The Genetics of Aging

I. Genome Level.- 1 Molecular Genetics of Aging.- 1. Introduction.- 2. Mechanisms for the Inheritance of the Patterns of Senescence and Longevity.- 2.1. Explicit Inheritance.- 2.2. Implicit Inheritance.- 3. Molecular-Genetic Mechanisms of Senescence.- 3.1. Altered Molecules.- 3.1.1. Somatic Mutations.- 3.1.2. Error Catastrophe.- 3.1.3. Compensation and Repair.- 3.2. Programmed Aging.- 4. Conclusion.- References.- 2 Cytogenetics of Aging.- 1. Introduction.- 2. Alterations in Lymphocyte Chromosome Complement with Human Aging.- 3. Population Studies.- 4. Aneuploidy, Aging, and Organic Brain Disease.- 5. Effect of Genotype on Aneuploidy.- 6. Specific vs. Nonspecific Chromosome Loss.- 7. Polyploidy.- 8. Cross-Sectional vs. Longitudinal Studies.- 9. Chromosomal Alterations with Aging in Tissues Other than Lymphocytes.- 10. Effect of Experimental Conditions on Chromosome Number.- 11. In Vivo Examination of Aneuploidy.- 12. Studies of the Stability of the Chromosome Complement with in Vitro “Aging”.- 13. Chromosomal Alteration, Malignancy, and Aging.- 14. Mechanisms for the Loss of Specific Chromosomes with Aging.- 14.1. Survival of Cells Missing Specific Chromosomes.- 14.2. Selective Loss of Specific Chromosomes.- 14.3. Effect of Aging on Selection.- 15. Future Research on the Cytogenetics of Aging.- 16. Summary.- References.- 3 Aging and DNA-Repair Capability.- 1. Introduction.- 2. DNA-Repair Processes.- 2.1. Strand-Breakage Rejoining.- 2.2. Excision Repair.- 2.3. Postreplication Repair.- 2.4. Photoreactivation.- 2.5. Assay Systems for DNA Repair.- 3. Age-Related Occurrence of Unrepaired DNA Lesions.- 3.1. DNA Strand Breakage.- 3.2. DNA Cross-Linking.- 3.3. Chromosome Aberrations.- 4. DNA-Repair Capability as a Function of Age.- 4.1. In Vitro Investigations.- 4.2. In Vivo Investigations.- 5. Tissue-Specific DNA-Repair Capability.- 6. Acceleration of the Aging Process by Exposure to DNA-Damaging Agents.- 7. Human Genetic Syndromes.- 7.1. Syndromes of DNA-Repair Deficiency.- 7.2. Syndromes of Accelerated Aging.- 7.3. Conclusions.- 8. Longevity and DNA-Repair Processes.- 9. Summary and Conclusion.- References.- 4 Somatic Mutations and Aging.- 1. Introduction.- 2. Terminology of Mutagenesis.- 2.1. Concepts and Definitions.- 2.2. Mutations in Nondividing Cells.- 3. Metabolic Stability of DNA: Contrast to Turnover of Intracellular Macromolecules.- 4. Accumulation of Somatic Mutations with Aging.- 4.1. Chromosome Aberrations.- 4.2. Distinguishing Somatic Mutations from Errors.- 4.3. Base-Substitution Mutations.- 4.4. Germinal vs. Somatic Mutations.- 5. Mutagens, Carcinogens, Cancer, and Aging.- 5.1. Age-Associated Incidence of Cancer in Man and Other Mammals.- 5.2. Mutagenicity of Chemical Carcinogens.- 6. Special Genetic Mechanisms of Aging.- 7. Summary.- References.- II. Organism Level.- 5 Genetics of Aging in Lower Organisms.- 1. Introduction.- 2. Inheritance of Life Span.- 2.1. Effect of Chromosome Number on Longevity.- 2.2. Effect of Genotype on Longevity.- 2.3. Cytoplasmic Inheritance of Aging in Fungi.- 2.4. Effect of Parental Age on Longevity.- 3. Induction of Aging in Immortal Organisms.- 3.1. “Spanning” of Amoeba.- 3.2. Mutants of Neurospora.- 3.3. Autogamy-Deprived Paramecia.- 4. Summary and Conclusions.- References.- 6 Evolution of Longevity and Survival Characteristics in Mammals.- 1. Introduction.- 2. Evolutionary Gerontology: What Evolved, Aging or Longevity?.- 2.1. Allometry of Vertebrate Life Span.- 2.2. “Senescence Gene” Hypothesis of the Evolution of Aging.- 2.3. Evolution of Longevity by Means of Longevity-Assurance Genes.- 3. Evolution of Longevity in Man and the Other Mammals.- 4. Life Tables for Natural Populations.- 5. Evolutionary Change of the Parameters of the Gompertzian Survival Characteristic.- 6. Conclusion.- References.- III. Human Genetics.- 7 Human Genetic Disorders that Feature Premature Onset and Accelerated Progression of Biological Aging.- 1. Introduction.- 2. Specific Criteria of Aging.- 2.1. Physiological Markers.- 3. Premature Aging.- 3.1. General Criteria.- 3.2. A Specific Scoring System for Premature Aging.