NORC and The University of Chicago Protective Effects of Familial Longevity on Age-Specific Mortality Disappear at Older Ages Leonid A. Gavrilov, Ph.D. Natalia S. Gavrilova, Ph.D. Center on Aging NORC and The University of Chicago Chicago, Illinois, USA

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).

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). The third hypothesis suggests the life-long sustained mortality advantage for persons having protection of familial longevity (Perls et al. 2002).

Description of 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.

μ(x) = R e αx The Gompertz Law Risk of death increases exponentially with age. μ(x) = R e αx R – intercept coefficient (in semi-log scale) α – slope coefficient (in semi-log scale) x - age

Parental Longevity Effects (European Aristocracy) Mortality Kinetics for Progeny Born to Long-Lived (80+) vs Short-Lived Parents 1 1 2 1 1 2 2 2 Sons Daughters

Effect of parental longevity on the Gompertz parameters for daughters Offspring group Intercept [95% CI] Slope [95% CI] Both parents long lived (80+), N=323 -11.08 [-11.80, -10.36] 0.107 [0.098, 0.116] Long-lived mother, N=1,390 -9.93 [-10.22, -9.65] 0.093 [0.090, 0.097] Long-lived father, N=940 -10.17 [-10.53, -9.80] 0.097 [0.092, 0.102] Both parents short-lived, N=4,854 -9.60 [-9.74, -9.45] 0.091 [0.089, 0.093] European Aristocracy

Effect of parental longevity on the Gompertz parameters for sons Offspring group Intercept [95% CI] Slope [95% CI] Both parents long lived (80+), N=285 -9.21 [-9.79, -8.62] 0.089 [0.081, 0.098] Long-lived mother, N=1,401 -8.81 [-9.05, -8.57] 0.086 [0.082, 0.089] Long-lived father, N=1,026 -8.95 [-9.24, -8.66] [0.082, 0.090] Both parents short-lived, N=4,736 -8.49 [-8.61, -8.37] 0.083 [0.081, 0.085] European Aristocracy

American centenarians born in 1890-1897

Database on Exceptional Longevity About 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 age 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

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 Short-lived Long-lived

Mortality of women with different levels of familial longevity Short-lived Long-lived

Slope coefficients indicate mortality convergence at older ages. Parameters of the Gompertz model for siblings of long-lived and short-lived individuals Group Slope coefficient (95% CI) Intercept coefficient (95% CI) Men Siblings of long-lived 0.092 (0.088,0.096) -6.3598 (-6.5098, -6.2098) Siblings of short-lived 0.081 (0.077,0.084) -5.4648 (-5.5893, -5.3403) Women 0.095 (0.091,0.099) -6.8742 (-7.0620, -6.6865) 0.083 (0.079,0.086) -5.9931 (-6.1404, -5.8459) Slope coefficients indicate mortality convergence at older ages.

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.

This study was made possible thanks to: Acknowledgments This study was made possible thanks to: generous support from the National Institute on Aging and the Society of Actuaries

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Survival of Centenarians M