Maternal Age, Fertility, and Longevity Leonid A. Gavrilov, Natalia S. Gavrilova Center on Aging NORC and The University of Chicago Chicago, USA

The role of early-life conditions in shaping late-life mortality is now well recognized

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.

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.

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 5

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

Design of the Study 7

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

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)

A typical image of ‘centenarian’ family in 1900 census 10

Maternal age and chances to live to 100 for siblings survived to age 50 Conditional (fixed-effects) logistic regression N=5,778. Controlled for month of birth, paternal age and gender. Paternal and maternal lifespan >50 years Maternal age Odds ratio 95% CI P-value <20 1.59 1.06-2.39 0.025 20-24 1.53 1.14-2.05 0.005 25-29 1.49 1.12-1.98 0.007 30-34 1.16 0.86-1.55 0.339 35-39 1.06 0.78-1.44 0.720 40+ 1.00 Reference

Maternal age and chances to live to 100 for siblings survived to age 70 Conditional (fixed-effects) logistic regression N=4,813. Controlled for month of birth, paternal age and gender. Paternal and maternal lifespan >50 years Maternal age Odds ratio 95% CI P-value <20 1.65 1.08-2.51 0.019 20-24 1.55 1.15-2.11 0.005 25-29 1.52 1.13-2.04 0.006 30-34 1.15 0.85-1.56 0.373 35-39 1.06 0.77-1.45 0.711 40+ 1.00 Reference

Note: both parents lived 50 years or more People Born to Young Mothers Have Twice Higher Chances to Live to 100 Within-family study of 2,153 centenarians and their siblings survived to age 50. Family size <9 children. p=0.007 p=0.003 p=0.032 Note: both parents lived 50 years or more

Possible explanation These findings are consistent with the 'best eggs are used first' hypothesis suggesting that earlier formed oocytes are of better quality, and go to fertilization cycles earlier in maternal life.

Results were published in 15

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. 16

Study that confirmed our initial findings 273 French Canadian centenarians (104+) and their 2,477 siblings “… being born early in the sibling row may provide a biological advantage related in part to the quality of the female reproductive system” 17

Fertility and Longevity How are they related?

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 Burke’s ‘Landed Gentry’ for males.

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.”

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).

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

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

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 (1653-­1741) 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 (1776-­1864) 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 (1803­-1886), Henry (1806­-1889), Charles (1807­-1882), Arabella (1809-1884), and William (1815­-1881).

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

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

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.

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

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

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.

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

This study was made possible thanks to: 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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