Gender Specific Effects of Early-Life Events on Adult Lifespan

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CONTEMPORARY METHODS OF MORTALITY ANALYSIS
CONTEMPORARY METHODS OF MORTALITY
ANALYSIS Biodemography of Mortality and Longevity
Lecture 1 Leonid Gavrilov Natalia
Gavrilova Center on Aging NORC and the
University of Chicago Chicago, Illinois, USA
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Empirical Laws of Mortality
4
The Gompertz-Makeham Law
Death rate is a sum of age-independent component
(Makeham term) and age-dependent component
(Gompertz function), which increases
exponentially with age.
µ(x) A R e ax A Makeham term or background
mortality R e ax age-dependent mortality x -
age
risk of death
5
Gompertz Law of Mortality in Fruit Flies
Based on the life table for 2400 females of
Drosophila melanogaster published by Hall (1969).
Source Gavrilov, Gavrilova, The Biology of
Life Span 1991
6
Gompertz-Makeham Law of Mortality in Flour Beetles
Based on the life table for 400 female flour
beetles (Tribolium confusum Duval). published by
Pearl and Miner (1941). Source Gavrilov,
Gavrilova, The Biology of Life Span 1991
7
Gompertz-Makeham Law of Mortality in Italian
Women
Based on the official Italian period life table
for 1964-1967. Source Gavrilov, Gavrilova,
The Biology of Life Span 1991
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How can the Gompertz-Makeham law be used?
By studying the historical dynamics of the
mortality components in this law µ(x) A R e
ax
Makeham component
Gompertz component
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The Strehler-Mildvan Correlation Inverse
correlation between the Gompertz parameters
Limitation Does not take into account the
Makeham parameter that leads to spurious
correlation
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Modeling mortality at different levels of Makeham
parameter but constant Gompertz parameters
1 A0.01 year-1 2 A0.004 year-1 3 A0
year-1
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Coincidence of the spurious inverse correlation
between the Gompertz parameters and the
Strehler-Mildvan correlation
Dotted line spurious inverse correlation
between the Gompertz parameters Data points for
the Strehler-Mildvan correlation were obtained
from the data published by Strehler-Mildvan
(Science, 1960)
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Compensation Law of Mortality(late-life
mortality convergence)
Relative differences in death rates are
decreasing with age, because the lower initial
death rates are compensated by higher slope
(actuarial aging rate)
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Compensation Law of MortalityConvergence of
Mortality Rates with Age
1 India, 1941-1950, males 2 Turkey,
1950-1951, males 3 Kenya, 1969, males 4 -
Northern Ireland, 1950-1952, males 5 - England
and Wales, 1930-1932, females 6 - Austria,
1959-1961, females 7 - Norway, 1956-1960,
females Source Gavrilov, Gavrilova, The
Biology of Life Span 1991
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Compensation Law of Mortality (Parental
Longevity Effects) Mortality Kinetics for
Progeny Born to Long-Lived (80) vs Short-Lived
Parents
Sons
Daughters
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Compensation Law of Mortality in Laboratory
Drosophila
1 drosophila of the Old Falmouth, New Falmouth,
Sepia and Eagle Point strains (1,000 virgin
females) 2 drosophila of the Canton-S strain
(1,200 males) 3 drosophila of the Canton-S
strain (1,200 females) 4 - drosophila of the
Canton-S strain (2,400 virgin females) Mortality
force was calculated for 6-day age
intervals. Source Gavrilov, Gavrilova, The
Biology of Life Span 1991
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Implications

• Be prepared to a paradox that higher actuarial
  aging rates may be associated with higher life
  expectancy in compared populations (e.g., males
  vs females)
• Be prepared to violation of the proportionality
  assumption used in hazard models (Cox
  proportional hazard models)
• Relative effects of risk factors are
  age-dependent and tend to decrease with age

17
The Late-Life Mortality Deceleration (Mortality
Leveling-off, Mortality Plateaus)
The late-life mortality deceleration law states
that death rates stop to increase exponentially
at advanced ages and level-off to the late-life
mortality plateau.
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Mortality deceleration at advanced ages.

• After age 95, the observed risk of death red
  line deviates from the value predicted by an
  early model, the Gompertz law black line.
• Mortality of Swedish women for the period of
  1990-2000 from the Kannisto-Thatcher Database on
  Old Age Mortality
• Source Gavrilov, Gavrilova, Why we fall apart.
  Engineerings reliability theory explains human
  aging. IEEE Spectrum. 2004.

