Transcript Testing Biological Ideas on Evolution, Aging and Longevity

Testing Biological Ideas
on Evolution, Aging and
Longevity with Demographic
and Genealogical Data
Natalia S. Gavrilova
Leonid A. Gavrilov
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
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Links between human longevity and
fertility
Lifespan heritability in humans
Quality of offspring conceived to
older parents
Founding Fathers
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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.
Findings and Conclusions
by Beeton et al., 1900
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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.”
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.”
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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.
Studies that Found no Relationship
Between Postreproductive Longevity
and Reproduction
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Henry L. 1956. Travaux et Documents.
Gauter, E. and Henry L. 1958. Travaux
et Documents, 26.
Knodel, J. 1988. Demographic Behavior
in the Past.
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Le Bourg et al., 1993. Experimental
Gerontology, 28: 217-232.
Study that Found a Trade-Off
Between Reproductive Success and
Postreproductive Longevity
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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 743746
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
Proportion childless
(years)
Number of children
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
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 ?
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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
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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).
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Is it a fact or artifact ?
General Methodological Principle:
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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
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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 (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 (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).
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!
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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
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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
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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
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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
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.
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.
Short Conclusion:
Exceptional human longevity is
NOT associated with infertility or
childlessness
More Detailed Conclusions
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We have found that previously reported high rate
of childlessness among long-lived women is an
artifact of data incompleteness, caused by underreporting of children. After data cleaning, crosschecking 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.
More Detailed Conclusions (2)
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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)
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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
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Mutation accumulation theory
predicts that those deleterious
mutations that are expressed in
later life should have higher
frequencies (because mutationselection 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
Offspring Lifespan
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20
10
0
0
20
40
60
Parental Lifespan
80
Linearity Principle of Inheritance
in Quantitative Genetics
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Dependence
between parental
traits and offspring
traits is linear
The Best Possible Source on Familial Longevity
Genealogies of European Royal and Noble Families
Marie-Antoinette von
Habsburg-Lothringen
(1765-1793)
Charles IX d’Anguleme
(1550-1574)
Henry VIII Tudor
(1491-1547)
Characteristic of our
Over 16,000 persons
Dataset
belonging to the
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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
Daughter's Lifespan (deviation), years
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6
4
2
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0
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-2
40
50
60
70
80
90
Paternal Lifespan, years
100
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
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
Ljungquist et al.,
1998
Heritability
estimate
Population
0.22
Danish twins
<0.33
Swedish twins
Bocquet-Appel,
Jacobi, 1990
0.10-0.30
French village
Mayer, 1991
0.10-0.33
New England
families
Gavrilova et al.,
1998
0.18
European
aristocracy
Cournil et al., 2000
0.27
French village
Mitchell et al., 2001
0.25
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
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Offspring Lifespan at Age 30
as a Function of Paternal Lifespan
Data are adjusted for other predictor variables
p=0.001
4
4
2
p=0.006
Lifespan difference, years
Lifespan difference, years
p=0.0003
p=0.05
0
p<0.0001
p=0.001
2
0
-2
-2
40
50
60
70
80
90
Paternal Lifespan, years
Daughters, 8,284 cases
100
40
50
60
70
80
90
Paternal Lifespan, years
Sons, 8,322 cases
100
Offspring Lifespan at Age 30
as a Function of Maternal Lifespan
Data are adjusted for other predictor variables
4
p=0.0004
p=0.02
Lifespan difference, years
Lifespan difference, years
4
2
p=0.01
p=0.05
0
2
0
-2
-2
40
50
60
70
80
90
Maternal Lifespan, years
Daughters, 8,284 cases
100
40
50
60
70
80
90
Maternal Lifespan, years
Sons, 8,322 cases
100
Is the effect of non-linear
inheritance observed for
non-biological relatives?
We need to test an alternative
hypothesis that positive effects of longlived 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
4
4
3
3
Lifespan difference, years
Lifespan difference, years
Data are adjusted for other predictor variables
2
1
0
-1
-2
2
1
0
-1
-2
-3
-3
-4
-4
40
50
60
70
80
90
Husband Lifespan, years
Married Women, 4,530 cases
40
50
60
70
80
90
Wife Lifespan, years
Married Men, 5,102 cases
What about lifespan
of other relatives?
(sisters vs sisters-in-law)
Person’s Lifespan as a Function
of Sisters Lifespan
Data are adjusted for other predictor variables
5
4
Lifespan difference, years
Lifespan difference, years
5.0
2.5
0.0
-2.5
3
2
1
0
-1
-2
-3
-5.0
-4
-5
40
50
60
70
80
Sisters Lifespan, years
Females, 5,421 cases
90
40
50
60
70
80
Sisters Lifespan, years
Males, 7,378 cases
90
Person’s Lifespan as a Function
of Sisters-In-Law Lifespan
Data are adjusted for other predictor variables
4
3
Lifespan difference, years
Lifespan difference, years
3.0
1.5
0.0
-1.5
-3.0
2
1
0
-1
-2
-3
-4
40
50
60
70
80
Sisters-In-Law Lifespan, years
Females, 4,789 cases
90
40
50
60
70
80
Sisters-In-Law Lifespan, years
Males, 4,707 cases
90
Mortality Kinetics for Progeny Born to
Long-Lived (80+) vs Short-Lived Parents
Data are adjusted for historical changes in lifespan
1
Log(Hazard Rate)
Log(Hazard Rate)
1
0.1
0.01
0.1
0.01
short-lived parents
long-lived parents
short-lived parents
long-lived parents
Linear Regression Line
Linear Regression Line
0.001
0.001
40
50
60
70
Age
Sons
80
90
100
40
50
60
70
Age
Daughters
80
90
100
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
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"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.
Genetic Justification for
Paternal Age Effects
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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.
Paternal Age and Risk of
Schizophrenia
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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.
Paternal Age as a Risk Factor
for Alzheimer Disease
Parental age at childbirth (years)
40
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p = 0.04
35
NS
p=0.04
NS
MGAD - major
gene for
Alzheimer
Disease
NS
30
NS
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25
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
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1
Lifespan Difference (yr)
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
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-2
-3
p = 0.04
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-4
15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
Paternal Age at Reproduction
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.
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
Paternal Age at Person's Birth, years
60
55
3
2
1
0
-1
-2
-3
7984 cases
1800-1880 birth
cohorts
50
45
European
aristocratic
families
40
35
Distance weighted
least squares
smooth
30
25
20
40
50
60
70
Pate rnal Life span, ye ars
80
90
Daughters’ Lifespan as a Function of
Paternal Age at Daughters’ Birth
Data are adjusted for other predictor variables
4
1
2
Lifespan Difference (yr)
Lifespan Difference (yr)
0
-1
-2
0
-2
-3
-4
-4
15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
15-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
Paternal Age at Person's Birth
Paternal Age at Person's Birth
Daughters of shorter-lived
fathers (<80), 6727 cases
Daughters of longer-lived
fathers (80+), 1349 cases
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
Acknowledgments
This study was made possible
thanks to:
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generous support from the National
Institute on Aging, and
stimulating working environment at the
Center on Aging, NORC/University of
Chicago
For More Information and Updates
Please Visit Our Scientific and
Educational Website on Human
Longevity:
http://longevity-science.org