Familial Factors in Longevity: Exploring Complex Environmental and Genetic Effects Leonid A. Gavrilov, Ph.D. Natalia S. Gavrilova, Ph.D. Center on Aging NORC and The University of Chicago Chicago, 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, 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

The Best Possible Source on Familial Longevity Genealogies of European Royal and Noble Families Charles IX d’Anguleme ( ) Henry VIII Tudor ( ) Marie-Antoinette von Habsburg-Lothringen ( )

Characteristic of our Dataset Over 16,000 persons belonging to the European aristocracy 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 ) European aristocratic families. 6,443 cases

“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 Paradox of low heritability of lifespan vs high familial clustering of longevity

Heritability Estimates of Human Lifespan Author(s)Heritability estimate Population McGue et al., Danish twins Ljungquist et al., 1998<0.33Swedish twins Bocquet-Appel, Jacobi, French village Mayer, New England families Cournil et al., French village Mitchell et al., Old Order Amish

Compensation Law of Mortality Convergence of Mortality Rates with Age 1 – India, , males 2 – Turkey, , males 3 – Kenya, 1969, males 4 - Northern Ireland, , males 5 - England and Wales, , females 6 - Austria, , females 7 - Norway, , females Source: Gavrilov, Gavrilova, “The Biology of Life Span” 1991

Compensation Law of Mortality (Parental Longevity Effects) Mortality Kinetics for Progeny Born to Long-Lived (80+) vs Short-Lived Parents SonsDaughters

Numerous studies showed that biological relatives of centenarians have substantial survival advantage compared to biological relatives of shorter- lived individuals.

Who lives longer in centenarian families? Siblings > Spouses > Siblings-in-law Relatives: MenWomen NLS50*N Parents Spouses Siblings Siblings in law US birth cohort *Mean lifespan conditional on survival to age 50 Relatives of 1,711 centenarians born in

Little is known about effects of centenarian’s sex on longevity of relatives In this study effects of centenarian’s sex were used to explore genetic and environmental effects on longevity

Dataset We have developed and analyzed a new computerized database on 1,711 validated centenarians born in in the the United States, their parents and 13,185 shorter-lived siblings.

Methods Gompertz multivariate regression models were used to model survival time between age 50 and death for centenarian siblings. Models for brothers and sisters were analyzed separately. Student t-test was used to compare mean life spans.

Steps of the study 23,127 records of centenarians born in with known information about parents were identified using the Rootsweb genealogical website 2,834 centenarians having detailed information on their 21,893 siblings were selected 1,711 centenarians with their death dates verified using the Social Security Death Index were used for further analyses Finally data on 398 male and 1,313 female centenarians, their 13,419 siblings, 1,307 spouses, and 7,924 siblings in law were used in the study

Having centenarian brother is ‘better’ than centenarian sister (for males only) Siblings of cente- narians Male centenarians Female centenarians P-value NLE50N Brothers <0.001 Sisters Life expectancy of siblings at age 50 depending on the sex of centenarian

Survival of male siblings of centenarians, by sex of centenarian

Male centenarians Female centenarians P-value NLE50N Fathers Mothers Life expectancy of parents at age 50 depending on the sex of centenarian Having centenarian son is ‘better’ than centenarian daughter (for fathers only)

Male sex of centenarian is ‘better’ for brother’s longevity Gomperz hazard regression model for survival of brothers of centenarians after age 50. N=5,287 Covariate Hazard ratio 95% CI P- value Father lived <0.001 Mother lived Married Birth Year Female sex of centenarian <0.001

Sex of centenarian is not important for sister’s longevity Gomperz hazard regression model for survival of sisters of centenarians after age 50. N=4,849 Covariate Hazard ratio 95% CI P- value Father lived Mother lived Married Birth Year Female sex of centenarian

Sex-specific Survival Threshold (SSST) Hypothesis Because of male and female centenarians have different survival threshold to reach age 100, sex-specific effects are observed

Test of the SSST hypothesis Compare siblings of male centenarians to siblings of females survived to age 103 Probability of survival to 103 for females is similar to probability of reaching age 100 for males (according to the 1900 U.S. cohort)

It is ‘better’ to have the same sex as your centenarian-sibling Male centenarians Females survived to age 103 P-value (diff.in LS) NLE50N Brothers Sisters Fathers Mothers Life expectancy of siblings at age 50 depending on the sex of centenarian

SSST Hypothesis is confirmed for brothers of centenarians Gomperz hazard regression model for survival of male centenarian brothers and brothers of females lived 103+ years after age 50. N=2,243 Covariate Hazard ratio 95% CI P- value Father lived Mother lived Married Birth Year Female sex of centenarian

SSST Hypothesis is NOT confirmed for sisters of centenarians: sex is still important Gomperz hazard regression model for survival of male centenarian sisters and sisters of females lived 103+ years after age 50. N=2,022 Covariate Hazard ratio 95% CI P- value Father lived Mother lived Married Birth Year Female sex of centenarian

Using siblings-in-law as a control group Siblings-in-law do not share genetic background and living conditions with centenarians On the other hand, they usually come from a similar socio-economic background, so may be a good control group

Sex of centenarian is important for siblings but not for siblings-in-law Married relatives: Male centenarians Females centenarians P-value NLE50N Brothers <0.001 Sisters Brothers in law Sisters in law Life expectancy of relatives at age 50 depending on the sex of centenarian

Only women benefit from having centenarian spouse Centenarian spouses Sibling spouses P-value Sex of spouse NLE50N Men Men (married to 103+ centenarians) NS Women Life expectancy of spouses at age 50 depending on the sex of centenarian

For sisters of centenarians father’s longevity becomes unimportant Gomperz hazard regression model for survival of centenarian sisters after age 50. N=3,141 Covariate Hazard ratio 95% CI P- value Father lived Mother lived Spouse lived Birth Year Female sex of centenarian

For brothers of centenarians father’s longevity is still important Gomperz hazard regression model for survival of centenarian married brothers after age 50. N=3,141 Covariate Hazard ratio 95% CI P- value Father lived Mother lived Spouse lived <0001 Birth Year Female sex of centenarian <0001

Conclusion Familial factors in human longevity are likely to be sex-specific. Exploring complex environmental and genetic effects in longevity could be facilitated by further analysis of sex-specific effects

Acknowledgments This study was made possible thanks to: generous support from the National Institute on Aging grant #R01AG028620

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Exceptional longevity in a family of Iowa farmers Father: Mike Ackerman, Farmer, lived 74 years Mother: Mary Hassebroek lived 91 years 1. Engelke "Edward" M. Ackerman b: 28 APR 1892 in Iowa Fred Ackerman b: 19 JUL 1893 in Iowa Harmina "Minnie" Ackerman b: 18 SEP 1895 in Iowa Lena Ackerman b: 21 APR 1897 in Iowa Peter M. Ackerman b: 26 MAY 1899 in Iowa Martha Ackerman b: 27 APR 1901 in IA Grace Ackerman b: 2 OCT 1904 in IA Anna Ackerman b: 29 JAN 1907 in IA Mitchell Johannes Ackerman b: 25 FEB 1909 in IA 85