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Mortality Leveling-Off in House Fly Musca
domestica
Based on life table of 4,650 male house flies
published by Rockstein Lieberman, 1959
20
Non-Aging Mortality Kinetics in Later Life
Source A. Economos. A non-Gompertzian paradigm
for mortality kinetics of metazoan animals and
failure kinetics of manufactured products. AGE,
1979, 2 74-76.
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Non-Aging Failure Kinetics of Industrial
Materials in Later Life(steel, relays, heat
insulators)
Source A. Economos. A
non-Gompertzian paradigm for mortality kinetics
of metazoan animals and failure kinetics of
manufactured products. AGE, 1979, 2 74-76.
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Mortality Deceleration in Animal Species

• Mammals
• Mice (Lindop, 1961 Sacher, 1966 Economos, 1979)
• Rats (Sacher, 1966)
• Horse, Sheep, Guinea pig (Economos, 1979 1980)
• However no mortality deceleration is reported for
• Rodents (Austad, 2001)
• Baboons (Bronikowski et al., 2002)

• Invertebrates
• Nematodes, shrimps, bdelloid rotifers, degenerate
  medusae (Economos, 1979)
• Drosophila melanogaster (Economos, 1979
  Curtsinger et al., 1992)
• Housefly, blowfly (Gavrilov, 1980)
• Medfly (Carey et al., 1992)
• Bruchid beetle (Tatar et al., 1993)
• Fruit flies, parasitoid wasp (Vaupel et al., 1998)

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Existing Explanations of Mortality Deceleration

• Population Heterogeneity (Beard, 1959 Sacher,
  1966). sub-populations with the higher injury
  levels die out more rapidly, resulting in
  progressive selection for vigour in the surviving
  populations (Sacher, 1966)
• Exhaustion of organisms redundancy (reserves) at
  extremely old ages so that every random hit
  results in death (Gavrilov, Gavrilova, 1991
  2001)
• Lower risks of death for older people due to less
  risky behavior (Greenwood, Irwin, 1939)
• Evolutionary explanations (Mueller, Rose, 1996
  Charlesworth, 2001)

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Testing the Limit-to-Lifespan Hypothesis
Source Gavrilov L.A., Gavrilova N.S. 1991. The
Biology of Life Span
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Implications

• There is no fixed upper limit to human longevity
  - there is no special fixed number, which
  separates possible and impossible values of
  lifespan.
• This conclusion is important, because it
  challenges the common belief in existence of a
  fixed maximal human life span.

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Latest Developments
Was the mortality deceleration law overblown? A
Study of the Extinct Birth Cohorts in the United
States
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More recent birth cohort mortality
Nelson-Aalen monthly estimates of hazard rates
using Stata 11
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What about other mammals?

• Mortality data for mice
• Data from the NIH Interventions Testing Program,
  courtesy of Richard Miller (U of Michigan)
• Argonne National Laboratory data,
  courtesy of Bruce Carnes (U of Oklahoma)

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Mortality of mice (log scale) Miller data
males
females

• Actuarial estimate of hazard rate with 10-day age
  intervals

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What are the explanations of mortality laws?
Mortality and aging theories
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What Should the Aging Theory Explain

• Why do most biological species including humans
  deteriorate with age?
• The Gompertz law of mortality
• Mortality deceleration and leveling-off at
  advanced ages
• Compensation law of mortality

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Additional Empirical ObservationMany age
changes can be explained by cumulative effects of
cell loss over time

• Atherosclerotic inflammation - exhaustion of
  progenitor cells responsible for arterial repair
  (Goldschmidt-Clermont, 2003 Libby, 2003
  Rauscher et al., 2003).
• Decline in cardiac function - failure of cardiac
  stem cells to replace dying myocytes (Capogrossi,
  2004).
• Incontinence - loss of striated muscle cells in
  rhabdosphincter (Strasser et al., 2000).

