Transcript Gender Specific Effects of Early

Unraveling the Secrets of Human
Longevity
Leonid A. Gavrilov
Natalia S. Gavrilova
Center on Aging
NORC and The University of Chicago
Chicago, USA
Retreat 2012 Keynote lecture
Gavrilov, L., Gavrilova, N.
Reliability theory of
aging and longevity.
In: Handbook of the
Biology of Aging.
Academic Press, 6th
edition, 2006
Existing myths related to
aging and longevity
Myth:
Aging problem is just a problem of old age
Facts:
Aging problem is a problem of EVERYONE
older than 10 years
 Aging starts very early!
 Death rates begin to increase with age
after the 10th birthday
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Aging starts early – at age 10
1
log (mortality rate)
0.1
0.01
Men
Women
0.001
0.0001
0.00001
0
20
40
60
Age
Source: Swedish official life table, 2005
80
100
Myth:
There are stages in human life, and old age
is just one of them
Fact:
Death rates are doubling every eight
years of age, with negligible effect of
menopause or retirement on this process
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Smooth Increase of Risk of Death with Age
U.S. population, 1999
Myth:
Human beings are so complex that their aging
is very special
Fact:
We are not much different from worms and
flies: There are general laws of aging and
mortality, common for humans and many
animals
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Mortality of Humans and Fruit Flies
Myth:
Those people who live longer are aging more
slowly.
Fact:
Actuarial aging rate is higher in low mortality
populations with higher life expectancy. This is
known as “compensation law of mortality.”
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Compensation Law of Mortality
Convergence of Mortality Rates with Age
1
2
3
4
– India, 1941-1950, males
– Turkey, 1950-1951, males
– Kenya, 1969, males
- Northern Ireland, 19501952, males
5 - England and Wales, 19301932, females
6 - Austria, 1959-1961, females
7 - Norway, 1956-1960, females
Source: Gavrilov, Gavrilova,
“The Biology of Life Span” 1991
Compensation Law of Mortality (Parental Longevity Effects)
Mortality Kinetics for Progeny Born to Long-Lived (80+) vs Short-Lived Parents
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
0.001
40
50
60
70
Age
Sons
80
90
100
Linear Regression Line
0.001
40
50
60
70
80
Age
Daughters
90
100
Myth:
Longevity is achieved at the cost of
reproductive success
Fact:
For humans, existing facts tell the opposite:
centenarians usually have higher fertility
compared to their shorter-lived peers
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Where did this myth originate?
Poor reproduction of
centenarians is a prediction
of popular evolutionary
theory of aging called a
“disposable soma” theory
suggested by Thomas
Kirkwood (UK)
"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).
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.
Unfortunately
Westendorp and
Kirkwood used very
incomplete data source
and did not check for
data quality
Source: Westendorp, R. G. J., Kirkwood, T. B. L. Human longevity at the cost
of reproductive success. Nature, 1998, 396, pp 743-746
An example of incompleteness in dataset used by Westendorp and Kirkwood
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
Childlessness and lifespan in aristocratic women
Childlessness Odds Ratio Estimates
as a Function of Wife's Lifespan
Multivariate logistic regression analysis of
3,723 European aristocratic families
Our results were based on
carefully checked data
(genealogies for European
aristocratic families)
Childlessness Odds Ratio (Net Effect)
10
Source:
8
6
4
31 case
2
0
<20
20-29 30-39 40-49 50-59 60-69 70-79 80-89
Wife's Lifespan
90+
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.
Short Conclusion:
Exceptional human longevity
is NOT associated with
infertility or childlessness
Common Myth:
Biomedical war on aging will lead to
catastrophic overpopulation.
Fact: Population changes are surprisingly
small and slow in their response to a
dramatic life extension.
Population forecast for Sweden assuming intervention
that stops aging at age 60 (no migration assumed)
Extension of healthy life is one
of possible ways to resolve a
looming problem of population
aging
When does longevity start?
