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Early-Life Programming of Human Longevity

Early-Life Programming of Human Longevity. Leonid A. Gavrilov Natalia S. Gavrilova Center on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL 60637. What are the Theoretical and Empirical Arguments for Early-Life Programming of Human Longevity?.

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Early-Life Programming of Human Longevity

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

  2. What are the Theoretical and Empirical Arguments for Early-Life Programming of Human Longevity? • Theoretical Arguments: HIDL (High Initial Damage Load) Hypothesis • Empirical Evidence: (1) Season-of-Birth Effects (2) Parental-Age Effects (3) Unusual Non-Linear Pattern of Lifespan Inheritance

  3. 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.

  4. 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: • Cell cycle checkpoints are disabled in early development     (Handyside, Delhanty,1997. Trends Genet. 13, 270-275 ) • 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) • ischemia-reperfusion injury and asphyxia-reventilation injury   during traumatic process of 'normal' birth

  5. 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.

  6. 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.

  7. Empirical Evidence for the Importance of Early-Life Events and Conditions (1) Season-of-Birth Effects (2) Parental-Age Effects (3) Unusual Non-Linear Pattern of Lifespan Inheritance

  8. Characteristic 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.

  9. Season of Birth and Female Lifespan8,284 females from European aristocratic families born in 1800-1880Seasonal 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.

  10. Mean Lifespan of FemalesBorn in December and Februaryas a Function of Birth Year • Life expectancy of adult women (30+) as a function of year of birth

  11. Daughters' Lifespan (30+) as aFunctionof Paternal Age at Daughter's Birth6,032 daughters from European aristocratic familiesborn 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

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

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

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

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