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Like humans, nematode C. elegans
experience muscle loss
Herndon et al. 2002. Stochastic and genetic
factors influence tissue-specific decline in
ageing C. elegans. Nature 419, 808 - 814. many
additional cell types (such as hypodermis and
intestine) exhibit age-related deterioration.
Body wall muscle sarcomeres Left - age 4 days.
Right - age 18 days
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What Is Reliability Theory?
Reliability theory is a general theory of
systems failure developed by mathematicians
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Aging is a Very General Phenomenon!
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Stages of Life in Machines and Humans
Bathtub curve for human mortality as seen in the
U.S. population in 1999 has the same shape as the
curve for failure rates of many machines.
The so-called bathtub curve for technical systems
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Gavrilov, L., Gavrilova, N. Reliability theory
of aging and longevity. In Handbook of the
Biology of Aging. Academic Press, 6th edition,
2006, pp.3-42.
38
The Concept of Systems Failure
In reliability theory failure is defined as
the event when a required function is terminated.
39
Definition of aging and non-aging systems in
reliability theory

• Aging increasing risk of failure with the
  passage of time (age).
• No aging 'old is as good as new' (risk of
  failure is not increasing with age)
• Increase in the calendar age of a system is
  irrelevant.

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Aging and non-aging systems

Progressively failing clocks are aging (although
their 'biomarkers' of age at the clock face may
stop at 'forever young' date)
Perfect clocks having an ideal marker of their
increasing age (time readings) are not aging
41
Mortality in Aging and Non-aging Systems
aging system
non-aging system
Example radioactive decay
42
According to Reliability TheoryAging is NOT
just growing oldInsteadAging is a degradation
to failure becoming sick, frail and
dead

• 'Healthy aging' is an oxymoron like a healthy
  dying or a healthy disease
• More accurate terms instead of 'healthy aging'
  would be a delayed aging, postponed aging, slow
  aging, or negligible aging (senescence)

43
The Concept of Reliability Structure

• The arrangement of components that are important
  for system reliability is called reliability
  structure and is graphically represented by a
  schema of logical connectivity

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Two major types of systems logical connectivity

• Components connected in series
• Components connected in parallel

Fails when the first component fails
Ps p1 p2 p3 pn pn
Fails when all components fail
Qs q1 q2 q3 qn qn

• Combination of two types Series-parallel system

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Series-parallel Structure of Human Body

• Vital organs are connected in series

• Cells in vital organs are connected in parallel

46
Redundancy Creates Both Damage Tolerance and
Damage Accumulation (Aging)
System without redundancy dies after the first
random damage (no aging)
System with redundancy accumulates damage
(aging)
47
Reliability Model of a Simple Parallel System
Failure rate of the system
Elements fail randomly and independently with a
constant failure rate, k n initial number of
elements
? nknxn-1 early-life period approximation,
when 1-e-kx ? kx ? k late-life
period approximation, when 1-e-kx ? 1
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Failure Rate as a Function of Age in Systems
with Different Redundancy Levels
Failure of elements is random
49
Standard Reliability Models Explain

• Mortality deceleration and leveling-off at
  advanced ages
• Compensation law of mortality

50
Standard Reliability Models Do Not Explain

• The Gompertz law of mortality observed in
  biological systems
• Instead they produce Weibull (power) law of
  mortality growth with age

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An Insight Came To Us While Working With
Dilapidated Mainframe Computer

• The complex unpredictable behavior of this
  computer could only be described by resorting to
  such 'human' concepts as character, personality,
  and change of mood.

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Reliability structure of (a) technical devices
and (b) biological systems
Low redundancy Low damage load
High redundancy High damage load
X - defect
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Models of systems with distributed redundancy
Organism can be presented as a system constructed
of m series-connected blocks with binomially
distributed elements within block (Gavrilov,
Gavrilova, 1991, 2001)
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Model of organism with initial damage load
Failure rate of a system with binomially
distributed redundancy (approximation for initial
period of life)
Binomial law of mortality
- the initial virtual age of the system
where
The initial virtual age of a system defines the
law of systems mortality

• x0 0 - ideal system, Weibull law of mortality
• x0 gtgt 0 - highly damaged system, Gompertz law of
  mortality

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People age more like machines built with lots of
faulty parts than like ones built with pristine
parts.

• As the number of bad components, the initial
  damage load, increases bottom to top, machine
  failure rates begin to mimic human death rates.

