The National Institute on Aging Workshop on Uses

The National Institute on Aging Workshop on Uses of Survival Data in Research on Factors Affecting Aging Contributions from Dr. Leonid A. Gavrilov, Ph. D. Dr. Natalia S. Gavrilova, Ph. D. Center on Aging, NORC and the University of Chicago, Illinois, USA

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

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

Unusual Non-linear Pattern of Lifespan Inheritance It is theoretically predicted (by quantitative genetics) and experimentally confirmed that the dependence of most offspring quantitative traits (body weight for example) on parental traits is linear. However, if some parents are damaged during early development and therefore have shorter lifespan (despite having normal germ cell DNA), the dependence for lifespan inheritance should become non-linear. This is because the offspring born to these short-lived parents with normal germ cell DNA should have normal rather than shorter lifespan

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

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

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

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

Person’s Lifespan as a Function of Spouse Lifespan Data are adjusted for other predictor variables Married Women, 4, 530 cases Married Men, 5, 102 cases

Mortality Kinetics Long-Lived Mutants of Mouse and Drosophila Mouse Snell dwarf mutant. Flurkey et al. , PNAS, 2001. Drosophila mutant methuselah. Lin et al. , Science, 1998.

Mortality Kinetics for Progeny Born to Long-Lived (80+) vs Short-Lived Parents Data are adjusted for historical changes in lifespan Sons Daughters

Parental-Age Effects (accumulation of mutation load in parental germ cells) Does progeny conceived to older parents live shorter lives?

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.

Contour plot for daughters’ lifespan (deviation from cohort mean) as a function of paternal lifespan (X axis) and paternal age at daughters’ birth (Y axis) 7984 cases 1800 -1880 birth cohorts European aristocratic families Distance weighted least squares smooth

Daughters’ Lifespan as a Function of Paternal Age at Daughters’ Birth Data are adjusted for other predictor variables Daughters of shorter-lived fathers (<80), 6727 cases Daughters of longer-lived fathers (80+), 1349 cases

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