7/28/2019 Gavrilov Genetics http://slidepdf.com/reader/full/gavrilov-genetics 1/64 Testing Biological Ideas on Evolution, Ageing and Longevity with Demographic and Genealogical Data Leonid A. Gavrilov Natalia S. GavrilovaCenter on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL 60637
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• They tested predictions of the Darwinianevolutionary theory that the fittest individualsshould leave more offspring.
• Findings: Slightly positive relationship between postreproductive lifespan (50+) of both mothersand fathers and the number of offspring.
• Conclusion: “ fertility is correlated with longevityeven after the fecund period is passed ” and“ selective mortality reduces the numbers of theoffspring of the less fit relatively to the fitter.”
• Before making strong conclusions, consider all otherpossible explanations, including potential flaws indata quality and analysis
• Previous analysis by Westendorp and Kirkwood wasmade on the assumption of data completeness:Number of chi ldren born = Number of chi ldren recorded
• Potential concerns: data incompleteness, under-reportingof short-lived children, women (because of patrilinealstructure of genealogical records), persons who did notmarry or did not have children.Number of chi ldren born >> Number of chi ldren recorded
Direct Test: Cross-checking of the initial dataset with other data sources
We examined 335 claims of childlessness in the dataset used by Westendorp andKirkwood. 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).
for „Reproduction-Longevity‟ Studies • 3,723 married women
born in 1500-1875 and belonging to the upper
European nobility.
• Women with two or moremarriages (5%) wereexcluded from the analysisin order to facilitate theinterpretation of results(continuity of exposure tochildbearing).
•Every case of
childlessness has beenchecked using at least twodifferent genealogicalsources.
6,032 daughters from European aristocratic familiesborn in 1800-1880
• Life expectancy of adult women(30+) as a function of father'sage when these women wereborn (expressed as a difference
from the reference level forthose born to fathers of 40-44years).
• The data are point estimates(with standard errors) of thedifferential interceptcoefficients adjusted for otherexplanatory variables usingmultiple regression withnominal variables.
• Daughters of parents whosurvived to 50 years.
Paternal Age at Reproduction15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
4,832 daughters from European aristocratic familiesborn in 1800-1880
• Life expectancy of olderwomen (60+) as a function of father's age when these womenwere born (expressed as a
difference from the referencelevel for those born to fathers of 40-44 years).
• The data are point estimates(with standard errors) of thedifferential interceptcoefficients adjusted for otherexplanatory variables usingmultiple regression withnominal variables.
• Daughters of parents whosurvived to 50 years.
Paternal Age at Reproduction15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
Ideas and Findings by Bruce Ames:• The rate of damage accumulation is NOT immutable, but it can be
dramatically decreased by PREVENTING INFLAMMATION:
Inflammation causes tissue damage through many mechanismsincluding production of Hypochlorous acid (HOCl), which producesDNA damage (through incorporation of chlorinated nucleosides).
Chronic inflammation may contribute to many age-related degenerativediseases including cancer
Hypothesis:
Remarkable improvement in the oldest-old survival may reflect an unintendedretardation of the aging process, caused by decreased damage accumulation,
because of partial PREVENTION of INFLAMMATION through better controlover infectious diseases in recent decades
Season of Birth and Female Lifespan8,284 females from European aristocratic families
born in 1800-1880
Seasonal Differences in Adult Lifespan at Age 30
• Life expectancy of adultwomen (30+) as a function of month of birth (expressed as
a difference from thereference level for thoseborn in February).
• The data are point estimates(with standard errors) of thedifferential interceptcoefficients adjusted forother explanatory variablesusing multivariateregression with categorizednominal variables.
Month of Birth
FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC JAN FEB.
Season of Birth and Female Lifespan6,517 females from European aristocratic families
born in 1800-1880
Seasonal Differences in Adult Lifespan at Age 60
• Life expectancy of adultwomen (60+) as a function of month of birth (expressed as
a difference from thereference level for thoseborn in February).
• The data are point estimates(with standard errors) of thedifferential interceptcoefficients adjusted forother explanatory variablesusing multivariateregression with categorizednominal variables.
Month of Birth
FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC JAN FEB.
Percent surviving (in log scale) is plotted as a function of age of Swedishwomen for calendar years 1900, 1980,and 1999 (cross-sectional data). Notethat after age 100, the logarithm of
survival fraction is decreasing withoutmuch further acceleration (aging) inalmost a linear fashion. Also note anincreasing pace of survival improvementin history: it took less than 20 years(from year 1980 to year 1999) to repeatessentially the same survivalimprovement that initially took 80 years(from year 1900 to year 1980).
Source: cross-sectional (period) lifetables at the Berkeley MortalityDatabase (BMD):
• General argument:-- In contrast to technical devices, which are built from pre-tested high-quality components, biological systems are formed byself-assembly without helpful external quality control.
• Specific arguments:
1. Cell cycle checkpoints are disabled in earlydevelopment (Handyside, Delhanty,1997. TrendsGenet. 13, 270-275 )
2. extensive copy-errors in DNA, because most celldivisions responsible for DNA copy-errors occur inearly-life (loss of telomeres is also particularly high inearly-life)
3. ischemia-reperfusion injury and asphyxia-reventilation
Source of High Initial Damage• During birth, the future child is deprived
of oxygen by compression of theumbilical cord and suffers severehypoxia and asphyxia. Then, just afterbirth, a newborn child is exposed tooxidative stress because of acute
reoxygenation while starting to breathe.It is known that acute reoxygenationafter hypoxia may produce extensiveoxidative damage through the samemechanisms that produce ischemia-reperfusion injury and the relatedphenomenon, asphyxia-reventilation
injury. Asphyxia is a commonoccurrence in the perinatal period, andasphyxial brain injury is the mostcommon neurologic abnormality in theneonatal period that may manifest inneurologic disorders in later life.
Initial PeriodThe dependence of logarithm of mortality force(failure rate) as afunction of age inmixtures of parallelredundant systemshaving Poissondistribution byinitial numbers of functional elements(mean number of elements, = 1, 5,
• Redundancy is a key notion for understandingaging and the systemic nature of aging inparticular. Systems, which are redundant innumbers of irreplaceable elements, do deteriorate
(i.e., age) over time, even if they are built of non-aging elements.
• An actuarial aging rate or expression of aging
(measured as age differences in failure rates,including death rates) is higher for systems withhigher redundancy levels.
• Redundancy exhaustion over the life course explains theobserved „compensation law of mortality‟ (mortalityconvergence at later life) as well as the observed late-lifemortality deceleration, leveling-off, and mortality plateaus.
• Living organisms seem to be formed with a high load of
initial damage, and therefore their lifespans and agingpatterns may be sensitive to early-life conditions thatdetermine this initial damage load during early
development. The idea of early-life programming of agingand longevity may have important practical implicationsfor developing early-life interventions promoting healthand longevity.