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Statement of the HIDL hypothesis(Idea of High
Initial Damage Load )
"Adult organisms already have an exceptionally
high load of initial damage, which is comparable
with the amount of subsequent aging-related
deterioration, accumulated during the rest of the
entire adult life."
Source Gavrilov, L.A. Gavrilova, N.S. 1991.
The Biology of Life Span A Quantitative
Approach. Harwood Academic Publisher, New York.
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Why should we expect high initial damage load in
biological systems?

• General argument--  biological systems are
  formed by self-assembly without helpful external
  quality control.
• Specific arguments

• Most cell divisions responsible for  DNA
  copy-errors occur in early development leading to
  clonal expansion of mutations
• Loss of telomeres is also particularly high in
  early-life
• Cell cycle checkpoints are disabled in early
  development

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Practical implications from the HIDL hypothesis
"Even a small progress in optimizing the
early-developmental processes can potentially
result in a remarkable prevention of many
diseases in later life, postponement of
aging-related morbidity and mortality, and
significant extension of healthy lifespan."
Source Gavrilov, L.A. Gavrilova, N.S. 1991.
The Biology of Life Span A Quantitative
Approach. Harwood Academic Publisher, New York.
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Life Expectancy and Month of Birth
Data source Social Security Death Master File
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Evolution of Species Reliability

• Reliability theory of aging is perfectly
  compatible with the idea of biological evolution.
• Moreover, reliability theory helps evolutionary
  theories to explain how the age of onset of
  diseases caused by deleterious mutations could be
  postponed to later ages during the evolution.

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Evolution in the Direction of Low Mortality at
Young Ages

• This could be easily achieved by simple increase
  in the initial redundancy levels (e.g., initial
  cell numbers).

Log risk of death
Age
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Evolution of species reliability

• Fruit flies from the very beginning of their
  lives have very unreliable design compared to
  humans.
• High late-life mortality of fruit flies compared
  to humans suggests that fruit flies are made of
  less reliable components (presumably cells),
  which have higher failure rates compared to human
  cells.

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Reliability of Birds vs Mammals

• Birds should be very prudent in redundancy of
  their body structures (because it comes with a
  heavy cost of additional weight).
• Result high mortality at younger ages.
• Flight adaptation should force birds to evolve in
  a direction of high reliability of their
  components (cells).
• Result low rate of elements (cells)
  damage resulting in low mortality at older ages

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Effect of extrinsic mortality on the evolution of
senescence in guppies.Reznick et al. 2004.
Nature 431, 1095 - 1099

• Reliability-theory perspective
• Predators ensure selection for better
  performance and lower initial damage load.
• Hence life span would increase in high predator
  localities.

Solid line high predator locality Dotted line
low predator locality
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Conclusions (I)

• Redundancy is a key notion for understanding
  aging and the systemic nature of aging in
  particular. Systems, which are redundant in
  numbers of irreplaceable elements, do deteriorate
  (i.e., age) over time, even if they are built of
  non-aging elements.
• An apparent aging rate or expression of aging
  (measured as age differences in failure rates,
  including death rates) is higher for systems with
  higher redundancy levels.

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Conclusions (II)

• Redundancy exhaustion over the life course
  explains the observed compensation law of
  mortality (mortality convergence at later life)
  as well as the observed late-life mortality
  deceleration, leveling-off, and mortality
  plateaus.
• Living organisms seem to be formed with a high
  load of initial damage, and therefore their
  lifespans and aging patterns may be sensitive to
  early-life conditions that determine this initial
  damage load during early development. The idea of
  early-life programming of aging and longevity may
  have important practical implications for
  developing early-life interventions promoting
  health and longevity.

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Testing Biological Theories of Aging with
Demographic and Genealogical Data
69
What are the data and the predictions of the
evolutionary theory on

• Links between human longevity and fertility
• Lifespan heritability in humans
• Quality of offspring conceived to older parents

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Founding Fathers

• Beeton, M., Yule, G.U., Pearson, K. 1900. Data
  for the problem of evolution in man. V. On the
  correlation between duration of life and the
  number of offspring. Proc. R. Soc. London, 67
  159-179.
• Data used English Quaker records and Whitney
  Family of Connectucut records for females and
  American Whitney family and Burkes Landed
  Gentry for males.

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Findings and Conclusions by Beeton et al., 1900

• They tested predictions of the Darwinian
  evolutionary theory that the fittest individuals
  should leave more offspring.
• Findings Slightly positive relationship between
  postreproductive lifespan (50) of both mothers
  and fathers and the number of offspring.
• Conclusion fertility is correlated with
  longevity even after the fecund period is passed
  and selective mortality reduces the numbers of
  the offspring of the less fit relatively to the
  fitter.

