Maternal%20Age,%20Fertility,%20and%20Longevity

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Maternal Age, Fertility, and Longevity

• Leonid A. Gavrilov
• Natalia S. Gavrilova
• Center on Aging
• NORC and The University of Chicago
• Chicago, USA

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New Vision of Aging-Related Diseases
3
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.
4
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.
5
Hypothesis

• Ovarian aging (decline in egg quality) may have
  long-term effects on offspring quality, health
  and longevity. Down syndrome is just a tip of the
  iceberg of numerous less visible defects.
• Testable prediction
• Odds of longevity decrease with maternal age
• Negative impact of maternal aging on offspring
  longevity

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Within-Family Approach How centenarians are
different from their shorter-lived siblings?

• Allows researchers to eliminate between-family
  variation including the differences in genetic
  background and childhood living conditions

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Design of the Study
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Within-family study of longevity
Cases - 1,081 centenarians survived to age 100
and born in USA in 1880-1889 Controls 6,413
their shorter-lived brothers and sisters (5,778
survived to age 50) Method Conditional logistic
regression Advantage Allows to eliminate
between-family variation
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Age validation is a key moment in human longevity
studies

• Death date was validated using the U.S. Social
  Security Death Index
• Birth date was validated through linkage of
  centenarian records to early U.S. censuses (when
  centenarians were children)

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A typical image of centenarian family in 1900
census
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Maternal age and chances to live to 100 for
siblings survived to age 50
Conditional (fixed-effects) logistic regression N5,778. Controlled for month of birth, paternal age and gender. Paternal and maternal lifespan gt50 years Conditional (fixed-effects) logistic regression N5,778. Controlled for month of birth, paternal age and gender. Paternal and maternal lifespan gt50 years Conditional (fixed-effects) logistic regression N5,778. Controlled for month of birth, paternal age and gender. Paternal and maternal lifespan gt50 years Conditional (fixed-effects) logistic regression N5,778. Controlled for month of birth, paternal age and gender. Paternal and maternal lifespan gt50 years
Maternal age Odds ratio 95 CI P-value
lt20 1.73 1.05-2.88 0.033
20-24 1.63 1.11-2.40 0.012
25-29 1.53 1.10-2.12 0.011
30-34 1.16 0.85-1.60 0.355
35-39 1.06 0.77-1.46 0.720
40 1.00 Reference
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People Born to Young Mothers Have Twice Higher
Chances to Live to 100Within-family study of
2,153 centenarians and their siblings survived to
age 50. Family size lt9 children.
p0.020
p0.013
p0.043
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Being born to Young Mother Helps Laboratory Mice
to Live Longer

• Source
• Tarin et al., Delayed Motherhood
  Decreases Life Expectancy of Mouse Offspring.
• Biology of Reproduction 2005 72 1336-1343.

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Hypothesis

• Egg Quality could be modulated by living
  conditions (e.g. diet), which may have seasonal
  variation
• Testable prediction
• Odds of longevity should depend on month of birth

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Within-Family Study of Season of Birth and
Exceptional Longevity
Month of birth is a useful proxy characteristic
for environmental effects acting during in-utero
and early infancy development
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Siblings Born in September-November Have Higher
Chances to Live to 100Within-family study of
9,724 centenarians born in 1880-1895 and their
siblings survived to age 50
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Possible explanations

• These are several explanations of season-of birth
  effects on longevity pointing to the effects of
  early-life events and conditions
• seasonal exposure to infections,
• nutritional deficiencies,
• environmental temperature and sun exposure.
• All these factors were shown to play role in
  later-life health and longevity.

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Life Expectancy and Month of Birth
Data source Social Security Death Master
File Published in Gavrilova, N.S., Gavrilov,
L.A. Search for Predictors of Exceptional Human
Longevity. In Living to 100 and Beyond
Monograph. The Society of Actuaries, Schaumburg,
Illinois, USA, 2005, pp. 1-49.
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Fertility and Longevity

• How are they related?

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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
  post-reproductive 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 the 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 the 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).

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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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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.

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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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Data published by Westendorp and Kirkwood (1998)
Our corrected data
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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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Childlessness and lifespan in aristocratic women
Our results were based on carefully checked data
(genealogies for European aristocratic families)
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.
31 case
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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.
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Short Conclusion

• Exceptional human longevity is NOT associated
  with infertility or childlessness

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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.

