1. Bio-Actuarial Studies of Human Longevity Leonid A. Gavrilov Natalia S. Gavrilova Center on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL 60637

3. “ 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

4. Heritability Estimates of Human Lifespan Author(s) Heritability estimate Population McGue et al., 1993 0.22 Danish twins Ljungquist et al., 1998 <0.33 Swedish twins Bocquet-Appel, Jacobi, 1990 0.10-0.30 French village Mayer, 1991 0.10-0.33 New England families Gavrilova et al., 1998 0.18 European aristocracy Cournil et al., 2000 0.27 French village Mitchell et al., 2001 0.25 Old Order Amish

7. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. Person’s Lifespan as a Function of Sisters Lifespan Data are adjusted for other predictor variables Females, 5,421 cases Males, 7,378 cases

15. Person’s Lifespan as a Function of Sisters-In-Law Lifespan Data are adjusted for other predictor variables Females, 4,789 cases Males, 4,707 cases

16. 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.

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

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

22. Statement of the HIDL hypothesis: (Idea of High Initial Damage Load ) &quot;Adult organisms already have an exceptionally high load of initial damage, which is comparable with the amount of subsequent aging-related deterioration, accumulated during the rest of the entire adult life .&quot; Source: Gavrilov, L.A. & Gavrilova, N.S. 1991. The Biology of Life Span: A Quantitative Approach. Harwood Academic Publisher, New York.

25. Spontaneous mutant frequencies with age in heart and small intestine Source: Presentation of Jan Vijg at the IABG Congress, Cambridge, 2003

26. Practical implications from the HIDL hypothesis: &quot;Even a small progress in optimizing the early-developmental processes can potentially result in a remarkable prevention of many diseases in later life, postponement of aging-related morbidity and mortality, and significant extension of healthy lifespan.&quot; &quot;Thus, the idea of early-life programming of aging and longevity may have important practical implications for developing early-life interventions promoting health and longevity.&quot; Source: Gavrilov, L.A. & Gavrilova, N.S. 1991. The Biology of Life Span: A Quantitative Approach. Harwood Academic Publisher, New York.

28. Is There Any Link Between Longevity and Fertility? What are the data and the predictions of the evolutionary theory on this issue?

44. The Gompertz-Makeham Law μ(x) = A + R 0 exp(α x) A – Makeham term or background mortality R 0 exp(α x) – age-dependent mortality

48. Historical Changes in Mortality Swedish Females

49. Historical Changes in Survival from Age 90 to 100 years. France

50. Historical Changes in Survival from Age 90 to 100 years. Japan

51. Extension of the Gompertz-Makeham Model through the Factor Analysis of Mortality Trends Mortality force (age, time) = = a 0 (age) + a 1 (age) x F 1 (time) + a 2 (age) x F 2 (time)

52. Factor Analysis of Mortality Swedish Females