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Other Studies, Which Found Positive Correlation
Between Reproduction and Postreproductive
Longevity
Telephone inventor Alexander Graham Bell (1918)
The longer lived parents were the most
fertile.

• Bettie Freeman (1935) Weak positive correlations
  between the duration of postreproductive life in
  women and the number of offspring borne. Human
  Biology, 7 392-418.
• Bideau A. (1986) Duration of life in women after
  age 45 was longer for those women who borne 12 or
  more children. Population 41 59-72.

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Studies that Found no Relationship Between
Postreproductive Longevity and Reproduction

• Henry L. 1956. Travaux et Documents.
• Gauter, E. and Henry L. 1958. Travaux et
  Documents, 26.
• Knodel, J. 1988. Demographic Behavior in the
  Past.
• Le Bourg et al., 1993. Experimental Gerontology,
  28 217-232.

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Study that Found a Trade-Off Between
Reproductive Success and Postreproductive
Longevity

• Westendorp RGJ, Kirkwood TBL. 1998. Human
  longevity at the cost of reproductive success.
  Nature 396 743-746.
• Extensive media coverage including BBC and over
  100 citations in scientific literature as an
  established scientific fact. Previous studies
  were not quoted and discussed in this article.

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Point estimates of progeny number for married
aristocratic women from different birth cohorts
as a function of age at death. The estimates of
progeny number are adjusted for trends over
calendar time using multiple regression.

• Source Westendorp, Kirkwood, Human longevity at
  the cost of reproductive success. Nature, 1998,
  396, pp 743-746

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it is not a matter of reduced fertility, but a
case of 'to have or have not'.
Source Toon Ligtenberg Henk Brand. Longevity
does family size matter? Nature, 1998, 396, pp
743-746
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Number of progeny and age at first childbirth
dependent on the age at death of married
aristocratic women

• Source Westendorp, R. G. J., Kirkwood, T. B. L.
  Human longevity at the cost of reproductive
  success. Nature, 1998, 396, pp 743-746

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• Source Westendorp, R. G. J., Kirkwood, T. B. L.
  Human longevity at the cost of reproductive
  success. Nature, 1998, 396, pp 743-746

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Do longevous women have impaired fertility ?Why
is this question so important and interesting?
Scientific Significance

• This is a testable prediction of some
  evolutionary theories of aging - disposable soma
  theory of aging (Kirkwood)

"The disposable soma theory on the evolution of
ageing states that longevity requires investments
in somatic maintenance that reduce the resources
available for reproduction (Westendorp,
Kirkwood, Nature, 1998).
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Do longevous women have impaired fertility ?

• Practical Importance.
• Do we really wish to live a long life at the
  cost of infertility?
• the next generations of Homo sapiens will
  have even longer life spans but at the cost of
  impaired fertility
• Rudi Westendorp Are we becoming less
  disposable? EMBO Reports, 2004, 5 2-6.

"... increasing longevity through genetic
manipulation of the mechanisms of aging raises
deep biological and moral questions. These
questions should give us pause before we embark
on the enterprise of extending our lives
Walter Glennon "Extending the Human Life Span",
Journal of Medicine and Philosophy, 2002, Vol.
27, No. 3, pp. 339-354.
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• Educational Significance
• Do we teach our students right?
• Impaired fertility of longevous women is
  often presented in scientific literature and mass
  media as already established fact (Brandt et al.,
  2005 Fessler et al., 2005 Schrempf et al.,
  2005 Tavecchia et al., 2005 Kirkwood, 2002
  Westendorp, 2002, 2004 Glennon, 2002 Perls et
  al., 2002, etc.).
• This "fact" is now included in teaching
  curriculums in biology, ecology and anthropology
  world-wide (USA, UK, Denmark).
• Is it a fact or artifact ?

