rwj scholars in health policy research program seminar biodemography of human longevity: new...
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RWJ Scholars in Health Policy Research Program Seminar
Biodemography of Human Longevity:
New Findings and Ideas
Dr. Leonid A. Gavrilov, Ph.D.Dr. Natalia S. Gavrilova, Ph.D.
Center on Aging
NORC and The University of Chicago Chicago, Illinois, USA
RWJ Scholars in Health Policy Research Program Seminar
Approach
To study “success stories” in long-term avoidance of fatal diseases (survival to 100 years) and factors correlated with this remarkable survival success
RWJ Scholars in Health Policy Research Program Seminar
Centenarians represent the fastest growing age group in the industrialized countries
Yet, factors predicting exceptional longevity and its time trends remain to be fully understood
In this study we explored the new opportunities provided by the ongoing revolution in information technology, computer science and Internet expansion to explore early-childhood predictors of exceptional longevity Jeanne Calment
(1875-1997)
RWJ Scholars in Health Policy Research Program Seminar
Revolution in Information Technology
What does it mean for longevity studies?
Over 75 millions of computerized genealogical records are available online now!
RWJ Scholars in Health Policy Research Program Seminar
Computerized genealogies is a promising source of information about potential predictors of exceptional longevity: life-course events, early-life conditions and family history of longevity
RWJ Scholars in Health Policy Research Program Seminar
Computerized Genealogies as a Resource for Longevity
Studies Pros: provide important information
about family and life-course events, which otherwise is difficult to collect (including information about lifespan of parents and other relatives)
Cons: Uncertain data quality Uncertain validity and generalizability
RWJ Scholars in Health Policy Research Program Seminar
For longevity studies the genealogies with detailed birth dates and death
dates for long-lived individuals (centenarians) and their relatives are of
particular interest
In this study 1,001 genealogy records for centenarians born in 1875-1899 were collected and used for further age validation
RWJ Scholars in Health Policy Research Program Seminar
RWJ Scholars in Health Policy Research Program Seminar
Steps of Centenarian Age Verification
1. Internal consistency checks of dates
2. Verification of death dates – linkage to the Social Security Administration Death Master File (DMF)
3. Verification of birth dates – linkage to early Federal censuses (1900, 1910, 1920, 1930)
RWJ Scholars in Health Policy Research Program Seminar
Results of Centenarian Age Verification
1001 records consistency checks
990 records used for further verification
990 records were linked to the SSA Death Master File
Linkage success rate 77% (80% for centenarians born after 1890) In 3% of cases centenarian status was not confirmed
548 records found in DMF for persons born in 1890-1899 were then linked to early US censuses
Linkage success rate 80% when using Genealogy.com and 91% after supplementation with Ancestry.com. In 8% of cases a 1-year disagreement between genealogy and census record was observed
RWJ Scholars in Health Policy Research Program Seminar
Conclusions of the Age Verification Study
Death dates of centenarians recorded in genealogies always require verification because of strong outliers (1.3%, misprints)
Birth dates of centenarians recorded in genealogies are sufficiently accurate - 92% are correct; for the remaining 8% only one-year disagreements
Quality of genealogical data is good enough if these data are pre-selected for high data quality
RWJ Scholars in Health Policy Research Program Seminar
Predictors of Exceptional Longevity
RWJ Scholars in Health Policy Research Program Seminar
Within-Family Study of Exceptional Longevity
Cases - 198 Centenarians born in U.S. in 1890-1893
Controls – Their own siblings
Method: Conditional logistic regression
Advantage: Allows researchers to eliminate confounding effects of between-family variation
RWJ Scholars in Health Policy Research Program Seminar
Design of the Study
RWJ Scholars in Health Policy Research Program Seminar
A typical image of ‘centenarian’ family in 1900
census
RWJ Scholars in Health Policy Research Program Seminar
First-born siblings are more likely to become centenarians
(odds = 1.8)
Conditional (fixed-effects) logistic regressionN=950, Prob > chi2=0.0000
VariableOdds ratio
95% CIP-
value
First-born status
1.771.18-2.66
0.006
Male sex 0.400.28-0.58
<0.001
RWJ Scholars in Health Policy Research Program Seminar
Birth Order and Odds to Become a Centenarian
RWJ Scholars in Health Policy Research Program Seminar
Can the birth-order effect be a result of selective child
mortality, thus not applicable to adults?
