1. Testing Biological Theories of Aging with Demographic and Genealogical Data
Natalia S. Gavrilova
Leonid A. Gavrilov
Center on Aging, NORC/University of Chicago,
1155 East 60th Street, Chicago, IL 60637

2. 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

3. Founding Fathers
Beeton, M., Yule, G.U., Pearson, K 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:
Data used: English Quaker records and Whitney Family of Connectucut records for females and American Whitney family and Burke’s ‘Landed Gentry’ for males.

4. 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.”

5. 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:
Bideau A. (1986): Duration of life in women after age 45 was longer for those women who borne 12 or more children. Population 41:

6. Studies that Found no Relationship Between Postreproductive Longevity and Reproduction
Henry L Travaux et Documents.
Gauter, E. and Henry L Travaux et Documents, 26.
Knodel, J Demographic Behavior in the Past.
Le Bourg et al., Experimental Gerontology, 28:

7. Study that Found a Trade-Off Between Reproductive Success and Postreproductive Longevity
Westendorp RGJ, Kirkwood TBL Human longevity at the cost of reproductive success. Nature 396:
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.

8. 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

9. “… 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

10. 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

11. Source: Westendorp, R. G. J. , Kirkwood, T. B. L
Source: Westendorp, R. G. J., Kirkwood, T. B. L. Human longevity at the cost of reproductive success. Nature, 1998, 396, pp

12. Do longevous women have impaired fertility
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).

13. 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

14. 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 ?

15. 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 completeness: Number 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   >> Number of children recorded

16. 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 ( ), 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).

17. 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

18. 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 ( ), who became a mother of famous Queen of Scotland, Mary Stuart.
Our data cross-checking revealed that in fact Antoinette had 12 children!
Marie
Francois Ier
Louise
Renee
Charles
Claude
Louis
Philippe
Pierre 1529
Antoinette
Francois
Rene

19. Characteristics of Our Data Sample for ‘Reproduction-Longevity’ Studies
3,723 married women born in 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.

20. 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

21. 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

23. 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:

24. 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,

25. Short Conclusion:
Exceptional human longevity is NOT associated with infertility or childlessness

26. 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.

27. 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.

28. 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.

29. 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, Evolution in Age-structured Populations).
This should result in higher heritability estimates for lifespan of offspring born to longer-lived parents.

30. Linearity Principle of Inheritance in Quantitative Genetics
Dependence between parental traits and offspring traits is linear

31. The Best Possible Source on Familial Longevity Genealogies of European Royal and Noble Families
Marie-Antoinette von Habsburg-Lothringen ( )
Charles IX d’Anguleme ( )
Henry VIII Tudor ( )

32. Characteristic of our Dataset
Over 16,000 persons belonging to the European aristocracy
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.

33. 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 year running average.
Extinct birth cohorts (born in )
European aristocratic families ,443 cases

34. “… long life runs in families”
Paradox of low heritability of lifespan vs high familial clustering of longevity
“The Heritability of Life-Spans Is Small” C.E. Finch, R.E. Tanzi, Science, 1997, p.407
“… long life runs in families”
A. Cournil, T.B.L. Kirkwood, Trends in Genetics, 2001, p.233

35. Heritability Estimates of Human Lifespan
Author(s)
Heritability estimate
Population
McGue et al., 1993
0.22
Danish twins
Ljungquist et al., 1998
<0.33
Swedish twins
Bocquet-Appel, Jacobi, 1990
French village
Mayer, 1991
New England families
Cournil et al., 2000
0.27
Mitchell et al., 2001
0.25
Old Order Amish

36. Is the effect of non-linear inheritance remain valid after controlling for other explanatory variables?
Lifespan of other parent
Parental ages at child’s conception
Ethnicity
Month of birth

37. Offspring Lifespan at Age 30 as a Function of Paternal Lifespan Data are adjusted for other predictor variables
Daughters, 8,284 cases
Sons, 8,322 cases

38. Offspring Lifespan at Age 30 as a Function of Maternal Lifespan Data are adjusted for other predictor variables
Daughters, 8,284 cases
Sons, 8,322 cases

39. Is the effect of non-linear inheritance observed for non-biological relatives?
We need to test an alternative hypothesis that positive effects of long-lived parents on the offspring survival may be non-biological and caused by common environment and life style
What about lifespan of spouses?

40. Person’s Lifespan as a Function of Spouse Lifespan Data are adjusted for other predictor variables
Married Women, 4,530 cases
Married Men, 5,102 cases

41. Does progeny conceived to older parents live shorter lives?
Parental-Age Effects in Humans (accumulation of mutation load in parental germ cells)
What are the Data and the Predictions of Evolutionary Theory on the Quality of Offspring Conceived to Older Parents?
Does progeny conceived to older parents live shorter lives?

42. Evolutionary Justification for Parental-Age Effects
"The evolutionary explanation of senescence proposes that selection against alleles with deleterious effects manifested only late in life is weak because most individuals die earlier for extrinsic reasons.
This argument also applies to alleles whose deleterious effects are nongenetically transmitted from mother to progeny, that is, that affect the performance of progeny produced at late ages rather than of the aging individuals themselves.
… a decline of offspring quality with parental age should receive more attention in the context of the evolution of aging.”
Stearns et al. "Decline in offspring viability as a manifestation of aging in Drosophila melianogaster." Evolution, 2001, Vol. 55, No. 9, pp. 1822–1831.

