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.

1. Longevity
HDE/ENT 117

2. UC
University
of C alifornia
Longevity
HDE 117/ENT 117

3. Selected Topics
on Mortality

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

21. PERC ENT
40
30
20
40%
b
30%
a
25%
c
b
a
d
c
b
a
0-1
1-2
2-3
3-4
a
10
0
5%
Age
PERC ENT
40
40%
a
30
20
10
0
a
a
30%
b
25%
c
b
c
a
b
0-1
1-2
Time-to-Death
5%
d
2-3
3-4

22. Life Table Identity
d x*
cx

25. Sex Mortality
Differentials

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)

28. U.S. 2000
.4
Death Rate
.3
Male
Female
.2
.1
0
0
25
50
Age
75
100

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

41. Experimental Biodemography
Multidisciplinary Paradigm
Demography
Anthropology

42. Hierarchical Paradigm
(nested hierarchies)
Demography
Anthropology

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

51. Phylogeny
nematodes
reptiles
insects
birds
mouse
100 million years
humans

52. Conserved M echanisms

53. Conserved M echanisms

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

69. The Laboratory Mouse

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