Approach: To compare centenarians with
those siblings only who survived to adulthood (age 20)
RWJ Scholars in Health Policy Research Program Seminar
First-born adult siblings (20+years) are more likely
to become centenarians (odds = 1.95)
Conditional (fixed-effects) logistic regressionN=797, Prob > chi2=0.0000
VariableOdds ratio
95% CIP-
value
First-born status
1.951.26-3.01
0.003
Male sex 0.460.32-0.66
<0.001
RWJ Scholars in Health Policy Research Program Seminar
Are young fathers responsible for birth order effect?
Conditional (fixed-effects) logistic regressionN=950, Prob > chi2=0.0000
VariableOdds ratio
95% CIP-
value
Born to young father
1.860.99-3.50
0.056
Male sex 0.420.29-0.59
<0.001
RWJ Scholars in Health Policy Research Program Seminar
Birth order is more important than paternal age for chances
to become a centenarianConditional (fixed-effects) logistic regressionN=950, Prob > chi2=0.0000
VariableOdds ratio
95% CIP-
value
First-born status
1.641.03-2.61
0.039
Born to young father
1.290.63-2.67
0.484
Male sex 0.410.29-0.58
<0.001
RWJ Scholars in Health Policy Research Program Seminar
Are young mothers responsible for the birth order
effect?
Conditional (fixed-effects) logistic regressionN=950, Prob > chi2=0.0000
VariableOdds ratio
95% CIP-
value
Born to young mother
2.031.33-3.11
0.001
Male sex 0.410.29-0.59
<0.001
RWJ Scholars in Health Policy Research Program Seminar
Maternal Age at Person’s Birth and Odds to Become a
Centenarian
RWJ Scholars in Health Policy Research Program Seminar
Birth order effect explained:Being born to young mother!
Conditional (fixed-effects) logistic regressionN=950, Prob > chi2=0.0000
VariableOdds ratio
95% CIP-
value
First-born status
1.360.86-2.15
0.189
Born to young mother
1.761.09-2.85
0.021
Male sex 0.410.29-0.58
<0.001
RWJ Scholars in Health Policy Research Program Seminar
Even at age 75 it still helps to be born to young mother (age
<25)(odds = 1.9)
Conditional (fixed-effects) logistic regressionN=557, Prob > chi2=0.0000
VariableOdds ratio
95% CIP-
value
Born to young mother
1.861.15-3.05
0.012
Male sex 0.460.31-0.69
<0.001
RWJ Scholars in Health Policy Research Program Seminar
Question Families were quite large in the past,
particularly those covered by genealogical records (large family size bias).
Is the "young mother effect" robust to the family size, and is it observed in smaller families too?
Or is it confined to extremely large families only?
Approach:To split data in two equal parts by median family
size (9 children) and re-analyze the data in each group separately.
RWJ Scholars in Health Policy Research Program Seminar
Results In smaller families (less than 9 children) the
effect of young mother is even larger:Odds ratio = 2.23, P=0.004; 95%CI = 1.30 -
3.98 Compare to larger families (more than 9
children):Odds ratio = 1.72, P=0.11; 95%CI = 0.88 - 3.34
Conclusion:"Young mother effect" is not confined to
extremely large family size
RWJ Scholars in Health Policy Research Program Seminar
New Striking Findings: Invitation for discussion
and brain-storming!