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General Methodological Principle

• Before making strong conclusions, consider all
  other possible explanations, including potential
  flaws in data quality and analysis
• Previous analysis by Westendorp and Kirkwood was
  made on the assumption of data completenessNumbe
  r of children born Number of children
  recorded
• Potential concerns data incompleteness,
  under-reporting of short-lived children, women
  (because of patrilineal structure of genealogical
  records), persons who did not marry or did not
  have children.Number of children born   gtgt
  Number of children recorded

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Test for Data Completeness

• Direct Test Cross-checking of the initial
  dataset with other data sources
• We examined 335 claims of childlessness in
  the dataset used by Westendorp and Kirkwood.
  When we cross-checked these claims with other
  professional sources of data, we  found that at
  least 107 allegedly childless women (32) did
  have children!
• At least 32 of childlessness claims proved to
  be wrong ("false negative claims") !
• Some illustrative examples
• Henrietta Kerr (16531741) was apparently
  childless in the dataset used by Westendorp and
  Kirkwood and lived 88 years. Our cross-checking
  revealed that she did have at least one child,
  Sir William Scott (2nd Baronet of Thirlstane,
  died on October 8, 1725).
•  Charlotte Primrose (17761864) was also
  considered childless in the initial dataset and
  lived 88 years. Our cross-checking of the data
  revealed that in fact she had as many as five
  children Charlotte (18031886), Henry
  (18061889), Charles (18071882), Arabella
  (1809-1884), and William (18151881).
• Wilhelmina Louise von Anhalt-Bernburg
  (17991882), apparently childless, lived 83
  years. In reality, however, she had at least
  two children, Alexander (18201896) and Georg
  (18261902).

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Point estimates of progeny number for married
aristocratic women from different birth cohorts
as a function of age at death. The estimates of
progeny number are adjusted for trends over
calendar time using multiple regression.

• Source Westendorp, R. G. J., Kirkwood, T. B. L.
  Human longevity at the cost of reproductive
  success. Nature, 1998, 396, pp 743-746

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Antoinette de Bourbon(1493-1583)

• Lived almost 90 years
• She was claimed to have only one child in the
  dataset used by Westendorp and Kirkwood Marie
  (1515-1560), who became a mother of famous Queen
  of Scotland, Mary Stuart.
• Our data cross-checking revealed that in fact
  Antoinette had 12 children!
• Marie 1515-1560
• Francois Ier 1519-1563
• Louise 1521-1542
• Renee 1522-1602
• Charles 1524-1574
• Claude 1526-1573
• Louis 1527-1579
• Philippe 1529-1529
• Pierre 1529
• Antoinette 1531-1561
• Francois 1534-1563
• Rene 1536-1566

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Characteristics of Our Data Sample for
Reproduction-Longevity Studies

• 3,723 married women born in 1500-1875 and
  belonging to the upper European nobility.
• Women with two or more marriages (5) were
  excluded from the analysis in order to facilitate
  the interpretation of results (continuity of
  exposure to childbearing).

• Every case of childlessness has been checked
  using at least two different genealogical
  sources.

87
Typical Mistakes in Biological Studies of Human
Longevity

• Using lifespan data for non-extinct birth cohorts
  (cemetery effect)
• Failure to control for birth cohort spurious
  correlations may be found if variables have
  temporal dynamics
• Failure to take into account social events and
  factors e.g., failure to control for age at
  marriage in longevity-reproduction studies

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Childlessness is better outcome than number of
children for testing evolutionary theories of
aging on human data

• Applicable even for population practicing birth
  control (few couple are voluntarily childless)
• Lifespan is not affected by physiological load of
  multiple pregnancies
• Lifespan is not affected by economic hardship
  experienced by large families

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Source Gavrilova et al. Does exceptional human
longevity come with high cost of infertility?
Testing the evolutionary theories of aging.
Annals of the New York Academy of Sciences, 2004,
1019 513-517.
91
Source Gavrilova, Gavrilov. Human longevity and
reproduction An evolutionary perspective. In
Grandmotherhood - The Evolutionary Significance
of the Second Half of Female Life. Rutgers
University Press, 2005, 59-80.
92
Short Conclusion

• Exceptional human longevity is NOT associated
  with infertility or childlessness

93
More Detailed Conclusions

• We have found that previously reported high rate
  of childlessness among long-lived women is an
  artifact of data incompleteness, caused by
  under-reporting of children. After data cleaning,
  cross-checking and supplementation the
  association between exceptional longevity and
  childlessness has disappeared.
• Thus, it is important now to revise a highly
  publicized scientific concept of heavy
  reproductive costs for human longevity. and to
  make corrections in related teaching curriculums
  for students.

