Longevity set 4 fall_2013 (1)
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This document discusses various topics related to mortality and longevity using different animal models for aging research. It provides information on the three most commonly used species for aging studies - the nematode C. elegans, the fruit fly D. melanogaster, and the laboratory mouse. Each species has advantages for research including short lifespans, ease of maintenance, and genetic manipulation. Conserved mechanisms of aging are studied across these different animal models to gain insights on the fundamental biology of the aging process and lifespan in humans.
Longevity set 4 fall_2013 (1)
- 2. UC University of C alifornia Longevity HDE 117/ENT 117
- 4. Selected Topics on Mortality Probability Long intervals: What is probability of male surviving from 50 to 90? 40p50 = l90/l50 = 0.104/0.901 = 0.115 (=1-of-8.7)
- 5. Selected Topics on Mortality Elimination of Mortality Elimination to age x e0 (years) increase 0 20 40 60 80 79.9 80.1 80.5 81.6 86.1 .0 .2 .6 1.7 6.2
- 6. 100% Survival to Age 50 Original: Hypothetical: 79.2 years 81.4 years Difference = 2.2 years
- 7. 100% Survival to Age 60 Original: Hypothetical: 79.2 years 82.8 years Difference = 3.6 years
- 8. 100% Survival to Age 70 Original: Hypothetical: 79.2 years 85.3years Difference = 6.1 years
- 9. 100% Survival to Age 80 Original: Hypothetical: 79.2 years 89.0 years Difference = 9.8 years
- 10. UC University of C alifornia Model #1: Life Table Identity
- 11. C aptive L ife Span Captive life span free ranging in wild capture death Q uestion: estimate life table properties
- 12. PERC ENT 40 30 40% a Population Age Distribution 30% b 25% 20 5% 10 0 d 0 b 1 2 3 Age Time-to-Death Distribution PERC ENT 40 30 20 10 0 0 1 Time-to-Death 2 3
- 13. PERC ENT 40 30 20 10 0 40% b 30% a 25% c b a a Black Box of Unknown Ages d b c 0-1 1-2 5% a 2-3 3-4 2-3 3-4 Age PERC ENT 40 30 20 10 0 0-1 1-2 Time-to-Death
- 14. PERC ENT 40 30 20 40% b 30% a 25% c b a a 10 0 d 0-1 Black Box c 5% a 2-3 1-2 b 3-4 2-3 3-4 Age PERC ENT 40 30 20 10 0 0-1 1-2 Time-to-Death
- 15. PERC ENT 40 30 20 b c 10 0 d 0-1 b Black Box c 1-2 b 2-3 3-4 2-3 3-4 Age PERC ENT 40 a 30 20 10 0 a a a 0-1 1-2 Time-to-Death
- 16. PERC ENT 40 30 b 20 c 10 0 b Black Box d 0-1 1-2 c b 2-3 3-4 2-3 3-4 Age PERC ENT 40 a 30 20 10 0 a a a 0-1 1-2 Time-to-Death
- 17. PERC ENT 40 30 20 c 10 0 Black Box d 0-1 1-2 c 2-3 3-4 2-3 3-4 Age PERC ENT 40 a 30 20 10 0 a a b b a b 0-1 1-2 Time-to-Death
- 18. PERC ENT 40 30 20 c 10 0 Black Box 0-1 c 2-3 1-2 d 3-4 2-3 3-4 Age PERC ENT 40 a 30 20 10 0 a a b b a b 0-1 1-2 Time-to-Death
- 19. PERC ENT 40 30 20 10 0 Black Box 0-1 1-2 d 2-3 3-4 Age PERC ENT 40 a 30 20 10 0 a a b c b c a b 0-1 1-2 Time-to-Death 2-3 3-4
- 20. PERC ENT 40 30 20 10 0 Black Box 0-1 1-2 d 2-3 3-4 Age PERC ENT 40 a 30 20 10 0 a a b c b c a b 0-1 1-2 Time-to-Death 2-3 3-4
- 22. Life Table Identity d x* cx
- 26. R IS K Y B E H AV I O R
- 27. Major Factors Determining Gender Gap: 1. Constitutional endowment 2. Reproductive biology 3. Behavioral predisposition Note: susceptibility and probability are different concepts Donner Party Mortality (1846-1847) Out of 90 individuals in the Donner party 32-of-55 males or 58% died whereas 10of-32 females or 29% of females died. Source: S. McCurdy, Western J. Medicine 160, 338-342 (1994)
- 29. U.S. M ale and F emale Mortality Ratio (2000) Ratio (male:female) 4 MortalityRatio m q x ale q xfe male 3 2 1 0 25 50 Age 75 100
