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

2. Three scientific problems: Mechanisms of familial transmission of human longevity Paradox of low heritability of lifespan vs high familial clustering of longevity Parental-age effects (accumulation of mutation load in parental germ cells) Does progeny conceived to older parents live shorter lives? Does exceptional human longevity come with high cost of infertility? Testing the evolutionary theories of aging

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., 19930.22Danish twins Ljungquist et al., 1998<0.33Swedish twins Bocquet-Appel, Jacobi, 1990 0.10-0.30French village Mayer, 19910.10-0.33New England families Gavrilova et al., 19980.18European aristocracy Cournil et al., 20000.27French village Mitchell et al., 20010.25Old Order Amish

5. Early Study on Familial Longevity This study found that the relatives of nonagenarians and centenarians live longer than relatives of shorter- lived individuals These findings were confirmed in later studies (Gudmundsson et al., 2000; Perls et al., 2002 and others )

6. Characteristics of our Dataset Over 16,000 persons belonging to the European aristocracy 1800-1880 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.

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

8. 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

9. 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

10. 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

11. 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

12. 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

13. Person’s Lifespan as a Function of Spouse Lifespan Data are adjusted for other predictor variables Married Women, 4,530 casesMarried 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 SonsDaughters

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

19. Daughters' Lifespan (30+) as a Function of Paternal Age at Daughter's Birth 6,032 daughters from European aristocratic families born in 1800-1880 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 40-44 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.

20. Paternal Age as a Risk Factor for Alzheimer Disease MGAD - major gene for Alzheimer Disease Source: L. Bertram et al. Neurogenetics, 1998, 1: 277-280.

21. 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.

22. Statement of the HIDL hypothesis: (Idea of High Initial Damage Load ) "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." Source: Gavrilov, L.A. & Gavrilova, N.S. 1991. The Biology of Life Span: A Quantitative Approach. Harwood Academic Publisher, New York.

23. Why should we expect high initial damage load ? General argument: -- In contrast to technical devices, which are built from pre- tested high-quality components, biological systems are formed by self-assembly without helpful external quality control. Specific arguments: 1.Cell cycle checkpoints are disabled in early development (Handyside, Delhanty,1997. Trends Genet. 13, 270-275 ) 2.extensive copy-errors in DNA, because most cell divisions responsible for DNA copy-errors occur in early-life (loss of telomeres is also particularly high in early-life) 3.ischemia-reperfusion injury and asphyxia-reventilation injury during traumatic process of 'normal' birth

24. Birth Process is a Potential Source of High Initial Damage During birth, the future child is deprived of oxygen by compression of the umbilical cord and suffers severe hypoxia and asphyxia. Then, just after birth, a newborn child is exposed to oxidative stress because of acute reoxygenation while starting to breathe. It is known that acute reoxygenation after hypoxia may produce extensive oxidative damage through the same mechanisms that produce ischemia- reperfusion injury and the related phenomenon, asphyxia-reventilation injury. Asphyxia is a common occurrence in the perinatal period, and asphyxial brain injury is the most common neurologic abnormality in the neonatal period that may manifest in neurologic disorders in later life.

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: "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." "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." Source: Gavrilov, L.A. & Gavrilova, N.S. 1991. The Biology of Life Span: A Quantitative Approach. Harwood Academic Publisher, New York.

27. Season of Birth and Female Lifespan 8,284 females from European aristocratic families born in 1800-1880 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.

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

29. Brief Historical Note Beeton, M., Yule, G.U., Pearson, K. 1900. Data for the problem of evolution in man. V. On the correlation between duration of life and the number of offspring. Proc. R. Soc. London, 67: 159-179. Data used: English Quaker records and Whitney Family of Connectucut records for females and American Whitney family and Burke’s ‘Landed Gentry’ for males.

30. Findings and Conclusions by Beeton et al., 1900 They tested predictions of the Darwinian evolutionary theory that the fittest individuals should leave more offspring. Findings: Slightly positive relationship between postreproductive lifespan (50+) of both mothers and fathers and the number of offspring. Conclusion: “fertility is correlated with longevity even after the fecund period is passed” and “selective mortality reduces the numbers of the offspring of the less fit relatively to the fitter.”

31. Other Studies, Which Found Positive Correlation Between Reproduction and Postreproductive Longevity Alexander Graham Bell (1918): “The longer lived parents were the most fertile.” Bettie Freeman (1935): Weak positive correlations between the duration of postreproductive life in women and the number of offspring borne. Human Biology, 7: 392-418. Bideau A. (1986): Duration of life in women after age 45 was longer for those women who borne 12 or more children. Population 41: 59-72.

32. Studies that Found no Relationship Between Postreproductive Longevity and Reproduction Henry L. 1956. Travaux et Documents. Gauter, E. and Henry L. 1958. Travaux et Documents, 26. Knodel, J. 1988. Demographic Behavior in the Past. Le Bourg et al., 1993. Experimental Gerontology, 28: 217-232.

33. Study that Found a Trade-Off Between Reproductive Success and Postreproductive Longevity Westendorp RGJ, Kirkwood TBL. 1998. Human longevity at the cost of reproductive success. Nature 396: 743-746. Extensive media coverage including BBC and over 70 citations in scientific literature as an established scientific fact. Previous studies were not quoted and discussed in this article.