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)
Daughter's Lifespan
(Mean Deviation from the Birth 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
-2
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40
50
60
70
80
90
100
Paternal Lifespan, years
Source: Gavrilova, Gavrilov, JAAM, 2001
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
Our Findings do not Agree with the
Linearity Principle of Inheritance
in Quantitative Genetics
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Dependence between
parental traits and
offspring traits is
linear
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
Exceptional longevity in a
family of Iowa farmers
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1.
2.
3.
4.
5.
6.
7.
8.
9.
Father: Mike Ackerman, Farmer, 1865-1939 lived 74 years
Mother: Mary Hassebroek 1870-1961 lived 91 years
Engelke "Edward" M. Ackerman b: 28 APR 1892 in Iowa 101
Fred Ackerman b: 19 JUL 1893 in Iowa
103
Harmina "Minnie" Ackerman b: 18 SEP 1895 in Iowa 100
Lena Ackerman b: 21 APR 1897 in Iowa
105
Peter M. Ackerman b: 26 MAY 1899 in Iowa
86
Martha Ackerman b: 27 APR 1901 in IA
95
Grace Ackerman b: 2 OCT 1904 in IA
104
Anna Ackerman b: 29 JAN 1907 in IA
101
Mitchell Johannes Ackerman b: 25 FEB 1909 in IA
85
Our Approach
To study “success stories” in
long-term avoidance of fatal
diseases (survival to 100 years)
and factors correlated with this
remarkable survival success
An example of incredible vitality
Winnie ain’t quitting now.
Smith G D Int. J. Epidemiol. 2011;40:537-562
Published by Oxford University Press on behalf of the International Epidemiological Association ©
The Author 2011; all rights reserved.
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)
Studies of centenarians were
very popular in the Soviet Union
“Blue” zones of longevity
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Areas with high density of
centenarians
Studies of centenarians
require careful design and
serious work on age
validation
There are two factors of
longevity
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Modifiable factors – lifestyle,
nutrition, early-life events and
conditions, etc.
Non-modifiable factors – sex, race,
ethnicity, genotype
The role of early-life
conditions in shaping late-life
mortality is now well
recognized
New Vision of Aging-Related Diseases
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.
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."
Source: Gavrilov, L.A. & Gavrilova, N.S. 1991. The Biology of Life Span:
A Quantitative Approach. Harwood Academic Publisher, New York.
Life Expectancy and Month of Birth
life expectancy at age 80, years
7.9
1885 Birth Cohort
1891 Birth Cohort
Data source:
Social Security
Death Master File
7.8
Published in:
7.7
Gavrilova, N.S.,
Gavrilov, L.A. Search
for Predictors of
Exceptional Human
Longevity. In: “Living
to 100 and Beyond”
Monograph. The
Society of Actuaries,
Schaumburg, Illinois,
USA, 2005, pp. 1-49.
7.6
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Month of Birth
Household Property Status During Childhood
and Survival to Age 100
Odds for household to be in a ‘centenarian’ group
Males
Females
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
A – Rented House
B – Owned House
C – Rented Farm
D – Owned farm
(reference group)
A
B
C
D
How centenarians are
different from their
shorter-lived sibling?