- 30. Age- and sex- specific Mortality U.S. 2000 0.0040 0.0035 Death Rate 0.0030 Men 0.0025 0.0020 0.0015 1-in-1000 Women 0.0010 1-in-2000 0.0005 0.0000 1 5 9 13 17 21 25 A G E (years) 29 33 37
- 31. U.S. 2000 4% Frequency Distribution of Deaths Percentage 3% Females 2% Males 1% 0% 0 25 50 Age 75 100
- 32. Life Expectancy (years) 90 U.S. Life Expectancy in 20th Century 80 female 70 male 60 50 40 30 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
- 33. Female Advantage (years) U.S. Gender Gap in 20th Century 8 6 4 2 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
- 34. Life Expectancy Gains (in weeks) per year 25 U.S. Population 20 15 3 months 10 5 0 1950 1960 1970 1980 1990
- 35. Widening of sex gap in e0 thru most of the 20th century Often attributed to social & behavioral factors (e.g., smoking, heavy drinking, violence, occupational hazards) Recent narrowing of sex gap in most low mortality countries Explanation generally focuses on behavioral and medical factors
- 36. Finland USA Canada Australia New Zealand England & Wales 0 2 4 6 8 10 12 14 Onset of Narrowing 1972-1981 1750 1775 1800 1825 1850 1875 1900 1925 1950 1975 2000 Year SO U R C E: Dana Glei
- 37. Austria Germany, West (former) Norway Netherlands Sweden Denmark Iceland 0 2 4 6 8 10 12 14 Onset of Narrowing 1980-1987 1750 1775 1800 1825 1850 1875 1900 1925 1950 1975 2000 Year SO U R C E: Dana Glei
- 38. Hungary France Germany, East (former) Czech Republic Switzerland Italy 0 2 4 6 8 10 12 14 Onset of Narrowing 1991-1995 1750 1775 1800 1825 1850 1875 1900 1925 1950 1975 2000 Year SO U R C E: Dana Glei
- 39. Russia Latvia Lithuania Slovakia Spain Japan Belgium Bulgaria 0 2 4 6 8 10 12 14 Onset of Narrowing After 1996 1750 1775 1800 1825 1850 1875 1900 1925 1950 1975 2000 Year SO U R C E: Dana Glei
- 40. Biodemography
- 43. Hierarchical Paradigm (nested hierarchies) Demography Anthropology Primatology Evolutionary Biology Genetics Molecular Biology
- 44. Interdisciplinary Research Q uestions 1. Are there specific limits to lifespan? 2. Do females outlive males under all circumstances? 3. What is the relationship of healthspan to lifespan? 4. How does reproduction affect longevity?
- 45. 1. E pistemology 2. Paradigm* an entire constellation of beliefs, value and techniques shared by the members of a given scientific community. Referred to as normal science --what is to be observed and scrutinized --the kind of questions to be asked --how these questions are structured --how the results of investigation interpreted 3. Disciplinary research: --intra-disciplinary --multidisciplinary --interdisciplinary scientific study of how (scientific) knowledge is acquired *Kuhn, T.S., 1996. The Structure of Scientific Revolutions. The University of Chicago Press, Chicago.
- 46. Biodemography an area of interdisciplinary research in which principles of both biology and demography are integrated and brought to bear on questions concerned with aging, reproduction and health in humans but which include the use model (non-human animal) systems. Subdivisions: Biological biodemography (mostly animal research) --evolution --ecology --behavior Biomedical biodemography (mostly human research) --healthy aging --geriatrics-related
- 47. A nimal Models in Aging Research (Modified from presentation of Steven Austad, Keck Futures Conference, Newport Beach, CA October, 2007)
- 48. Biology of the F initude Three Primitive Questions 1. Why do we live as long as we do? 2. Why do we age? 3. Why do we die?
