EarlyLife Programming of Human Longevity

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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

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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

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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.
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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

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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.

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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.
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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

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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.

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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.

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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

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Daughters' Lifespan (30) as a Functionof
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.

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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.

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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.

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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

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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

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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
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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
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