The favorable "Young Mother Effect" is particularly strong when parents have particularly large differences in their lifespan
RWJ Scholars in Health Policy Research Program Seminar
Odds Ratio to live to 100 years if born to young mother
as a function of maternal and paternal lifespans (tertiles)
MOTHER
FATHERShorter-lived
Medium-lived
Longer-lived
Shorter-lived
0.93 1.29 4.04*
Medium-lived
3.49* 3.01 1.50
Longer-lived
11.62* 1.21 0.36
* p<0.05
RWJ Scholars in Health Policy Research Program Seminar
Being born to Young Mother Helps Laboratory Mice to Live
Longer Source:
Tarin et al., Delayed Motherhood Decreases Life Expectancy of Mouse Offspring.
Biology of Reproduction 2005 72: 1336-1343.
RWJ Scholars in Health Policy Research Program Seminar
Physical Characteristics at Young Age
and Survival to 100
A study of height and build of centenarians
when they were young using WWI civil draft
registration cards
RWJ Scholars in Health Policy Research Program Seminar
Height – What to Expect
1. Height seems to be a good indicator of nutritional status and infectious disease history in the past.
2. Historical studies showed a negative correlation between height and mortality.
3. Hence we may expect that centenarians were taller than average
RWJ Scholars in Health Policy Research Program Seminar
Build – What to Expect
1. Slender build may suggest a poor nutrition during childhood. We may expect that centenarians were less likely to be slender when young.
2. On the other hand, biological studies suggest that rapid growth may be harmful and somewhat delayed maturation may be beneficial for longevity.
RWJ Scholars in Health Policy Research Program Seminar
Data Sources
1. Social Security Administration Death Master File
2. WWI civil draft registration cards (completed for almost 100 percent men born between 1873 and 1900)
RWJ Scholars in Health Policy Research Program Seminar
Study Design
Cases: men centenarians born in 1887 (randomly selected from the SSA Death Master File) and linked to the WWI civil draft records. Out of 120 selected men, 19 were not eligible for draft. The linkage success for remaining 101 records was 75% (76 records)
Controls: men matched on birth year, race and county of WWI civil draft registration
RWJ Scholars in Health Policy Research Program Seminar
Height and Survival to 100
0
10
20
30
40
50
60
70
cases controls
short
medium
tall
RWJ Scholars in Health Policy Research Program Seminar
Body Build and Survival to 100
0
10
20
30
40
50
60
70
80
cases controls
slender
medium
stout
RWJ Scholars in Health Policy Research Program Seminar
Results of multivariate study
Variable OR P-value
Tall and medium height vs short height
1.98 0.308
Slender and medium build vs stout build
9.96* 0.032
Qualified jobs vs unqualified
1.57 0.300
Married vs unmarried 1.02 0.958
Natural born vs immigr.
1.12 0.782
RWJ Scholars in Health Policy Research Program Seminar
Conclusion
The study of height and build among men born in 1887 suggests that rapid growth and overweight at young adult age (30 years) might be harmful for attaining longevity
RWJ Scholars in Health Policy Research Program Seminar
What are the Links Between Human Longevity
and Fertility?
Testing the evolutionary theory of aging
RWJ Scholars in Health Policy Research Program Seminar
Founding Fathers
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.
RWJ Scholars in Health Policy Research Program Seminar
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.”
RWJ Scholars in Health Policy Research Program Seminar
Other Studies, Which Found Positive Correlation Between Reproduction and
Postreproductive Longevity
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.
Telephone inventor Alexander Graham Bell (1918): “The longer lived parents were the most fertile.”
RWJ Scholars in Health Policy Research Program Seminar
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.
RWJ Scholars in Health Policy Research Program Seminar
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 100 citations in scientific literature as an established scientific fact. Previous studies were not quoted and discussed in this article.
