Early-Life Programming of Human Longevity Empirical Evidence Natalia S. Gavrilova, Leonid A. Gavrilov Victoria Semyonova, Galina Evdokushkina Center on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL 60637

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.

Season of Birth and Female Lifespan 8,284 females from European aristocratic families born in Seasonal Differences in Adult Lifespan at Age 30 Life expectancy of adult women (30+) as a function of month of birth (expressed as a difference from the reference level for those born in February). The data are point estimates (with standard errors) of the differential intercept coefficients adjusted for other explanatory variables using multivariate regression with categorized nominal variables.

Season of Birth and Female Lifespan 6,517 females from European aristocratic families born in Seasonal Differences in Adult Lifespan at Age 60 Life expectancy of adult women (60+) as a function of month of birth (expressed as a difference from the reference level for those born in February). The data are point estimates (with standard errors) of the differential intercept coefficients adjusted for other explanatory variables using multivariate regression with categorized nominal variables.

Models Used in the Season-of-Birth Analyses Multiple linear regression models with nominal variables Multilevel linear regression models (with family as a second level) Proportional hazard models with stratification

Life expectancy of adult women (30+) as a function of year of birth Mean Lifespan of Females Born in December and February as a Function of Birth Year

Season of Birth and Female Lifespan 7,020 Mennonite females born in Seasonal Differences in Adult Lifespan at Age 30 Life expectancy of adult women (30+) as a function of month of birth (expressed as a difference from the reference level for those born in February). The data are point estimates (with standard errors) of the differential intercept coefficients adjusted for other explanatory variables using multivariate regression with categorized nominal variables.

Season of Birth and Male Lifespan 8,187 Mennonite males born in Seasonal Differences in Adult Lifespan at Age 30 Life expectancy of adult men (30+) as a function of month of birth (expressed as a difference from the reference level for those born in February). The data are point estimates (with standard errors) of the differential intercept coefficients adjusted for other explanatory variables using multivariate regression with categorized nominal variables.

Season-of-Birth Effects Found in Other Studies Female childlessness (born in January, July) – Smits et al., Schizoprenia is more frequent for persons born in February (Dassa et al., 1996) and this effect is more expressed among females

Molecular Effects on Ageing New Ideas and Findings by Bruce Ames: The rate of mutation damage is NOT immutable, but it can be dramatically decreased by very simple measures: -- Through elimination of deficiencies in vitamins and other micronutrients (iron, zinc, magnesium, etc). Micronutrient deficiencies are very common even in the modern wealthy populations These deficiencies are much more important than radiation, industrial pollution and most other hazards Our hypothesis: Remarkable improvement in the oldest-old survival may reflect an unintended retardation of the aging process, caused by decreased damage accumulation, because of improving the micronutrient status in recent decades

Molecular Effects on Ageing (2) Ideas and Findings by Bruce Ames: The rate of damage accumulation is NOT immutable, but it can be dramatically decreased by PREVENTING INFLAMMATION: Inflammation causes tissue damage through many mechanisms including production of Hypochlorous acid (HOCl), which produces DNA damage (through incorporation of chlorinated nucleosides). Chronic inflammation may contribute to many age-related degenerative diseases including cancer Hypothesis: Remarkable improvement in the oldest-old survival may reflect an unintended retardation of the aging process, caused by decreased damage accumulation, because of partial PREVENTION of INFLAMMATION through better control over infectious diseases in recent decades

Micronutrient Undernutrition in Americans 25% 50%90; 75 mg Men; Women C 5; ~10-25%10-20; %2.4 mcgMen; Women B12 25%; 50%75%400 mcgMen; Women Folate** 10% 50%1.7; 1.5 mgMen; Women B6 Vitamins 5-10% 25%8 mgWomen 50+ years 25% 75%18 mgWomen years Iron Minerals <50% RDA % ingesting < RDA Population GroupNutrient Wakimoto and Block (2001) J Gerontol A Biol Sci Med Sci. Oct; 56 Spec No 2(2): ** Before U.S. Food Fortification Source: Presentation by Bruce Ames at the IABG Congress RDA % ingesting < 50% RDA Zinc Men; Women 50+ years 11; 8 mg 50% 10%

Daughters' Lifespan (30+) as a Function of Paternal Age at Daughter's Birth 6,032 daughters from European aristocratic families born in Life expectancy of adult women (30+) as a function of father's age when these women were born (expressed as a difference from the reference level for those born to fathers of years). The data are point estimates (with standard errors) of the differential intercept coefficients adjusted for other explanatory variables using multiple regression with nominal variables. Daughters of parents who survived to 50 years.

Daughters' Lifespan (60+) as a Function of Paternal Age at Daughter's Birth 4,832 daughters from European aristocratic families born in Life expectancy of older women (60+) as a function of father's age when these women were born (expressed as a difference from the reference level for those born to fathers of years). The data are point estimates (with standard errors) of the differential intercept coefficients adjusted for other explanatory variables using multiple regression with nominal variables. Daughters of parents who survived to 50 years.

Paternal Age as a Risk Factor for Alzheimer Disease MGAD - major gene for Alzheimer Disease Source: L. Bertram et al. Neurogenetics, 1998, 1:

Paternal Age and Risk of Schizophrenia Estimated cumulative incidence and percentage of offspring estimated to have an onset of schizophrenia by age 34 years, for categories of paternal age. The numbers above the bars show the proportion of offspring who were estimated to have an onset of schizophrenia by 34 years of age. Source: Malaspina et al., Arch Gen Psychiatry.2001.

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

Offspring Lifespan at Age 30 as a Function of Paternal Lifespan Data are adjusted for other predictor variables Daughters, 8,284 casesSons, 8,322 cases

Offspring Lifespan at Age 60 as a Function of Paternal Lifespan Data are adjusted for other predictor variables Daughters, 6,517 casesSons, 5,419 cases

Offspring Lifespan at Age 30 as a Function of Maternal Lifespan Data are adjusted for other predictor variables Daughters, 8,284 casesSons, 8,322 cases

Offspring Lifespan at Age 60 as a Function of Maternal Lifespan Data are adjusted for other predictor variables Daughters, 6,517 casesSons, 5,419 cases

Person’s Lifespan as a Function of Spouse Lifespan Data are adjusted for other predictor variables Married Women, 6,442 casesMarried Men, 6,596 cases

Offspring Lifespan at Age 30 as a Function of Paternal Lifespan Data are adjusted for other predictor variables Mennonite daughters, 7020 casesMennonite sons, 8187 cases

Offspring Lifespan at Age 30 as a Function of Maternal Lifespan Data are adjusted for other predictor variables Mennonite daughters, 7020 casesMennonite sons, 8187 cases

Other Early-Life Markers Death of siblings before age 18 - a proxy for early childhood infections and risk factor for late-life mortality Found both in aristocratic and Mennonite populations

Acknowledgments This study was made possible thanks to: generous support from the National Institute on Aging, and stimulating working environment at the Center on Aging, NORC/University of Chicago