Testing biomedical theories of aging with population data Natalia S. Gavrilova, Ph.D. Center on Aging NORC and The University of Chicago Chicago, Illinois, USA

Heritability of Longevity

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.

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, 1994. Evolution in Age-structured Populations). This should result in higher heritability estimates for lifespan of offspring born to longer-lived parents.

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

Dataset on European Aristocracy 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.

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

Daughter's Lifespan (Mean Deviation from Cohort Life Expectancy) as a Function of Maternal 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. 5,779 cases

“… 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

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 0.10-0.30 French village Mayer, 1991 0.10-0.33 New England families Cournil et al., 2000 0.27 Mitchell et al., 2001 0.25 Old Order Amish

Conclusions The dependence of progeny lifespan on parental lifespan has very unusual non-linear (accelerating) pattern. This dependence remains to be non-linear even after adjusting for the effects of other variables: spousal lifespan, parental ages at person's conception, calendar year and month of person's birth, ethnicity and birth order. In other words, death becomes more selective at older ages. Daughters demonstrate particularly sharp, non-linear pattern of lifespan inheritance: women are more responsive to exceptional parental longevity. Our findings indicate that the importance of genetic heterogeneity increases at advanced ages.

Another Prediction of the Mutation Accumulation Theory of Aging (Medawar, 1946) The theory predicts that the observed pattern of familial transmission of human lifespan is caused by higher equilibrium frequency of late-acting deleterious mutations at older ages (Medawar 1952). Therefore, children born to long-lived parents should experience survival advantage mostly in their old ages (because they have less late-acting deleterious mutations).

The alternative hypotheses Reliability theory of aging predicts that children born to long living parents will experience survival advantage mostly in their younger adult ages, because of higher redundancy in functional elements (cells) not yet exhausted over time (Gavrilov and Gavrilova 2006). Finally, the third hypothesis suggests the life-long sustained mortality advantage for persons having protection of familial longevity (Perls et al. 2002).

Data on European aristocracy Parental Longevity Effects Mortality Kinetics for Progeny Born to Long-Lived (80+) vs Short-Lived Parents SSons Daughters Data on European aristocracy

American centenarians born in 1890-1897

Database on Exceptional Longevity Over 4,000 records of centenarians born in the United States. Age of centenarians was validated using the Social Security Death Master File linkage (82% validated) About 4,000 records of shorter-lived controls (died at 65 years) Both centenarians and controls have information about lifespan of parents Both centenarians and controls have information about siblings, children, souses, siblings-in-law and grandparents

Identified relatives of cases Data used in the study Shorter-lived persons (65 years) Longer-lived persons (100+) Men Women Identified cases 1648 1760 Identified relatives of cases Parents 3296 3520 Siblings 2183 1895 2018 1646

Hypotheses If prediction of the mutation accumulation theory is correct then familial longevity should be a significant predictor of mortality at advanced ages If parental longevity is of no importance for survival after age 100 years then it should not affect mortality of centenarians

Parental longevity does not affect survival after age 100 Variable Hazard Ratio 95% CI P-value Paternal lifespan 80+ 0.976 0.912, 1.045 0.486 Maternal lifespan 80+ 0.944 0.883, 1.010 0.094 Sex (0- men, 1-women) 0.854 0.799, 0.914 <0.001 Second analysis: Paternal lifespan 90+ 0.999 0.897, 1.112 0.981 Maternal lifespan 90+ 0.980 0.894, 1.074 0.855 0.800, 0.915

Survival of siblings with different levels of familial longevity I - siblings of shorter-lived persons (died at age 65) II - siblings of centenarians

Mortality of men with different levels of familial longevity

Mortality of women with different levels of familial longevity

Conclusions Familial longevity improves survival mostly at younger adult rather than older ages Parental longevity has no significant effect on survival of centenarians These findings support predictions of reliability theory of aging, but do not support predictions of the mutation accumulation theory of aging, as well as the hypothesis of life-long sustained mortality advantage.

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