- 4. Description of Selected Disorders That Feature Premature Aging.- 4.1. Classic Progeroid Syndromes.- 4.2. Numerical Chromosome Anomalies.- 4.3. Miscellaneous Inherited Syndromes.- 5. Comparison of Premature Aging Syndromes with Normal Biological Aging.- 6. Tissue Culture Approaches to Premature Aging.- 6.1. Studies on Cell Growth.- 6.2. Defective Molecules in Prematurely Aging Cells.- 7. Significance of Biochemical Defects in Prematurely Aging Fibroblasts.- 7.1. Defects in Protein Turnover.- 7.2. Defects in RNA Turnover.- 7.3. Defects in DNA Repair.- 7.4. Defects in DNA Replication.- 8. Conclusions and Future Directions.- References.- 8 Parental-Age Effects: Increased Frequencies of Genetically Abnormal Offspring.- 1. Introduction.- 2. Maternal- vs. Paternal-Age Effects.- 3. Maternal-Age-Related Disorders.- 4. Paternal-Age-Related Disorders.- 5. Proposed Etiological Agents.- 5.1. Radiation.- 5.2. Chemicals.- 5.3. Autoimmunity.- 5.4. Infectious Agents.- 5.5. Genetic Predisposition.- 5.6. Preovulatory Overripeness.- 5.7. Postovulatory Aging.- 6. Mechanisms of Nondisjunction.- 6.1. Nucleolar Organization.- 6.2. Univalent Formation.- 6.3. Premature Centromere Division.- 7. Approaches to Studying Parental-Age Effects.- 8. Prevention by Genetic Counseling and Prenatal Diagnosis.- 9. Summary.- References.- 9 Genetics of Longevity in Man.- 1. Introduction.- 2. Evolutionary Implications.- 3. Genetics and Length of Life.- 3.1. Aging May Be Ineluctable.- 3.2. Aging May Be a Programmed Self-Destruction.- 3.3. Aging May Be an Exogenous Process.- 4. Analysis of Empirical Data.- 5. Models of Aging.- 5.1. External Models.- 5.2. Internal Models.- 5.3. Composite Models.- 5.4. Constructive Models.- 6. Studies of the Inheritance of Longevity.- 6.1. Previous Studies.- 6.2. The Baltimore Longevity Study.- 6.3. Our Extension of the Baltimore Study.- 7. Summary and Conclusion.- References.- 10 A Longitudinal Study of Aging Human Twins.- 1. Introduction: History, Methodology, and Purpose.- 2. Genetic Factors and Survival.- 3. Genetic Factors and Mental Functioning.- 3.1. Test-Battery Description and Initial Assessment.- 3.2. Longitudinal Changes in Psychological Test Performance.- 3.3. Psychological Testing and Prediction of Survival.- 3.4. Test Performance, Ability, and Education as Factors in Aging.- 4. Chromosome Change and Survival.- 5. Chromosome Change and Mental Functioning.- 6. Sex Differences and Survival.- 7. Sex Differences and Mental Functioning.- 8. Summary and Conclusions.- References.- IV. Genetic Approaches to Aging Research.- 11 Somatic Cell Genetics in the Analysis of in Vitro Senescence.- 1. Introduction.- 2. Biology of Cultured Mammalian Cells.- 2.1. Historical Background.- 2.2. The Phenomenon of in Vitro Senescence.- 2.3. Relevance of in Vitro Senescence to in Vivo Senescence.- 3. Phenotype of the Senescent Culture.- 3.1. Alterations of Proliferative Behavior with Senescence.- 3.2. Cytogenetic Alterations.- 3.3. Morphology.- 3.4. Implication for Genetic Studies.- 4. Somatic Cell Genetic Studies of in Vitro Cellular Senescence.- 4.1. Theories of the Mechanism of in Vitro Senescence.- 4.2. Scope of Somatic Cell Genetics.- 4.3. Heterokaryon Studies.- 4.4. Enucleation—Fusion Studies.- 4.5. Synkaryon Studies.- 5. Discussion.- References.- 12 Immunogenetics of Aging.- 1. Introduction.- 2. Histocompatibility Systems and Immune Responses.- 3. Immune Functional Changes with Age.- 3.1. T-Dependent Immune Functions.- 3.2. T-Independent Immune Functions.- 3.3. Autoimmunity.- 4. Genetic Influences of Immune Function in Aging.- 4.1. Influence of Sex.- 4.2. Influence of Strain or Race.- 4.3. Studies in Congenic Mice.- 4.4. The Major Histocompatibility (HLA System) in Humans in Relation to Aging.- 5. Immunogenetic Diseases and Aging.- 6. Summary.- References.- 13 Behavior Genetics and Aging.- 1. Introduction.- 2. Life Span.- 2.1. Inbred Mice.- 2.2. Hybrid Mice.- 2.3. Mutant Mice.- 2.4. Body-Weight Increment and Longevity.- 3. Behavior.- 3.1. Exploration and Open-Field Activity.- 3.2. Wheel Activity.- 3.3. Responsiveness to Light Onset.- 3.4. Sucrose Discrimination and Fluid Intake.- 3.5. Alcohol Preference.- 4. Summary.- References.