CHAPTER 1: BASIC CONCEPTS IN THE BIOLOGY OF AGING
1.1 BIOGERONTOLOGY: STUDY OF BIOLOGICAL AGING
Biologists began studying aging when human life spans increased
Biogerontology became independent field of research during 1940s
Current aging research considers health of the total person
Biological aging in nonhuman species shares many traits observed in human aging
Study of aging is complex process
Cause and mechanisms of aging are two separate but linked processes
1.2 DEFINITIONS OF BIOLOGICAL AGING
First definitions of biological aging were based on mortality
Functional-based definitions help describe biological aging over specific time periods
Definition of aging for Biology of Aging
Development, maturity, and senescence are event-related stages used to describe aging
Biological aging is distinct from diseases of old age
1.3 HOW BIOGERONTOLOGISTS STUDY AGING: USE OF LABORATORY ORGANISMS IN HUMAN AGING RESEARCH
Isolated cell systems can be studied to describe basic biochemistry of aging and longevity
Fungi are good models for studying environmental factors that affect aging and longevity
Primitive invertebrates may provide clues to extended cellular life, cell signaling, and whole-body aging
Insects can be used to investigate how whole-body and intracellular signaling affect life history
Mice and rats are common research subjects in investigation of nutritional, genetic, and physiological questions
Nonhuman primates display many of same time-dependent changes as humans
Human progerias can be used to model normal human aging
1.4 HOW BIOGERONTOLOGISTS STUDY AGING: COMPARATIVE BIOGERONTOLOGY
Species' body size related to maximum life span
Reduced vulnerability to extrinsic dangers explains extended longevity
Highly organized social structure also extends longevity in wild
A few aquatic animals have extreme longevity
Planaria and hydra have negligible senescence and extreme longevity associated with high capacity for tissue regeneration
1.5 HOW BIOGERONTOLOGISTS STUDY AGING: SYSTEMS BIOLOGY
Systems biology will help transform biology into a predictive science
Reductive method of science has characterized biological research
Systems biology and reductionism work together to increase knowledge and improve predictions
Reductionism can predict emergent properties in simple biological systems; complex systems require quantitative methods
Modern systems biology and “omics” sciences began with sequencing of human genome
Biological networks provide method of evaluating interactions within system
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CHAPTER 2: MEASURING BIOLOGICAL AGING
2.1 MEASURING BIOLOGICAL AGING IN THE INDIVIDUAL
Differences in age-related phenotype affect measurement of aging in individuals
Lifestyle choices significantly affect phenotype
Cross-sectional studies compare changes in different age groups at single point in time
Longitudinal studies observe changes in a single individual over time
A precise and accurate biomarker of aging will be developed through the Precision Medicine Initiative
2.2 MEASURING BIOLOGICAL AGING IN POPULATION
Mortality rates estimate number of deaths in populations
Life tables contain information on mortality, life expectancy, and probability of dying
Age-specific mortality rate rises exponentially
Age-independent mortality can affect mortality rate
Mortality-rate doubling time corrects for differences in initial mortality rates
Survival curves approximate mortality rate
Deceleration of mortality rate at end of life suggests possibility of longevity genes
Era of precision medicine will change way we measure rate of aging in population
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CHAPTER 3: EVOLUTIONARY THEORIES OF LONGEVITY AND AGING
3.1 FOUNDATIONS OF EVOLUTIONARY THEORIES OF LONGEVITY AND AGING
Weismann established separation between soma and germ cells
Weismann proposed that aging is a nonadaptive trait
Population biologists developed logistic equations to calculate population growth
Population age structure describes Darwinian fitness in complex eukaryotes
Reproduction rate describes age-specific fitness in breeding populations
Fisher described the relationship between reproductive potential and Darwinian fitness in populations
3.2 EVOLUTION AND LONGEVITY
Extrinsic rate of aging leads to decline in force of natural selection
Medawar theorized that aging arose as result of genetic drift
Medawar proposed that aging and longevity arise separately in postreproductive populations
Hamilton's force of natural selection on mortality refined Medawar's theory
3.3 TESTING EVOLUTIONARY MODELS OF LONGEVITY
Late-reproducing organisms have a lower rate of intrinsic mortality
Genetic drift links life span to reproduction
Results from testing the evolutionary theory of longevity changed research in biogerontology
3.4 EVOLUTION AND AGING
Antagonistic pleiotropy is a special case of general pleiotropy
Disposable soma theory is based on allocation of finite resources