- 49. G O A L: To provide enough information about common aging research models to help non-biologists assess their utility and relevance with respect to alterations in human health span
- 50. O ver 90% of animal studies on the basic biology of aging involves three species: worm, fly, and mouse C. elegans (the worm) D. melanogaster (the fly) house mouse (the mouse) Size 1 mm 5 mm (1 mg) 35 g Longevity 15-20 days 50-60 days 2-3 yrs Reprod. length 6d 50 days Maturation 3d 10 days Reprod. rate 100 eggs/day Species: Caenorhabditis elegans Drosophila melanogaster Mus musculus 30-50 eggs/day 10-12 mo 2 mo 40 pups/yr
- 54. Similarities amount animal species used in aging research All are domesticated (altered from ancestral form) All are short lived compared to non-domesticated relatives
- 55. Nematodes (roundworms) Numerous in all habitats Free living vs parasitic All very similar in general structure
- 56. A dvantages of Worms for Aging Research Small, can be reared and maintained in huge quantities Short life cycle Simple, transparent body completely described Inbred strains (genetic uniformity) Unparalleled ease of genetic manipulation Excellent genome description Massive information available on-line
- 57. C . E legans Two sexes (males and hermaphrodites) Naturally inbred; males rare Constant somatic cell number=959 No somatic cell division Senses: taste, smell, touch, temperature Free-living; little known about ecology
- 58. C. elegans Cell Fate
- 59. C . elegans L ife C ycle L2d Egg dauer (days to months) L1 L4 L3 L2 3 days DEVELOPMENT Adult Death approx 2 wks aging
- 60. T he Dauer L arva Formation due to food shortage, crowding, or high temperatures Predominant stage in nature Not feed, move little, stress resistant and long-lived -
- 61. Worm Aging Longevity has been increased often dramatically methods (genes, chemical, diet restriction) in worms by many Greatest longevity increase up to 6-fold Some aging mutants slowed down in all aspects of life SOURCE: Garsin et al. (2003) Science 300, 1921
- 62. Worm Aging I I: Aging Phenotype Little evidence of structural damage except to body wall muscle and cuticle Reduced movement and feeding rate (pharyngeal pumping) with age Class A constant movement; sinusoidal paths Class B does not move unless prodded Class C does not move even when prodded; twitches head/tail Class D dead
- 63. T he fruit fly Drosophila melanogaster (different family than medfly) Small fly used for 100 years in study of genetics Maintained in huge numbers in lab Excellent demography Vastly more physically and behaviorally complex than worm --specialized organs for vision, hearing, excretion, circulation --neurons: 302 in worm; >100,000 in fly Minimal cell turnover in adult (no cancer)
- 65. Aspects of F ly Natural H istory Originated in Equatorial Africa Today: all continents except Antarctica Eggs laid in ripe/rotting fruit Hatching larvae feed on fruit Adults feed on fruit and microorganisms
- 66. F ly Aging Age is length of adult life (ignore larvae) Lifespan extended 2-fold Long-lived mutants resistant to multiple stressors (e.g. heat, UV, chemicals) Causes of death unknown
- 67. F ly Behaviors Useful for Assessing H ealth Spontaneous movement Flight speed endurance Negative geotaxis Olfactory sensitivity Various fertility measures Stress resistance Learning and memory Cardiac function Innate immune function
- 68. T he L aboratory Mouse Dozens of inbred strains available Most (70%) of published studies on aging relies on one inbred strain (C57BL/6) Lots of information about diseases and causes of death By far most common cause of death is cancer
- 70. Aging in L aboratory M ice Caloric restriction extends life (20-40%) in many lab strains Longevity mutants: more than a dozen; extend life up to 50% Most of these studies rely on only one survival study
- 72. The Life Span Concepts
- 73. Life Span: Conceptual Issues 1. Life duration (broader concept than life span) 2. Individual (discrete functional entity) 3. Genesis (conception; fetal stage; birth; adulthood) 4. State of existence (normal; arrested metabolism) 5. Time of existence (normal plus period of arrest) 6. Extinction (death; fission; fusion)
- 74. The Life Span Concept: Examples Where the Lines are Blurred 1. Amoeba 2. Hydra replacing all of cells every 10 days 3. Flatworm split into separate parts 4. Embryos dividing to form clones (e.g. identical twins) 5. Chimeras formed when embryos fuse MAIN POINT: issues concerning level of individualism birth and death processes, and the disappearance of original individuals invalidate the classic definition of life span for many organisms and/or for certain situations with humans
- 75. Quantum Nature of Death Coma Breath stoppage Heart stoppage Brain death Cessation of growth/metabolism Tissue degradation Loss of DNA integrity How can a person be deader than dead? Death of immediate family members, extended family
- 76. Related Concepts 1. Mortal destined to die 2. Immortal 3. Eternal life after death 4. Infinity endlessness 5. Determinate 6. Indeterminate living forever fixed growth or age open-ended growth or life span
- 80. Life Span and Age Two Types of Ages 1. Chronological 2. Physiological Two Types of Chronological Ages 1. Postnatal age from birth 2. Total age from conception
- 81. Tree of Life Crown group last is the smallest the last common ancestor of all extant members, and all of that ancestor's descendants A B C D E F G