Within-Family Approach
Allows researchers to eliminate
between-family variation
including the differences in
genetic background and
childhood living conditions
Computerized genealogies
is a promising source of
information about
potential predictors of
exceptional longevity: lifecourse events, early-life
conditions and family
history of longevity
Within-family study of longevity
Cases - 1,081 centenarians survived to age
100 and born in USA in 1880-1889
Controls – 6,413 their shorter-lived brothers
and sisters (5,778 survived to age 50)
Method: Conditional logistic regression
Advantage: Allows to eliminate betweenfamily variation
Design of the Study
Age validation is a key moment in
human longevity studies
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Death date was validated using the
U.S. Social Security Death Index
Birth date was validated through
linkage of centenarian records to
early U.S. censuses (when
centenarians were children)
A typical image of ‘centenarian’
family in 1900 census
Maternal age and chances to live to
100 for siblings survived to age 50
Conditional (fixed-effects) logistic regression
N=5,778. Controlled for month of birth, paternal age
and gender. Paternal and maternal lifespan >50 years
Maternal age Odds ratio
95% CI
P-value
<20
1.73
1.05-2.88
0.033
20-24
1.63
1.11-2.40
0.012
25-29
1.53
1.10-2.12
0.011
30-34
1.16
0.85-1.60
0.355
35-39
1.06
0.77-1.46
0.720
40+
1.00
Reference
People Born to Young Mothers Have
Twice Higher Chances to Live to 100
Within-family study of 2,153 centenarians and their siblings survived to age 50. Family size <9 children.
2.6
p=0.020
2.4
p=0.013
Odds ratio
2.2
2
p=0.043
1.8
1.6
1.4
1.2
1
0.8
<20
20-24
25-29
30-34
Maternal Age at Birth
35-39
40+
Being born to Young Mother Helps
Laboratory Mice to Live Longer
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Source:
Tarin et al.,
Delayed Motherhood
Decreases Life
Expectancy of
Mouse Offspring.
Biology of
Reproduction 2005
72: 1336-1343.
Possible explanation
These findings are consistent with
the 'best eggs are used first'
hypothesis suggesting that earlier
formed oocytes are of better quality,
and go to fertilization cycles earlier
in maternal life.
Within-Family Study
of Season of Birth and Exceptional
Longevity
Advantage: Allows researchers to
eliminate confounding effects of
between-family variation
Month of birth is a useful
proxy characteristic for
environmental effects acting
during in-utero and early
infancy development
Siblings Born in September-November
Have Higher Chances to Live to 100
Within-family study of 9,724 centenarians born in 1880-1895 and their siblings survived to age 50
Possible explanations
These are several explanations of season-of
birth effects on longevity pointing to the
effects of early-life events and conditions:
seasonal exposure to infections,
nutritional deficiencies,
environmental temperature and sun
exposure.
All these factors were shown to play role in
later-life health and longevity.
Centenarians and their
shorter-lived peers
How centenarians are different
from their shorter-lived peers when
compared at young adult age?
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
Small Dogs Live Longer
Miller RA. Kleemeier Award Lecture: Are there genes for aging? J Gerontol Biol Sci 54A:B297–B307, 1999.
Small Mice Live Longer
Source: Miller et al., 2000. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:B455-B461
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 240 selected men, 15
were not eligible for draft. The linkage success for
remaining records was 77.5% (174 records)
Controls: men matched on birth year,
race and county of WWI civil draft
registration
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)
WWI Civilian Draft Registration
In 1917 and 1918, approximately 24
million men born between 1873 and
1900 completed draft registration
cards. President Wilson proposed the
American draft and characterized it
as necessary to make "shirkers" play
their part in the war. This argument
won over key swing votes in
Congress.
WWI Draft Registration
Registration was done in
three parts, each designed
to form a pool of men for
three different military draft
lotteries. During each
registration, church bells,
horns, or other noise
makers sounded to signal
the 7:00 or 7:30 opening of
registration, while
businesses, schools, and
saloons closed to
accommodate the event.
Registration Day Parade
Information Available in the Draft
Registration Card
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age, date of birth, race, citizenship
permanent home address
occupation, employer's name
height (3 categories), build (3
categories), eye color, hair color,
disability
Draft Registration Card:
An Example
Height and survival to age 100
70
60
Percent
50
40
short
30
medium
20
tall
10
0
Centenarians
Controls
Body build and survival to age 100
70
60
Percent
50
40
slender
30
medium
20
stout
10
0
Centenarians
Controls
Multivariate Analysis
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Conditional multiple logistic regression
model for matched case-control
studies to investigate the relationship
between an outcome of being a case
(extreme longevity) and a set of
prognostic factors (height, build,
occupation, marital status, number of
children, immigration status)
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Statistical package Stata-10, command
clogit
Results of multivariate study
Variable
Odds
Ratio
P-value
Medium height vs short
and tall height
Slender and medium
build vs stout build
Farming
1.35
0.260
2.63*
0.025
2.20*
0.016
Married vs unmarried
0.68
0.268
Native born vs foreign b.