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CHAPTER 4: CELLULAR AGING
4.1 CELL CYCLE AND CELL DIVISION
Cell cycle consists of four phases plus one
DNA replication occurs during S phase
Cell division occurs during the M phase
4.2 REGULATION OF THE CELL CYCLE
S-cyclins and cyclin-dependent kinases initiate DNA replication
The p53 pathway can prevent DNA replication at G 1 -to-S phase transition
Many proteins are involved in replication of DNA
Cohesins and condensins help control chromosome segregation
Metaphase-to-anaphase transition marks final checkpoint in cell cycle
Fully functional cells can exit cycle at G 0 phase
Program cell death—apoptosis—is normal part of development and tissue maintenance
4.3 CELL SENESCENCE
A mistake delayed discovery of cell senescence for 50 years
Hayflick's and Moorhead's research findings created field of cytogerontology
Cells in culture have three phases of growth
Senescent cells have several common features
Cell senescence may protect cell against cancer
Mechanisms inducing cell senescence are not known
4.4 CAUSE OF CELLULAR AGING: ACCUMULATION OF DAMAGED BIOMOLECULES
Biomolecules are subject to laws of thermodynamics
Life requires constant maintenance of order and free energy
Mechanism underlying aging is loss of molecular fidelity
Aging reflects intracellular accumulation of damaged biomolecules
4.5 METABOLIC BASIS OF CELLULAR AGING
Multicellular organisms arose when oxygen levels in atmosphere increased
Oxidative metabolism creates reactive oxygen species
Mitochondrial ATP synthesis produces majority of superoxide ions
Enzymes catalyze reduction of superoxide radical to water
Cytosolic reduction also generates free radicals
Oxygen-centered free radicals lead to accumulation of damaged biomolecules
Cell membranes are susceptible to damage by reactive oxygen species
Antagonistic pleiotropy explains aging mechanism leading to damage caused by
reactive oxygen species
4.6 TELOMERES AND CELL SENESCENCE
Telomeres prevent lagging strands from removing vital DNA sequences
Shortening of telomere may cause somatic cell senescence
Short telomeres are associated with time-dependent functional loss and pathology
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CHAPTER 5: GENETICS OF LONGEVITY
5.1 OVERVIEW OF GENE EXPRESSION IN EUKARYOTES
Transcription of DNA produces complementary RNA
Eukaryotic cells modify RNA after transcription
Translation is RNA-directed synthesis of a protein
Proteins can be modified or degraded after translation
5.2 REGULATION OF GENE EXPRESSION
Gene expression can be controlled by changing nucleosome structure: The epigenome
Gene expression is controlled by binding of proteins to DNA
Posttranscriptional mechanisms can also control gene expression
5.3 ANALYZING GENE EXPRESSION IN BIOGERONTOLOGY
Genetic analysis in biogerontology begins with the screening of mutants
Identification of gene function requires DNA cloning
Function of gene can be partially determined from its sequence
In situ hybridization can reveal gene's function
Genetically altering organisms helps evaluate gene's impact on human longevity
DNA microarrays used to evaluate gene expression patterns at different ages
5.4 GENETIC REGULATION OF LONGEVITY IN SACCHAROMYCES CEREVISIAE
Saccharomyces cerevisiae reproduces both asexually and sexually
Environmental conditions influence reproduction and life span
Structural alteration in DNA affects life span
SIR2 pathway linked to longevity
Loss-of-function mutations in nutrient-responsive pathways may extend life span: Target of rapamycin
5.5 GENETIC REGULATION OF LONGEVITY IN CAENORHABDITIS ELEGANS
Regulation of dauer formation extends life span
Genetic pathways regulate dauer formation
Weak mutations in daf-2 extend life span
The daf-2 gene links longevity to neuroendocrine control
Mitochondrial proteins may be link between extended life span and metabolism
5.6 GENETIC REGULATION OF LONGEVITY IN DROSOPHILA MELANOGASTER
Drosophila has a long history in genetic research
Genes that extend longevity are associated with increased stress resistance
Genes controlling Drosophila's growth also extend life span
5.7 GENETIC REGULATION OF LONGEVITY IN MUS MUSCULUS
Many Mus musculus genes reported to affect longevity
Decreased insulin signaling links retarded growth to longevity
Diminished growth hormone signaling links insulin-like signaling pathways to increased longevity
Genetic regulation of longevity demonstrated in mice has implications for human aging
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CHAPTER 6: PLANT SENESCENCE
6.1 BASIC PLANT BIOLOGY
Plant cells have cell wall, central vacuole, and plastids
Photosynthesis takes place in chloroplast
Plant hormones regulate growth and development
6.2 BIOLOGY OF PLANT SENESCENCE
Mitotic senescence occurs in cells of apical meristem
Postmitotic plant senescence involves programmed and stochastic processes
Leaves of Arabidopsis thaliana are model for plant senescence
Leaf senescence is three-step process
Monosaccharides have important role in leaf senescence
Breakdown of the chloroplast provides nitrogen and minerals for other plant organs
Catabolic by-products may stimulate expression of genes involved in organelle dismantling
Plant membranes degrade during leaf senescence
6.3 INITIATING PLANT SENESCENCE
Light intensity affects initiation of plant senescence
Cytokinins delay senescence
Other plant hormones induce senescence
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CHAPTER 7: HUMAN LONGEVITY AND LIFE SPAN
7.1 ORIGINS OF HUMAN LONGEVITY
Human mortality rates are facultative
Genetic factors cause significant plasticity in human mortality rates
Mortality rates differ in long-lived humans
Genome-wide association studies identify genes associated with complex trait of human longevity
Human intelligence altered mortality rates
Human intelligence produced a unique longevity trajectory
Heredity has only a minor influence on human life span
7.2 RISE OF EXTENDED HUMAN LIFE SPAN IN TWENTIETH CENTURY
For most of human history, average human life span was less than 45 years
Control of infectious diseases increased mean life span
Decreases in infant mortality increased life expectancy
Improved medical treatments account for continuing increase in life expectancy
Women have longer mean life expectancy than men
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CHAPTER 8: COMMON FUNCTIONAL LOSS ASSOCIATED WITH AGING
8.1 CHANGES IN BODY COMPOSITION AND ENERGY METABOLISM
Energy balance is difference between intake and expenditure
Accumulation of fat occurs throughout maturity
Excessive loss of body weight near end of life span associated with mortality rate
8.2 CHANGES IN SKELETAL MUSCLE
Muscle contraction is result of molecular interactions between actin and myosin proteins within sarcomere
Process of skeletal muscle contraction begins as neurologic signal
Skeletal muscle contraction speed and force are determined by muscle fiber type
Skeletal muscle damage repair and renewal performed by satellite cells
Lack of physical activity and intrinsic aging influence time-dependent loss of muscle mass
Time-dependent loss in skeletal muscle strength and power correlate with aging muscle atrophy
Intrinsic underlying mechanisms causing aging muscle atrophy are multifactorial and remain unresolved
Denervation of motor neurons and structural fragmentation in neuromuscular junction are hallmarks of aging muscle
Satellite cell function decreases over time
Sarcopenia is pathological condition associated with excessive aging muscle atrophy and strength
8.3 CHANGES IN SKIN
Skin consists of three layers
Wrinkles are caused by loss of skin elasticity and subcutaneous fat
Ultraviolet light causes significant damage to skin over time
8.4 CHANGES IN SENSES: HEARING, VISION, TASTE, AND SMELL
Sense of hearing is based on physics of sound
Transmission of sound through human ear occurs in three steps
Loss of stereocilia contributes to time-dependent hearing loss
Sense of sight is based on physics of light
Presbyopia can be explained by time-dependent changes in refractive power of lens
Terminal differentiation of lens cells leads to formation of cataracts
Senses of taste and smell change only slightly with age
8.5 CHANGES IN DIGESTIVE SYSTEM
Time-dependent changes in mouth and esophagus do not impair digestion
Decline in stomach function is most often associated with atrophic gastritis
Changes in small intestine can affect digestion and nutrient absorption
8.6 CHANGES IN URINARY SYSTEM
Kidneys remove metabolic waste products from blood
Kidneys help regulate blood pressure
Renal blood flow and kidney function decline with aging
8.7 CHANGES IN IMMUNE SYSTEM
Innate immunity provides first line of defense against infection
Acquired immunity relies on lymphocytes reacting to antigens
Phagocytotic function of neutrophils and macrophages declines with age
Production of naive T cells, number of B cells, and effectiveness of antibodies all decline with age
8.8 CHANGES IN REPRODUCTIVE SYSTEM
Menopause is caused by declining secretion of sex hormones by gonads
Male fertility declines slightly with age
Old age is not barrier to sexual activity
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CHAPTER 9: COMMON TIME-DEPENDENT DISEASE IN HUMANS
9.1 NERVOUS SYSTEM AND NEURAL SIGNALS
Nervous system is composed of neurons and supporting cells
Membrane potentials establish conditions for neural signal transmission
Neurotransmitters chemically link neurons together at synapse
Human brain is collection of separate organs and cell types
9.2 TIME-DEPENDENT DISEASES OF HUMAN BRAIN: ALZHEIMER'S AND PARKINSON'S DISEASES
Changes in structure and neurotransmission seem to be minor in aging brain
Amyloid plaques and neurofibrillary tangles accumulate in the aged brain
Alzheimer's disease is a time-dependent, nonreversible brain disorder
Alzheimer's disease begins in entorhinal cortex and progresses into cortex