RWJ Scholars in Health Policy Research Program Seminar
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, Kirkwood, Human longevity at the cost of reproductive success. Nature, 1998, 396, pp 743-746
RWJ Scholars in Health Policy Research Program Seminar
“… it is not a matter of reduced fertility, but a case of 'to have or have not'.“
Table 1 Relationship between age at death and number of children for married aristocratic women
Age at death Proportion childless Number of children
(years) mean for all women mean for women having children
<20 0.66 0.45 1.32
21-30 0.39 1.35 2.21
31-40 0.26 2.05 2.77
41-50 0.31 2.01 2.91
51-60 0.28 2.4 3.33
61-70 0.33 2.36 3.52
71-80 0.31 2.64 3.83
81-90 0.45 2.08 3.78
>90 0.49 1.80 3.53
Source: Toon Ligtenberg & Henk Brand. Longevity — does family
size matter? Nature, 1998, 396, pp 743-746
RWJ Scholars in Health Policy Research Program Seminar
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
RWJ Scholars in Health Policy Research Program Seminar
Source: Westendorp, R. G. J., Kirkwood, T. B. L. Human longevity at the cost of reproductive success. Nature, 1998, 396, pp 743-746
RWJ Scholars in Health Policy Research Program Seminar
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 (Kirkwood)
"The disposable soma theory on the evolution of ageing states that longevity requires investments in somatic maintenance that reduce the resources available for reproduction“ (Westendorp, Kirkwood, Nature, 1998).
RWJ Scholars in Health Policy Research Program Seminar
Do longevous women have impaired fertility ?
Practical Importance. Do we really wish to live a long life at the cost of
infertility?: “the next generations of Homo sapiens will have even longer life
spans but at the cost of impaired fertility” Rudi Westendorp “Are we becoming less disposable?
EMBO Reports, 2004, 5: 2-6.
"... 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.
RWJ Scholars in Health Policy Research Program Seminar
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 (Brandt et al., 2005; Fessler et al., 2005; Schrempf et al., 2005; Tavecchia et al., 2005; Kirkwood, 2002; Westendorp, 2002, 2004; Glennon, 2002; Perls et al., 2002, etc.).
This "fact" is now included in teaching curriculums in biology, ecology and anthropology world-wide (USA, UK,
Denmark). Is it a fact or artifact ?
RWJ Scholars in Health Policy Research Program Seminar
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
RWJ Scholars in Health Policy Research Program Seminar
Test for Data CompletenessDirect 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 (1653 1741) 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 (1776 1864) 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 (1803 1886), Henry (1806 1889), Charles (1807 1882), Arabella (1809-1884), and William (1815 1881).
Wilhelmina Louise von Anhalt-Bernburg (1799 1882), apparently childless, lived 83 years. In reality, however, she had at least two children, Alexander (1820 1896) and Georg (1826 1902).
RWJ Scholars in Health Policy Research Program Seminar
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
RWJ Scholars in Health Policy Research Program Seminar
Antoinette de Bourbon(1493-1583)
Lived almost 90 yearsShe 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
RWJ Scholars in Health Policy Research Program Seminar
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.
RWJ Scholars in Health Policy Research Program Seminar
Childlessness is better outcome than number of children for testing
evolutionary theories of aging on human data
Applicable even for population practicing birth control (few couple are voluntarily childless)
Lifespan is not affected by physiological load of multiple pregnancies
Lifespan is not affected by economic hardship experienced by large families
RWJ Scholars in Health Policy Research Program Seminar
RWJ Scholars in Health Policy Research Program Seminar
Source:
Gavrilova et al. Does exceptional human longevity come with high cost of infertility? Testing the evolutionary theories of aging. Annals of the New York Academy of Sciences, 2004, 1019: 513-517.
RWJ Scholars in Health Policy Research Program Seminar
Source: Gavrilova, Gavrilov. Human longevity and reproduction: An evolutionary perspective. In: Grandmotherhood - The Evolutionary Significance of the Second Half of Female Life. Rutgers University Press, 2005, 59-80.
RWJ Scholars in Health Policy Research Program Seminar
Short Conclusion:
Exceptional human longevity is NOT associated with infertility or childlessness
RWJ Scholars in Health Policy Research Program Seminar
More Detailed Conclusions We have found that previously reported high rate
of childlessness among long-lived women is an artifact of data incompleteness, caused by under-reporting of children. After data cleaning, cross-checking and supplementation the association between exceptional longevity and childlessness has disappeared.
Thus, it is important now to revise a highly publicized scientific concept of heavy reproductive costs for human longevity. and to make corrections in related teaching curriculums for students.
RWJ Scholars in Health Policy Research Program Seminar
More Detailed Conclusions (2) It is also important to disavow the doubts and
concerns over further extension of human lifespan, that were recently cast in biomedical ethics because of gullible acceptance of the idea of harmful side effects of lifespan extension, including infertility (Glannon, 2002).
There is little doubt that the number of children can affect human longevity through complications of pregnancies and childbearing, as well as through changes in socioeconomic status, etc. However, the concept of heavy infertility cost of human longevity is not supported by data, when these data are carefully reanalyzed.
RWJ Scholars in Health Policy Research Program Seminar
Parental-Age Effects in Humans (accumulation of mutation load in
parental germ cells)
What are the Data and the Predictions of Evolutionary Theory
on the Quality of Offspring Conceived to Older Parents?
Does progeny conceived to older parents live shorter lives?
RWJ Scholars in Health Policy Research Program Seminar
Evolutionary Justification for Parental-Age Effects
"The evolutionary explanation of senescence proposes that selection against alleles with deleterious effects manifested only late in life is weak because most individuals die earlier for extrinsic reasons.
This argument also applies to alleles whose deleterious effects are nongenetically transmitted from mother to progeny, that is, that affect the performance of progeny produced at late ages rather than of the aging individuals themselves.
… a decline of offspring quality with parental age should receive more attention in the context of the evolution of aging.”
Stearns et al. "Decline in offspring viability as a manifestation of aging in Drosophila melianogaster." Evolution, 2001, Vol. 55, No. 9, pp. 1822–1831.
RWJ Scholars in Health Policy Research Program Seminar
Genetic Justification for Paternal Age Effects
Advanced paternal age at child conception is the main source of new mutations in human populations.
James F. Crow, geneticist
Professor Crow (University of Wisconsin-Madison) is recognized as a leader and statesman of science. He is a member of the National Academy of Sciences, the National Academy of Medicine, The American Philosophical Society, the American Academy of Arts and Sciences, the World Academy of Art and Science.
RWJ Scholars in Health Policy Research Program Seminar
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.
RWJ Scholars in Health Policy Research Program Seminar
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.
Paternal age Maternal age
Pa
ren
tal a
ge
at
ch
ild
bir
th (
ye
ars
)
25
30
35
40
Sporadic Alzheimer Disease (low likelihood of MGAD) Familial Alzheimer Disease (high likelihood of MGAD) Controls
p = 0.04
p=0.04
NS
NSNS
NS
RWJ Scholars in Health Policy Research Program Seminar
Daughters' Lifespan (30+) as a Functionof 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.
Paternal Age at Reproduction
15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
Lif
es
pa
n D
iffe
ren
ce
(y
r)
-4
-3
-2
-1
1
0
p = 0.04
RWJ Scholars in Health Policy Research Program Seminar
Contour plot for daughters’ lifespan (deviation from cohort mean) as a function of paternal lifespan (X axis) and paternal age at daughters’ birth (Y axis)
7984 cases
1800-1880 birth cohorts
European aristocratic families
Distance weighted least squares smooth
40 50 60 70 80 90
Paternal Lifespan, years
20
25
30
35
40
45
50
55
60
65
Pat
erna
l Age
at
Per
son'
s B
irth
, yea
rs
3 2 1 0 -1 -2 -3
RWJ Scholars in Health Policy Research Program Seminar
Daughters’ Lifespan as a Function of Paternal Age at Daughters’ Birth
Data are adjusted for other predictor variables
Daughters of shorter-lived fathers (<80), 6727 cases
Daughters of longer-lived fathers (80+), 1349 cases
Paternal Age at Person's Birth
15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
Lif
esp
an D
iffe
ren
ce (
yr)
-4
-3
-2
-1
1
0
Paternal Age at Person's Birth
15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
Lif
esp
an D
iffe
ren
ce (
yr)
-4
-2
2
4
0
RWJ Scholars in Health Policy Research Program Seminar
Conclusions
Being conceived to old fathers is a risk factor, but it is moderated by paternal longevity
It is OK to be conceived to old father if he lives more than 80 years
Methodological implications: Paternal lifespan should be taken into account in the studies of paternal-age effects
RWJ Scholars in Health Policy Research Program Seminar
Heritability of Longevity
RWJ Scholars in Health Policy Research Program Seminar
Mutation Accumulation Theory of Aging
(Medawar, 1946)
From the evolutionary perspective, aging is an inevitable result of the declining force of natural selection with age.
So, over successive generations, late-acting deleterious mutations will accumulate, leading to an increase in mortality rates late in life.
RWJ Scholars in Health Policy Research Program Seminar
Predictions of the Mutation Accumulation Theory of Aging
Mutation accumulation theory predicts that those deleterious mutations that are expressed in later life should have higher frequencies (because mutation-selection balance is shifted to higher equilibrium frequencies due to smaller selection pressure).
Therefore, ‘expressed’ genetic variability should increase with age (Charlesworth, 1994. Evolution in Age-structured Populations).
This should result in higher heritability estimates for lifespan of offspring born to longer-lived parents.
Parental Lifespan0 20 40 60 80
Off
sp
rin
g L
ifesp
an
0
10
20
30
40
RWJ Scholars in Health Policy Research Program Seminar
Linearity Principle of Inheritance in Quantitative Genetics
Dependence between parental traits and offspring traits is linear
RWJ Scholars in Health Policy Research Program Seminar
The Best Possible Source on Familial Longevity Genealogies of European Royal and Noble Families
Charles IX d’Anguleme (1550-1574)
Henry VIII Tudor (1491-1547)
Marie-Antoinette von Habsburg-Lothringen
(1765-1793)
RWJ Scholars in Health Policy Research Program Seminar
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.
RWJ Scholars in Health Policy Research Program Seminar
Daughter's Lifespan(Mean Deviation from Cohort Life Expectancy)
as a Function of Paternal Lifespan
Paternal Lifespan, years
40 50 60 70 80 90 100
Da
ug
hte
r's
Lif
es
pa
n (
de
via
tio
n),
ye
ars
-2
2
4
6
0
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
RWJ Scholars in Health Policy Research Program Seminar
“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
RWJ Scholars in Health Policy Research Program Seminar
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
Cournil et al., 2000 0.27 French village
Mitchell et al., 2001 0.25 Old Order Amish
RWJ Scholars in Health Policy Research Program Seminar
Is the effect of non-linear inheritance remain valid after
controlling for other explanatory variables?
Lifespan of other parent Parental ages at child’s conception Ethnicity Month of birth
RWJ Scholars in Health Policy Research Program Seminar
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
Paternal Lifespan, years
40 50 60 70 80 90 100
Lif
esp
an d
iffe
ren
ce, y
ears
-2
2
4
0
p=0.05
p=0.0003
p=0.006
Paternal Lifespan, years
40 50 60 70 80 90 100
Lif
esp
an d
iffe
ren
ce, y
ears
-2
2
4
0
p<0.0001p=0.001
p=0.001
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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 casesMaternal Lifespan, years
40 50 60 70 80 90 100
Life
span
diff
eren
ce, y
ears
-2
2
4
0
p=0.01
p=0.0004
p=0.05
Maternal Lifespan, years
40 50 60 70 80 90 100
Life
span
diff
eren
ce, y
ears
-2
2
4
0
p=0.02
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Is the effect of non-linear inheritance observed for non-biological relatives?
We need to test an alternative hypothesis that positive effects of long-lived parents on the offspring survival may be non-biological and caused by common environment and life style
What about lifespan of spouses?
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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
Husband Lifespan, years
40 50 60 70 80 90
Lif
esp
an d
iffe
ren
ce, y
ears
-3
-2
-1
1
2
3
-4
0
4
Wife Lifespan, years
40 50 60 70 80 90
Lif
esp
an d
iffe
ren
ce, y
ears
-4
-3
-2
-1
1
2
3
4
0
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AcknowledgmentsThis study was made possible thanks to:
generous support from the National Institute on Aging and
the Society of Actuaries
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