94
More Detailed Conclusions (2)

• It is also important to disavow the doubts and
  concerns over further extension of human
  lifespan, that were recently cast in biomedical
  ethics because of gullible acceptance of the idea
  of harmful side effects of lifespan extension,
  including infertility (Glannon, 2002).
• There is little doubt that the number of children
  can affect human longevity through complications
  of pregnancies and childbearing, as well as
  through changes in socioeconomic status,  etc. 
  However,  the concept of heavy infertility cost
  of human longevity is not supported by data, when
  these data are carefully reanalyzed.

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Heritability of Longevity
96
Mutation Accumulation Theory of Aging (Medawar,
1946)

• From the evolutionary perspective, aging is an
  inevitable result of the declining force of
  natural selection with age.
• So, over successive generations, late-acting
  deleterious mutations will accumulate, leading to
  an increase in mortality rates late in life.

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Predictions of the Mutation Accumulation Theory
of Aging

• Mutation accumulation theory predicts that those
  deleterious mutations that are expressed in later
  life should have higher frequencies (because
  mutation-selection balance is shifted to higher
  equilibrium frequencies due to smaller selection
  pressure).
• Therefore, expressed genetic variability should
  increase with age (Charlesworth, 1994. Evolution
  in Age-structured Populations).
• This should result in higher heritability
  estimates for lifespan of offspring born to
  longer-lived parents.

98
Linearity Principle of Inheritance in
Quantitative Genetics

• Dependence between parental traits and offspring
  traits is linear

99
The Best Possible Source on Familial Longevity
Genealogies of European Royal and Noble Families
Charles IX dAnguleme (1550-1574)
Marie-Antoinette von Habsburg-Lothringen
(1765-1793)
Henry VIII Tudor (1491-1547)
100
Characteristic of our Dataset

• Over 16,000 persons belonging to the European
  aristocracy
• 1800-1880 extinct birth cohorts
• Adult persons aged 30
• Data extracted from the professional genealogical
  data sources including Genealogisches Handbook
  des Adels, Almanac de Gotha, Burke Peerage and
  Baronetage.

101
Daughter's Lifespan(Mean Deviation from Cohort
Life Expectancy)as a Function of Paternal
Lifespan

• Offspring data for adult lifespan (30 years) are
  smoothed by 5-year running average.
• Extinct birth cohorts (born in 1800-1880)
• European aristocratic families. 6,443
  cases

102
The Heritability of Life-Spans Is SmallC.E.
Finch, R.E. Tanzi, Science, 1997, p.407
Paradox of low heritability of lifespan vs high
familial clustering of longevity
long life runs in families A. Cournil, T.B.L.
Kirkwood, Trends in Genetics, 2001, p.233
103
Heritability Estimates of Human Lifespan
Author(s) Heritability estimate Population
McGue et al., 1993 0.22 Danish twins
Ljungquist et al., 1998 lt0.33 Swedish twins
Bocquet-Appel, Jacobi, 1990 0.10-0.30 French village
Mayer, 1991 0.10-0.33 New England families
Cournil et al., 2000 0.27 French village
Mitchell et al., 2001 0.25 Old Order Amish
104
Compensation Law of MortalityConvergence of
Mortality Rates with Age
1 India, 1941-1950, males 2 Turkey,
1950-1951, males 3 Kenya, 1969, males 4 -
Northern Ireland, 1950-1952, males 5 - England
and Wales, 1930-1932, females 6 - Austria,
1959-1961, females 7 - Norway, 1956-1960,
females Source Gavrilov, Gavrilova, The
Biology of Life Span 1991
105
Compensation Law of Mortality (Parental
Longevity Effects) Mortality Kinetics for
Progeny Born to Long-Lived (80) vs Short-Lived
Parents
Sons
Daughters
106
Acknowledgments

• This study was made possible thanks to
• generous support from the
• National Institute on Aging (R01 AG028620)
• Stimulating working environment at the Center
  on Aging, NORC/University of Chicago

107
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Scientific and Educational Website on Human
Longevity

• http//longevity-science.org

And Please Post Your Comments at our Scientific
Discussion Blog

• http//longevity-science.blogspot.com/

108
Spontaneous mutant frequencies with age in heart
and small intestine
Source Presentation of Jan Vijg at the IABG
Congress, Cambridge, 2003