1. Is There a Trade-Off Between the Costs of Reproduction and Longevity? Natalia S. Gavrilova Leonid A. Gavrilov Center on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL 60637

2. 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 ?

3. 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

4. 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 (1806­ 1889), 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).

5. Test for Data Completeness (II) If data incompleteness exists then it should be particularly high among obscure families (with low nobility ranks). Prediction: The percentage of alleged “childlessness” claims should decrease with increasing data quality/completeness (proxy -- high nobility rank) Results: We sorted the dataset used by Westendorp and Kirkwood in order to determine exactly who are these “childless” long-lived women. We found that most of these claims belong to obscure, poorly studied branches of genealogical trees rather than to well-documented families (kings, princes, counts, and earls). The percentage of “childlessness” among long-lived women (lifespan above 80 years, born before 1800) dropped from 43% in poorly documented families to 23% in better-studied families (where husbands belonged to nobility ranks higher than barons and baronets). Conclusion: At least half of the "childless" claims are probably false in families with lower nobility rank.

6. Test for Data Completeness (III) If data incompleteness for the number of children exists then it should be particularly high among poorly documented families (with many missing dates). Prediction: The percentage of alleged “childlessness” claims should decrease with increasing data quality/completeness (proxy -- availability of birth dates, death dates for spouses and marriage dates) Results: A sample of nonagenarian women (90+ years) was split according to data completeness: 47.5% of women were "childless" in particularly incomplete sample (28 of total 59 cases with some missing dates for spouses including marriage dates); 44.3% of women were "childless" in initial unsorted sample (39 of total 88 cases); 37.9% of women were "childless" in more complete sample (11 of total 29 cases with available dates for spouses and marriage dates); 25.0% of women were "childless" in the most complete sample (3 of total 12 cases with available dates for spouses and for maternal grand parents);

7. 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

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

9. 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

10. Who are these 7 remarkable longevous women with impaired fertility? Antoinette de Bourbon (1493-1583), allegedly having one child only. However after data cross-checking we found that she had in fact 12 children! Sophia v.Braunschweig (1541-1631), allegedly childless. However her husband, Poppo XVIII of Henneburg (1513-1574), was already 49 years old by the time of their marriage in 1562 ! Should we blame this lady for her infertility? In all remaining five cases there were no even reliable birthdates for "longevous" ladies, just "ABOUT" guesses! Anne Stanhope, born ABOUT 1497. She allegedly had 5 children (Henry, Anne, Mary, Elizabeth, Edward). Our cross-checking revealed that in fact she had at least 8 children! They are: Ann, Edward, Henry, Mary, Elizabeth, Margaret, Catherine, Jane. Annabel Benn, born ABOUT 1607, allegedly had one child only (Elizabeth). She married at age 37 years, assuming that the guess for her birth-date is correct. Also her husband Henry Grey (1594-1651) was already 50 years old by the time of their marriage in 1644 ! Should we be puzzled by low fertility of this couple? Moreover, our cross-checking revealed at least one more child (Anthony). Helen Hope, born ABOUT 1677. When we cross-checked her records, we found that she had not just 2 children (Charles and John), but at least 2 more children (Margaret and Christian) Dorothy North, born ABOUT 1605, allegedly childless. Her first husband, Richard Lennard (1596-1630) died just 5 years after their marriage in 1624/25. Then she spend 20 years alone as widow until she finally married the second husband, Challoner Chute in 1650. By that time she was already 45 years old, assuming that the guess for her birth-date is correct. Yet, our cross-checking revealed that she had at least one child in the first marriage (Richard, died 1696) Margaret Dalrymple, born ABOUT 1677, had at least one child Final comment: How is it possible to make any claims about links between infertility (childlessness) and longevity with such kind of data ?

11. “… it is not a matter of reduced fertility, but a case of 'to have or have not'.“ Table 1 Relationship between age at death and number of children for married aristocratic women Age at deathProportion childlessNumber of children (years)mean for all womenmean for women having children <200.660.451.32 21-300.391.352.21 31-400.262.052.77 41-500.312.012.91 51-600.282.43.33 61-700.332.363.52 71-800.312.643.83 81-900.452.083.78 >900.491.803.53 Source: Toon Ligtenberg & Henk Brand. Longevity — does family size matter? Nature, 1998, 396, pp 743-746

12. Characteristics of Our Data Sample 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.

15. 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

21. Conclusions We performed a validation study of the earlier findings by Westendorp and Kirkwood published in Nature (1998, Vol. 396, pp. 743 -746) that human longevity comes with a high cost of infertility (almost a half of longevous women were reported to be childless). We have found that 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. 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.

22. Acknowledgments This study was made possible thanks to: generous support from the National Institute on Aging (NIH, USA), and stimulating working environment at the Center on Aging, NORC/University of Chicago