1.13
0.682
Other physical characteristics
Variable
Odds
Ratio
P-value
Blue eye color
1.62
0.069
‘Short’ body height
1.02
0.967
1.43
0.212
reference: tall height
‘Medium’ body height
reference: tall height
Other variables include body build and farming
Having children by age 30 and
survival to age 100
Conditional (fixed-effects) logistic regression
N=171. Reference level: no children
Variable
Odds ratio
95% CI
P-value
1-3 children
1.62
0.89-2.95
0.127
4+ children
2.71
0.99-7.39
0.051
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
Other Conclusions
Both farming and having large number
of children (4+) at age 30 significantly
increased the chances of exceptional
longevity by 100-200%.
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The effects of immigration status,
marital status, and body height on
longevity were less important, and they
were statistically insignificant in the
studied data set.
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Final Conclusion
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The shortest conclusion was
suggested in the title of the
New York Times article about
this study
Nutrition and longevity:
Study of Okinawa centenarians
109 years – still works in her field
100-years-old karate
instructor
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Traditional nutrition in Okinawa
island is strongly restricted in
calories (Craig Willcox, Bradley Willcox)
Japan has very high life expectancy,
probably because of low calorie diet
Calorie Restriction with
Optimal Nutrition Society
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«It is difficult only for the
first five years ...»
Roy Walford
Study of caloric restriction in monkeys
showed no effect on longevity
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Mattison et al. 2012. Impact of caloric restriction
on health and survival in rhesus monkeys from the
NIA study, Nature, 489, 318-322
The effect of diet was not significant
(P=0.934) and sex was the only
significant predictor (P = 0.003)
CR
Normal diet
People who are conscientious
since their childhood live longer
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Results of 80 years of longitudinal study of gifted
children called Genetic Studies of Genius (Lewis
Terman study started in 1921)
“The findings clearly revealed that
the best childhood personality
predictor of longevity was
conscientiousness, the qualities of
a prudent, persistent, wellorganized person, like a scientistprofessor — somewhat obsessive
and not at all carefree.”
Howard S. Friedman and Leslie R.
Martin, The Longevity Project
Genes and longevity
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Until recently, study of human
longevity genes encountered
problems related to proper study
design
The main problem – how to select a
control group?
Possible solution – to study children
of centenarians
Paper in Science about
longevity genes was retracted
Genes related to longevity
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APOE – Apolipoprotein E. Variant Е4 is
related to increased risk of Alzheimer’s
disease while variant Е2 has lower risk
compared to common variant E3
FOXO3A – homolog of longevity gene daf-16
in long-lived nematode mutants.
Participates in transforming nutrition to
energy (Bradley Willcox)
Attempts to develop new drugs
using longevity genes
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Centenarians have higher level and
particle size of high density cholesterol
(HDL cholesterol) (Nir Barzilai)
This is related to a special variant of gene
coding enzyme that decreases CETP
protein level
A drug called Torcetrapib increases both a
level of ‘good’ cholesterol and mortality
(clinical trial was stopped in 2006)
Centenarian features
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Improved lipid turnover and larger
cholesterol particles, less oxidized
lipids in plasma
High sensitivity to insulin, lower
levels of glucose
Less expressed chronic inflammation
Acknowledgment
This study was made possible
thanks to:
generous support from the
National Institute on Aging
grant #R01AG028620
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stimulating working environment
at the Center on Aging,
NORC/University of Chicago
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