43. Genetic Justification for Paternal Age Effects
Advanced paternal age at child conception is the main source of new mutations in human populations.
James F. Crow, geneticist
Professor Crow (University of Wisconsin-Madison) is recognized as a leader and statesman of science. He is a member of the National Academy of Sciences, the National Academy of Medicine, The American Philosophical Society, the American Academy of Arts and Sciences, the World Academy of Art and Science.

44. 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.

45. Paternal Age as a Risk Factor for Alzheimer Disease
MGAD - major gene for Alzheimer Disease
Source: L. Bertram et al. Neurogenetics, 1998, 1:

46. Daughters' Lifespan (30+) as a Function of Paternal Age at Daughter's Birth 6,032 daughters from European aristocratic families born in
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 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.

47. Contour plot for daughters’ lifespan (deviation from cohort mean) as a function of paternal lifespan (X axis) and paternal age at daughters’ birth (Y axis)
7984 cases
birth cohorts
European aristocratic families
Distance weighted least squares smooth

48. Daughters’ Lifespan as a Function of Paternal Age at Daughters’ Birth Data are adjusted for other predictor variables
Daughters of shorter-lived fathers (<80), 6727 cases
Daughters of longer-lived fathers (80+), 1349 cases

49. Conclusions
Being conceived to old fathers is a risk factor, but it is moderated by paternal longevity
It is OK to be conceived to old father if he lives more than 80 years
Methodological implications: Paternal lifespan should be taken into account in the studies of paternal-age effects

50. The Most Recent and Interesting Developments:
Young Mother and Exceptional Longevity

51. Within-Family Study of Exceptional Longevity
Cases Centenarians born in U.S. in
Controls – Their own siblings
Method: Conditional logistic regression
Advantage: Allows researchers to eliminate confounding effects of between-family variation

52. Design of the Study

53. A typical image of ‘centenarian’ family in 1900 census

54. Birth Order and Odds to Become a Centenarian

55. Can the birth-order effect be a result of selective child mortality, thus not applicable to adults?
Approach:
To compare centenarians with those siblings only who survived to adulthood (age 20)

56. First-born adult siblings (20+years) are more likely to become centenarians (odds ratio= 1.95)
Conditional (fixed-effects) logistic regression Number of obs =
LR chi2(2) =
Prob > chi2 =
Log likelihood = Pseudo R =
Variable | Odds Ratio P>|z| [95% Conf. Interval]
First-born status |
Male sex |

57. Even at age 75 it still helps to be a first-born child (odds ratio= 1
Conditional (fixed-effects) logistic regression Number of obs =
LR chi2(2) =
Prob > chi2 =
Log likelihood = Pseudo R =
Variable Odds Ratio P>|z| [95% Conf. Interval]
First-born status
Male sex

58. Birth order is more important than paternal age for chances to become a centenarian
Conditional (fixed-effects) logistic regression Number of obs =
LR chi2(3) =
Prob > chi2 =
Log likelihood = Pseudo R =
Variable Odds Ratio P>|z| [95% Conf. Interval]
First-born status
Born to young father
Male sex

59. Are young mothers responsible for the birth order effect?
Conditional (fixed-effects) logistic regression Number of obs =
LR chi2(2) =
Prob > chi2 =
Log likelihood = Pseudo R =
Variable Odds Ratio P>|z| [95% Conf. Interval]
Born to young mother
Male sex

60. Maternal Age at Person’s Birth and Odds to Become a Centenarian

61. Birth order effect explained: Being born to young mother!
Conditional (fixed-effects) logistic regression Number of obs =
LR chi2(3) =
Prob > chi2 =
Log likelihood = Pseudo R =
Variable Odds Ratio P>|z| [95% Conf. Interval]
First-born status
Born to young mother
Male sex

62. Even at age 75 it still helps to be born to young mother (age <25) (odds ratio= 1.9)
Conditional (fixed-effects) logistic regression Number of obs =
LR chi2(2) =
Prob > chi2 =
Log likelihood = Pseudo R =
Variable Odds Ratio P>|z| [95% Conf. Interval]
Born to young mother
Male sex

63. Younger Moms' Kids Get Longevity Edge
Children of women under 25 twice as likely to live to 100, study finds
HealthDay Monday, April 17, 2006
MONDAY, April 17 (HealthDay News) -- Society's oldest members are most likely to be born to its youngest mothers, new research suggests.
The odds of living to 100 and beyond double when a person is born to a woman under 25 years of age, compared to those people born to older mothers, according to one of the most rigorous studies on the subject yet conducted.
The finding may also help clear up a statistical mystery -- three years ago, the same husband-and-wife team of researchers found that being the first-born child in a family also boosted longevity, although no one knew why.

64. 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 :

65. Conclusions
The shortest conclusion was suggested in the title of the New York Times article about this study

67. 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

68. For More Information and Updates Please Visit Our Scientific and Educational Website on Human Longevity: