Testing Biological Ideas on Evolution, Aging and Longevity with Demographic and Genealogical Data Leonid A.
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Testing Biological Ideas on Evolution, Aging and Longevity with Demographic and Genealogical Data Leonid A. Gavrilov Natalia S. Gavrilova
Center on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL 60637
What are the data and the predictions of the evolutionary theory on
Links between human longevity and fertility
Lifespan heritability in humans
Quality of offspring conceived to older parents
Founding Fathers
Beeton, M., Yule, G.U., 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.
Pearson, K.
, Data used: English Quaker records and Whitney Family of Connectucut records for females and American Whitney family and Burke’s ‘Landed Gentry’ for males.
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: “
longevity even after the fecund period is passed fertility is correlated with
” and “
selective mortality reduces the numbers of the offspring of the less fit
relatively to the fitter.
”
Other Studies, Which Found Positive Correlation Between Reproduction and Postreproductive Longevity
Telephone inventor 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. 72.
Population 41: 59-
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.
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.
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
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
“… 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 (years) Proportion childless Number of children
mean for all women mean for women having children
<20 21-30 31-40 41-50 51-60
0.66 0.39 0.26 0.31 0.28 0.45 1.35 2.05 2.01 2.4 1.32 2.21 2.77 2.91 3.33
61-70 71-80 81-90
0.33 0.31 0.45 2.36 2.64 2.08 3.52 3.83 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
Source: Westendorp, R. G. J., Kirkwood, T. B. L. Human longevity at the cost of reproductive success. Nature, 1998, 396, pp 743-746
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).
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.
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 ?
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
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 1881).
(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 (18061889), Charles (18071882), Arabella (1809-1884), and William (1815 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).
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
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
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.
Typical Mistakes in Biological Studies of Human Longevity
Using lifespan data for non-extinct birth cohorts (“cemetery effect”) Failure to control for birth cohort – spurious correlations may be found if variables have temporal dynamics Failure to take into account social events and factors – e.g., failure to control for age at marriage in longevity-reproduction studies
Fertility Longevity Time
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
50 Proportion of Childless Women as a Function of Their Lifespan
Univariate data for 3,723 European aristocratic women born in 1500-1875
Compare these results with the Knodel's (1988) estimates for German villages in the 18th and 19th centuries: 6.7-16.2% 40 30 20 10 0 <20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 Women's Lifespan 90+
Childlessness Odds Ratio Estimates as a Function of Wife's Lifespan
Multivariate logistic regression analysis of 3,723 European aristocratic families
10 8
37 Net effects, adjusted for calendar year of birth, maternal age at marriage, husband's lifespan and husband's age at marriage
6 4 2
294 572 359 483 628 872 355
0 <20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 Wife's Lifespan 90+
123
Source: Gavrilova et al. Does exceptional human longevity come with high cost of infertility? Testing the evolutionary theories of aging. New York Academy of Sciences Annals of the , 2004, 1019: 513-517.
5 Childlessness Odds Ratio Estimates as a Function of Husband's Lifespan
Multivariate logistic regression analysis of 3,723 European aristocratic families Net effects, adjusted for calendar year of birth, wife's age at marriage, wife's lifespan and husband's age at marriage
4
61
3 2 1 0 <30 30-39 40-49 50-59 60-69 70-79 80-89 Husband's Lifespan 90+
51
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 (in press).
Short Conclusion:
Exceptional human longevity is NOT associated with infertility or childlessness
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.
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.
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.
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.
40 30 20 10 0 0 20 40
Parental Lifespan
60 80
Linearity Principle of Inheritance in Quantitative Genetics
Dependence between parental traits and offspring traits is linear
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)
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.
Daughter's Lifespan
(Mean Deviation from Cohort Life Expectancy)
as a Function of Paternal Lifespan
6 4 2 0 -2 40
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 50 60 70 80 Paternal Lifespan, years 90 100
Paradox of low heritability of lifespan vs high familial clustering of longevity
“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
Heritability Estimates of Human Lifespan
Author(s)
McGue et al., 1993
Heritability estimate
0.22
Population
Danish twins Ljungquist et al., 1998 Bocquet-Appel, Jacobi, 1990 Mayer, 1991 <0.33
0.10-0.30
0.10-0.33
Swedish twins French village Gavrilova et al., 1998 Cournil et al., 2000 Mitchell et al., 2001 0.18
0.27
0.25
New England families European aristocracy French village Old Order Amish
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
Offspring Lifespan at Age 30 as a Function of Paternal Lifespan
Data are adjusted for other predictor variables
p=0.0003
4 2 p=0.006
p=0.05
0 -2 40 50 60 70 80 Paternal Lifespan, years 90 100 Daughters, 8,284 cases 4 2 0 p=0.001
p<0.0001
p=0.001
-2 40 50 60 70 80 Paternal Lifespan, years 90 100 Sons, 8,322 cases
Offspring Lifespan at Age 30 as a Function of Maternal Lifespan
Data are adjusted for other predictor variables
4 2 0 p=0.0004
p=0.05
p=0.01
-2 40 50 60 70 80 Maternal Lifespan, years 90 100 Daughters, 8,284 cases 4 2 0 p=0.02
-2 40 50 60 70 80 Maternal Lifespan, years 90 100 Sons, 8,322 cases
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?
Person’s Lifespan as a Function of Spouse Lifespan
Data are adjusted for other predictor variables
4 3 2 1 0 -1 -2 -3 -4 40 50 60 70 80 Husband Lifespan, years 90 Married Women, 4,530 cases 2 1 4 3 0 -1 -2 -3 -4 40 50 60 70 Wife Lifespan, years 80 Married Men, 5,102 cases 90
What about lifespan of other relatives?
(sisters vs sisters-in-law)
5.0
2.5
0.0
-2.5
-5.0
Person’s Lifespan as a Function of Sisters Lifespan
Data are adjusted for other predictor variables
40 50 60 70 80 Sisters Lifespan, years 90 Females, 5,421 cases -3 -4 -5 0 -1 -2 5 4 3 2 1 40 50 60 70 80 Sisters Lifespan, years 90 Males, 7,378 cases
Person’s Lifespan as a Function of Sisters-In-Law Lifespan
Data are adjusted for other predictor variables
3.0
1.5
0.0
-1.5
-3.0
40 50 60 70 80 Sisters-In-Law Lifespan, years 90 Females, 4,789 cases -1 -2 -3 -4 4 3 2 1 0 40 50 60 70 80 Sisters-In-Law Lifespan, years 90 Males, 4,707 cases
Mortality Kinetics for Progeny Born to Long-Lived (80+) vs Short-Lived Parents
Data are adjusted for historical changes in lifespan
1 1 0.1
0.1
0.01
0.001
40 50 60 70 short-lived parents long-lived parents Linear Regression Line 80 90 Age 100 Sons 0.01
0.001
40 50 60 70 Age short-lived parents long-lived parents Linear Regression Line 80 90 100 Daughters
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?
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
Evolution .” Stearns et al. "Decline in offspring viability as a manifestation of aging in Drosophila melianogaster." , 2001, Vol. 55, No. 9, pp. 1822–1831.
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
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.
25 30 35 40
Paternal Age as a Risk Factor for Alzheimer Disease
p = 0.04
p=0.04
NS MGAD - major gene for Alzheimer Disease NS NS NS
Paternal age Maternal age Sporadic Alzheimer Disease (low likelihood of MGAD) Familial Alzheimer Disease (high likelihood of MGAD) Controls
Source: L. Bertram et al. Neurogenetics , 1998, 1: 277-280.
Daughters' Lifespan (30+) as a Function of Paternal Age at Daughter's Birth 6,032 daughters from European aristocratic families born in 1800-1880 1 0
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).
-1 -2 -3
The data are point estimates (with standard errors) of the differential intercept coefficients adjusted for other explanatory variables using multiple regression with nominal variables. p = 0.04
Daughters of parents who survived to 50 years.
-4 15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 Paternal Age at Reproduction
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) 65 60 55
3 2 1 0 -1 -2 -3
7984 cases 50 45 1800-1880 birth cohorts 40 35 European aristocratic families 30 25 Distance weighted least squares smooth 20 40 50 60 70 Paternal Lifespan, years 80 90
Daughters’ Lifespan as a Function of Paternal Age at Daughters’ Birth
Data are adjusted for other predictor variables
4 1 -2 -3 0 -1 -4 15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 Paternal Age at Person's Birth Daughters of shorter-lived fathers (<80), 6727 cases 2 0 -2 -4 15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 Paternal Age at Person's Birth Daughters of longer-lived fathers (80+), 1349 cases
Conclusions
Being conceived to old fathers is a risk factor, but it is modulated by paternal longevity It is OK to be conceived to old father if he lives more than 80 years
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
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