Genetics of Human Longevity: New Ideas and Findings

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Genetics of Human Longevity New Ideas and
Findings

• Dr. Natalia S. Gavrilova, Ph.D.
• Center on Aging,
• NORC and the University of Chicago,
• Chicago, Illinois, USA

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Three scientific problems

• Mechanisms of familial transmission of human
  longevity
• Paradox of low heritability of lifespan vs
  high familial clustering of longevity
• Parental-age effects (accumulation of mutation
  load in parental germ cells)
• Does progeny conceived to older parents
  live shorter lives?
• Does exceptional human longevity come with high
  cost of infertility?
• Testing the evolutionary theories of aging

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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
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Heritability Estimates of Human Lifespan
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Early Study on Familial Longevity

• This study found that the relatives of
  nonagenarians and centenarians live longer than
  relatives of shorter-lived individuals
• These findings were confirmed in later studies
  (Gudmundsson et al., 2000 Perls et al., 2002 and
  others )

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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.

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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

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Unusual Non-linear Pattern of Lifespan Inheritance

• It is theoretically predicted (by quantitative
  genetics) and experimentally confirmed that the
  dependence of most offspring quantitative traits
  (body weight for example) on parental traits is
  linear.
• However, if some parents are damaged during early
  development and therefore have shorter lifespan
  (despite having normal germ cell DNA), the
  dependence for lifespan inheritance should become
  non-linear.
• This is because the offspring born to these
  short-lived parents with normal germ cell DNA
  should have normal rather than shorter lifespan

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Offspring Lifespan at Age 30 as a Function
of Paternal LifespanData are adjusted for
other predictor variables
Daughters, 8,284 cases
Sons, 8,322 cases
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Offspring Lifespan at Age 60 as a Function
of Paternal LifespanData are adjusted for
other predictor variables
Daughters, 6,517 cases
Sons, 5,419 cases
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Offspring Lifespan at Age 30 as a Function
of Maternal LifespanData are adjusted for
other predictor variables
Daughters, 8,284 cases
Sons, 8,322 cases
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Offspring Lifespan at Age 60 as a Function
of Maternal LifespanData are adjusted for
other predictor variables
Daughters, 6,517 cases
Sons, 5,419 cases
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Persons Lifespan as a Function of Spouse
LifespanData are adjusted for other predictor
variables
Married Women, 4,530 cases
Married Men, 5,102 cases
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Persons Lifespan as a Function of Sisters
LifespanData are adjusted for other predictor
variables
Females, 5,421 cases
Males, 7,378 cases
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Persons Lifespan as a Function of
Sisters-In-Law LifespanData are adjusted for
other predictor variables
Females, 4,789 cases
Males, 4,707 cases
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Mortality Kinetics Long-Lived Mutants of Mouse
and Drosophila
Mouse Snell dwarf mutant. Flurkey et al., PNAS,
2001.
Drosophila mutant methuselah. Lin et al.,
Science, 1998.
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Mortality Kinetics for Progeny Born to Long-Lived
(80) vs Short-Lived Parents Data are adjusted
for historical changes in lifespan
Sons
Daughters
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Parental-Age Effects (accumulation of mutation
load in parental germ cells)

• Does progeny conceived to older parents live
  shorter lives?

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Daughters' Lifespan (30) as a Functionof
Paternal Age at Daughter's Birth6,032 daughters
from European aristocratic familiesborn in
1800-1880

• Life expectancy of adult women (30) as a
  function of father's age when these women were
  born (expressed as a difference from the
  reference level for those born to fathers of
  40-44 years).
• The data are point estimates (with standard
  errors) of the differential intercept
  coefficients adjusted for other explanatory
  variables using multiple regression with nominal
  variables.
• Daughters of parents who survived to 50
  years.

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Paternal Age as a Risk Factor for Alzheimer
Disease

• MGAD - major gene for Alzheimer Disease
• Source L. Bertram et al. Neurogenetics, 1998, 1
  277-280.

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Paternal Age and Risk of Schizophrenia

• Estimated cumulative incidence and percentage of
  offspring estimated to have an onset of
  schizophrenia by age 34 years, for categories of
  paternal age. The numbers above the bars show the
  proportion of offspring who were estimated to
  have an onset of schizophrenia by 34 years of
  age.
• Source Malaspina et al., Arch Gen
  Psychiatry.2001.

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Is There Any Link Between Longevity and Fertility?

• What are the data and the predictions of the
  evolutionary theory on this issue?

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Brief Historical Note

• 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

• 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
  70 citations in scientific literature as an
  established scientific fact. Previous studies
  were not quoted and discussed in this article.

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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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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, Westendorp,
  Kirkwood, 1998)
• Practical Importance. Do we really wish to live
  a long life at the cost of infertility? Based
  these concerns a suggestion was made
• "... 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
• 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
  (Kirkwood, 2002 Westendorp, 2002 Glennon,
  2002 Perls et al., 2002 etc.) Is it a fact or
  artifact ?

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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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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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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.

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Acknowledgments

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

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Longevity

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