extended. Indeed, it is difficult not to be fascinated by tales of the life and death of people who have succeeded in living a very long life. Because of this, we have placed at the head of this book the chapter by Perls et al. on Centenerians and the Genetics of Longevity. Perls and his coauthors convincingly argue that, while the average life expectancy might be mostly determined by environmental factors because the average person has an average genotype, extremely long life spans are genetically determined. Of course, studying humans to uncover the genetics of aging is not ideal, not so much because one cannot easily perform experiments as because they live such a long time. This is why most of this book describes the current state of research with model organisms such as yeast, worms, flies, and mice. J aswinski focuses on yeast and how metabolic activity and stress resistance affect the longevity of Saccharomyces cerevisiae. In the process, he discusses the concept of aging as applied to a unicellular organism such as yeast and the importance of metabolism and stress resistance for aging in all organisms.

Contents:

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.