The ε4 allele of the apolipoprotein E gene is risk factor for late-onset Alzheimer's disease
Treatments for Alzheimer's disease target neurotransmission and prevention and
degradation of amyloid plaques
Effective treatments for Alzheimer's disease will require reliable biomarkers
Brain imaging techniques serve as biomarkers for LAD
Early diagnosis of LAD focuses on detection of MCI and elimination of other dementias
Parkinson's disease is associated with loss of dopaminergic neurons
Increasing brain's concentration of dopamine is primary objective in treatment of Parkinson's disease
Lewy bodies are pathological hallmark of Parkinson's disease
Several genes are associated with early onset Parkinson's disease
Several factors may predispose individuals to Parkinson's disease
Deep brain stimulation can help control movement disorders associated with
Parkinson's disease
9.3 CARDIOVASCULAR SYSTEM
Cardiovascular system is closed system of fluid transport
Heart and arteries are excitable tissues
Heart controls blood flow and pressure by adjusting cardiac output
Principles of fluid dynamics govern overall blood flow
9.4 TIME-DEPENDENT DISEASES OF THE CARDIOVASCULAR SYSTEM: CARDIOVASCULAR DISEASE
Environmental factors influence time-dependent decline in cardiovascular system
Arterial plaques can lead to atherosclerosis and ischemic events
Risk factors for atherosclerosis are mixture of genetic and environmental conditions
Statins reduce synthesis of cholesterol in liver and lower serum cholesterol
Hypertension is most common chronic condition in the aged
Heart failure results in decline in cardiac output
Prevalence may be better descriptor of cardiovascular disease than is mortality
9.5 ENDOCRINE SYSTEM AND GLUCOSE REGULATION
Blood glucose concentration must be maintained within narrow range
Insulin facilitates glucose uptake into liver, muscle, and adipose cells
9.6 TIME-DEPENDENT DISEASE OF ENDOCRINE SYSTEM: TYPE 2 DIABETES MELLITUS
Insulin resistance is a precursor to type 2 diabetes
Type 2 diabetes impairs microvascular blood flow
Altered glucose metabolism may increase cell damage in people with type 2 diabetes
Risk factors for diabetes include increasing age, obesity, and genetic background
9.7 SKELETAL SYSTEM AND BONE CALCIUM METABOLISM
Parathyroid and thyroid hormones balance blood calcium
Hormones regulate balance between bone mineral deposition and resorption
9.8 TIME-DEPENDENT DISEASES OF BONE: OSTEOPOROSIS
Increased rate of bone mineral loss at menopause can lead to osteoporosis
Environmental factors influence risk of developing osteoporosis
Drug therapies can slow bone loss in postmenopausal women
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CHAPTER 10: MODULATING HUMAN AGING AND LONGEVITY
10.1 MODULATING BIOLOGICAL AGING
衰老是无法调控的
Mechanisms that lead to loss of molecular fidelity may be modulated in future
10.2 MODULATING LONGEVITY AND RATE OF AGING: CALORIE RESTRICTION
Calorie restriction increases life span and slows rate of aging in rodents
Calorie restriction in simple organisms used to investigate genetic and molecular mechanisms
Calorie restriction in nonhuman primates may delay age-related disease
Effectiveness of calorie restriction to extend life span in humans remains unknown and controversial
10.3 MODULATING RATE OF AGING: EXERCISE
Definition of exercise for Biology of Aging
Exercise increases muscles' demand for oxygen
Overloading cellular oxidative pathways increases capacity for ATP synthesis
Regular exercise prevents decline in cellular reserve capacity
10.4 CHANGING DEFINITIONS OF HEALTH AND AGING
World Health Organization's definition of health includes subjective measure of well-being and prospect of complete health
Individual ability to adapt to health circumstances will define health in era of precision medicine
Growing old was once viewed as time of disease, disability, and disengagement from life
Heterogeneity of function within older population led to concept of successful aging
Successful aging includes physical, behavioral, and social components
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CHAPTER 11: IMPLICATIONS OF AN EXTENDED HEALTHSPAN
11.1 ACHIEVING THE PROMISE OF EXTENDED HEALTHSPAN
Healthspan combines measures of life span and disability
Preventing or curing chronic disease will not continue to reduce disability
Improving healthspan by increasing levels of exercise and reducing caloric intake will be challenging
Prescribable protocols will help to increase participation in exercise and diet treatments
Medical interventions postponing the proximal mechanisms of aging are being developed
11.2 SOCIAL AND CULTURAL CHANGE IN AN AGING SOCIETY
Healthier and longer life may modify perception of personal achievement and progressive society
Extended longevity and health may change responsibility for renewal of species
Low birth rates and extended longevity may alter current life cycle of generations
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APPENDIX: US LIFE TABLE CALCULATIONS
GLOSSARY
INDEX
