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

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

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 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 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 5

6. 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

7. Design of the Study 7

8. Within-family study of longevity
Cases - 1,081 centenarians survived to age 100 and born in USA in
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

9. 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)

10. A typical image of ‘centenarian’ family in 1900 census10

11. 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
0.025
20-24
1.53
0.005
25-29
1.49
0.007
30-34
1.16
0.339
35-39
1.06
0.720
40+
1.00
Reference

12. 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
0.019
20-24
1.55
0.005
25-29
1.52
0.006
30-34
1.15
0.373
35-39
1.06
0.711
40+
1.00
Reference

13. 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

14. 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.

15. Results were published in15

16. 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 : 16

17. 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

18. Fertility and Longevity
How are they related?

19. 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.

20. 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.”

21. 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).

22. 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 200 citations in the scientific literature as an established scientific fact. Previous studies were not quoted and discussed in this article.

23. 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

24. 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 ( ), and William (1815­-1881).

25. 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

26. 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

27. 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.

28. 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

29. 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:
31 case

30. 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,

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

32. 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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