NORC and The University of Chicago 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

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

Relatives of 1,711 centenarians born in 1880-1895 Who lives longer in centenarian families? Siblings > Spouses > Siblings-in-law Relatives of 1,711 centenarians born in 1880-1895 Relatives: Men Women N LS50* Parents 1590 76.2 1557 77.2 Spouses 877 75.4 283 81.4 Siblings 5324 77.6 4877 82.4 Siblings in law 2363 75.1 2410 79.5 1900 US birth cohort 73.3 79.4 *Mean lifespan conditional on survival to age 50

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 1880-1895 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.

Computerized genealogies is a promising source of information about potential predictors of exceptional longevity: life-course events, early-life conditions and family history of longevity

Steps of the study 23,127 records of centenarians born in 1880-1895 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 N LE50 Brothers 1268 29.25 4056 27.09 <0.001 Sisters 1071 32.06 3806 32.45 0.328 Life expectancy of siblings at age 50 depending on the sex of centenarian

Survival of male siblings of centenarians, by sex of centenarian

Having centenarian son is ‘better’ than centenarian daughter (for fathers only) Male centenarians Female centenarians P-value N LE50 Fathers 374 27.22 1216 25.93 0.023 Mothers 362 27.97 1195 27.03 0.176 Life expectancy of parents at age 50 depending on the sex of centenarian

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 80+ 0.883 0.836-0.933 <0.001 Mother lived 80+ 0.930 0.881-0.982 0.009 Married 0.913 0.843-0.988 0.025 Birth Year 1.003 1.001-1.006 0.011 Female sex of centenarian 1.172 1.100-1.249

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 80+ 0.978 0.924-1.035 0.443 Mother lived 80+ 0.931 0.879-0.985 0.013 Married 0.975 0.895-1.062 0.563 Birth Year 0.996 0.994-0.999 Female sex of centenarian 1.019 0.952-1.091 0.590 13

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) N LE50 Brothers 1268 29.25 990 27.65 0.0009 Sisters 1071 32.06 963 33.85 0.0008 Fathers 374 27.22 294 25.82 0.112 Mothers 362 27.97 291 26.96 0.276 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 80+ 0.899 0.826-0.978 0.013 Mother lived 80+ 0.910 0.837-0.990 0.027 Married 0.926 0.822-1.043 0.209 Birth Year 1.005 1.001-1.009 0.025 Female sex of centenarian 1.064 0.978-1.157 0.147 17

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 80+ 0.984 0.901-1.075 0.727 Mother lived 80+ 0.895 0.820-0.978 0.014 Married 1.028 0.896-1.179 0.695 Birth Year 0.996 0.991-1.001 0.113 Female sex of centenarian 0.858 0.786-0.937 0.001 18

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 N LE50 Brothers 784 29.53 2437 27.12 <0.001 Sisters 650 31.36 2378 32.40 0.045 Brothers in law 492 24.95 1857 25.06 0.846 Sisters in law 611 29.22 1796 29.55 0.539 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 N LE50 Men 875 25.40 2349 25.04 0.411 Men (married to 103+ centenarians) 214 25.36 NS Women 283 31.40 2407 29.46 0.007 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 80+ 1.005 0.933-1.081 0.902 Mother lived 80+ 0.923 0.858-0.993 0.032 Spouse lived 80+ 0.905 0.832-0.985 0.020 Birth Year 0.994 0.990-0.997 0.001 Female sex of centenarian 0.975 0.893-1.065 0.577 22

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 80+ 0.918 0.855-0.986 0.019 Mother lived 80+ 0.919 0.857-0.987 0.020 Spouse lived 80+ 0.868 0.806-0.935 <0001 Birth Year 1.002 0.999-1.006 0.178 Female sex of centenarian 1.183 1.090-1.284 23

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 24

This study was made possible thanks to: Acknowledgments This study was made possible thanks to: generous support from the National Institute on Aging grant #R01AG028620 25

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Exceptional longevity in a family of Iowa farmers Father: Mike Ackerman, Farmer, 1865-1939 lived 74 years Mother: Mary Hassebroek 1870-1961 lived 91 years Engelke "Edward" M. Ackerman b: 28 APR 1892 in Iowa 101 Fred Ackerman b: 19 JUL 1893 in Iowa 103 Harmina "Minnie" Ackerman b: 18 SEP 1895 in Iowa 100 Lena Ackerman b: 21 APR 1897 in Iowa 105 Peter M. Ackerman b: 26 MAY 1899 in Iowa 86 Martha Ackerman b: 27 APR 1901 in IA 95 Grace Ackerman b: 2 OCT 1904 in IA 104 Anna Ackerman b: 29 JAN 1907 in IA 101 Mitchell Johannes Ackerman b: 25 FEB 1909 in IA 85