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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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Current state of research

• Some studies found support for disposable soma
  theory Lycett, Dunbar et al. 2000 Doblhammer and
  Oeppen 2003 Tabatabaie, Atzmon et al. 2011)
• Other studies found no relation between longevity
  and reproduction (Gavrilova, Gavrilov et al.
  2004 Chereji, Gatz et al. 2013) or even higher
  fertility among long-lived individuals (Goegele,
  Pattaro et al. 2011).
• Conclusion This issue is still not resolved
• We plan to revisit this issue using data on
  validated American centenarians and their
  shorter-lived controls

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Acknowledgment

• This study was made possible thanks to
• generous support from the National Institute on
  Aging grant R01AG028620
• stimulating working environment at the Center
  on Aging, NORC/University of Chicago

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Longevity

• http//longevity-science.org

And Please Post Your Comments at our Scientific
Discussion Blog

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

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Testing Predictions of the Programmed and
Stochastic Theories of Aging Comparison of
Variation in Age at Death, Menopause, and Sexual
Maturation
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One of the arguments used by the opponents of
programmed aging is a too high variation in
individual lifespans compared to the observed
variation of programmed events (such as the age
of sexual maturation).

• The main goal of this study was to test the
  validity of this argument.

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Measures of variability

• Absolute measure standard deviation
• For distribution of lifespan, demographers often
  calculate standard deviation at age 10 SD10
  (Edwards Tuljapurkar 2005).
• Relative measure coefficient of variation.
  Equals the standard deviation divided by the mean

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Age at natural menopause as a marker of
reproductive aging
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Mean age (SD) at natural menopause
Population Mean age (SD) at menopause, years Source
South Korean women 46.9 (4.9) Hong et al., MATURITAS, 2007
Viennese women aged 47 to 68 49.2 (3.6) Kirchengast et al., International Journal of Anthropology , 1999
Mexico Puebla Mexico city 46.7 (4.77) 46.5 (5.00) Sievert, Hautaniemi, Human Biology, 2003
Black women in South Africa rural urban 49.5 (4.7) 48.9 (4.2) Walker et al., International Journal of Obstetrics Gynaecology, 2005
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Our results using the MIDUS study
57

• National survey conducted in 1994/95
• Americans aged 25-74
• core national sample (N3,485)
• city oversamples (N957)
• Additional samples twins, siblings
• Subsample used in this study women having
  natural menopause (no surgeries affecting the age
  at menopause) aged 60-74

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DISTRIBUTION OF AGE AT MENARCHE IN THE MIDUS
SAMPLE
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DISTRIBUTION OF AGE AT MENOPAUSE IN THE MIDUS
SAMPLE
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DISTRIBUTION OF AGE AT DEATH, SWEDISH FEMALES,
1995
Data source Human Mortality Database
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Variation for characteristics of human aging and
development
Characteristic Mean age (SD) years Coefficient of variation Source
Age at onset of menarche 12.9 (1.6) 12.4 MIDUS data
Age at onset of menopause 49.7 (5.2) 10.5 MIDUS data
Age at death 78.7 (16.1) 20.5 USA, women, 1995. Human mortality database
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Variation of age at onset of menarche and age at
death (in 2005)
Country Mean age (SD) for onset of menarche CV Mean age (SD) at death CV
France 12.84 (1.40) 10.9 83.3 (13.8) 16.6
Italy 12.54 (1.46) 11.6 83.3 (13.1) 15.7
Sweden 13.59 (1.41) 10.4 82.3 (12.9) 15.7
UK 12.89 (1.54) 12.0 80.2 (14.0) 17.5
USA 12.9 (1.60) 12.4 78.7 (16.1) 20.5
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Variation of age at onset of menarche and age at
death (in 2005) after 10 years
Country Mean age (SD) for onset of menarche CV Mean age (SD10) at death after 10 CV10
France 12.84 (1.40) 10.9 83.7 (12.7) 15.2
Italy 12.54 (1.46) 11.6 83.7 (11.9) 14.2
Sweden 13.59 (1.41) 10.4 82.5 (12.0) 14.5
UK 12.89 (1.54) 12.0 81.2 (12.6) 15.5
USA 12.9 (1.60) 12.4 79.4 (14.3) 18.0
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Standard Deviations (Y-axis) and Mean Values
(X-axis) for Human Life Cycle Characteristics
Mean ages at menarche (1), menopause (2), and
death (3)
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Conclusions

• Standard deviations for age at onset of menarche
  are about 10 times lower than standard deviations
  for ages at death
• Coefficients of variation for ages at onset of
  menarche and ages at death for contemporary
  populations are of the same order of magnitude