34. Number of progeny and age at first childbirth dependent on the age at death of married aristocratic women Source: Westendorp, R. G. J., Kirkwood, T. B. L. Human longevity at the cost of reproductive success. Nature, 1998, 396, pp 743-746

35. Do longevous women have impaired fertility ? Why is this question so important and interesting : Scientific Significance. This is a testable prediction of some evolutionary theories of aging (disposable soma theory of aging, Westendorp, Kirkwood, 1998) Practical Importance. Do we really wish to live a long life at the cost of infertility? Based these concerns a suggestion was made: "... increasing longevity through genetic manipulation of the mechanisms of aging raises deep biological and moral questions. These questions should give us pause before we embark on the enterprise of extending our lives“ Walter Glennon "Extending the Human Life Span", Journal of Medicine and Philosophy, 2002, Vol. 27, No. 3, pp. 339-354 Educational Significance. Do we teach our students right? Impaired fertility of longevous women is often presented in scientific literature and mass media as already established fact (Kirkwood, 2002; Westendorp, 2002; Glennon, 2002; Perls et al., 2002 etc.) Is it a fact or artifact ?

36. Point estimates of progeny number for married aristocratic women from different birth cohorts as a function of age at death. The estimates of progeny number are adjusted for trends over calendar time using multiple regression. Source: Westendorp, R. G. J., Kirkwood, T. B. L. Human longevity at the cost of reproductive success. Nature, 1998, 396, pp 743- 746

37. General Methodological Principle: Before making strong conclusions, consider all other possible explanations, including potential flaws in data quality and analysis Previous analysis by Westendorp and Kirkwood was made on the assumption of data completeness: Number of children born = Number of children recorded Potential concerns: data incompleteness, under-reporting of short-lived children, women (because of patrilineal structure of genealogical records), persons who did not marry or did not have children. Number of children born >> Number of children recorded

38. Test for Data Completeness Direct Test: Cross-checking of the initial dataset with other data sources We examined 335 claims of childlessness in the dataset used by Westendorp and Kirkwood. When we cross-checked these claims with other professional sources of data, we found that at least 107 allegedly childless women (32%) did have children! At least 32% of childlessness claims proved to be wrong ("false negative claims") ! Some illustrative examples: Henrietta Kerr (1653­1741) was apparently childless in the dataset used by Westendorp and Kirkwood and lived 88 years. Our cross-checking revealed that she did have at least one child, Sir William Scott (2nd Baronet of Thirlstane, died on October 8, 1725). Charlotte Primrose (1776­1864) was also considered childless in the initial dataset and lived 88 years. Our cross- checking of the data revealed that in fact she had as many as five children: Charlotte (1803­1886), Henry (1806­ 1889), Charles (1807­1882), Arabella (1809-1884), and William (1815­1881). Wilhelmina Louise von Anhalt-Bernburg (1799­1882), apparently childless, lived 83 years. In reality, however, she had at least two children, Alexander (1820­1896) and Georg (1826­1902).

39. Antoinette de Bourbon (1493-1583) Lived almost 90 years She was claimed to have only one child in the dataset used by Westendorp and Kirkwood: Marie (1515-1560), who became a mother of famous Queen of Scotland, Mary Stuart. Our data cross-checking revealed that in fact Antoinette had 12 children! Marie 1515-1560 Francois Ier 1519-1563 Louise 1521-1542 Renee 1522-1602 Charles 1524-1574 Claude 1526-1573 Louis 1527-1579 Philippe 1529-1529 Pierre 1529 Antoinette 1531-1561 Francois 1534-1563 Rene 1536-1566

40. Characteristics of Our Data Sample for ‘Reproduction-Longevity’ Studies 3,723 married women born in 1500-1875 and belonging to the upper European nobility. Women with two or more marriages (5%) were excluded from the analysis in order to facilitate the interpretation of results (continuity of exposure to childbearing). Every case of childlessness has been checked using at least two different genealogical sources.

43. Questions of Scientific and Practical (Actuarial) Significance How far could mortality decline go? (absolute zero seems implausible) Are there any ‘biological’ limits to human mortality decline, determined by ‘reliability’ of human body? (lower limits of mortality dependent on age, sex, and population genetics) Were there any indications for ‘biological’ mortality limits in the past? Are there any indications for mortality limits now?

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

45. Historical Changes in Mortality for 40-year-old Swedish Males 1.Total mortality 2.Background mortality 3.Age-dependent mortality Source: Gavrilov, Gavrilova, “The Biology of Life Span” 1991

46. Historical Changes in Mortality for 40-year-old Women in Norway and Denmark 1.Norway, total mortality 2.Denmark, total mortality 3.Norway, age-dependent mortality 4.Denmark, age- dependent mortality Source: Gavrilov, Gavrilova, “The Biology of Life Span” 1991

47. Historical Changes in Mortality for 40-year-old Italian Women and Men 1.Women, total mortality 2.Men, total mortality 3.Women, age- dependent mortality 4.Men, age-dependent mortality Source: Gavrilov, Gavrilova, “The Biology of Life Span” 1991

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

53. Preliminary Conclusions There was some evidence for ‘ biological’ mortality limits in the past, but these ‘limits’ proved to be responsive to the recent technological and medical progress. Thus, there is no convincing evidence for absolute ‘biological’ mortality limits now. Analogy for illustration and clarification: There was a limit to the speed of airplane flight in the past (‘sound’ barrier), but it was overcome by further technological progress. Similar observations seems to be applicable to current human mortality decline.

54. 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

55. For More Information and Updates Please Visit Our Scientific and Educational Website on Human Longevity: http://longevity-science.org