the national institute on aging workshop on uses of survival data in research on factors affecting...
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The National Institute on Aging Workshop on Uses of Survival Data in Research on Factors
Affecting Aging
Contributions fromDr. Leonid A. Gavrilov, Ph.D.Dr. Natalia S. Gavrilova, Ph.D.
Center on Aging,
NORC and the University of Chicago, Chicago, Illinois, USA
“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
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
Unusual Non-linear Pattern of Lifespan Inheritance
It is theoretically predicted (by quantitative genetics) and experimentally confirmed that the dependence of most offspring quantitative traits (body weight for example) on parental traits is linear.However, if some parents are damaged during early development and therefore have shorter lifespan (despite having normal germ cell DNA), the dependence for lifespan inheritance should become non-linear. This is because the offspring born to these short-lived parents with normal germ cell DNA should have normal rather than shorter lifespan
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
Offspring Lifespan at Age 60 as a Function of Paternal Lifespan
Data are adjusted for other predictor variables
Daughters, 6,517 cases Sons, 5,419 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=0.04
p=0.0001
p=0.04
Paternal Lifespan, years
40 50 60 70 80 90 100
Lif
esp
an d
iffe
ren
ce, y
ears
-2
2
4
0
p=0.006
p=0.004
p=0.0003
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 cases
Maternal Lifespan, years
40 50 60 70 80 90 100
Lif
esp
an d
iffe
ren
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
Lif
esp
an d
iffe
ren
ce, y
ears
-2
2
4
0
p=0.02
Offspring Lifespan at Age 60 as a Function of Maternal Lifespan
Data are adjusted for other predictor variables
Daughters, 6,517 cases Sons, 5,419 cases
Maternal Lifespan, years
40 50 60 70 80 90 100
Lif
esp
an d
iffe
ren
ce, y
ears
-2
2
4
0
p=0.01
p<0.0001
p=0.01
Maternal Lifespan, years
40 50 60 70 80 90 100
Lif
esp
an d
iffe
ren
ce, y
ears
-2
2
4
0
p=0.04
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
es
pan
dif
fere
nc
e, ye
ars
-3
-2
-1
1
2
3
-4
0
4
Wife Lifespan, years
40 50 60 70 80 90
Lif
esp
an
dif
fere
nc
e, ye
ars
-4
-3
-2
-1
1
2
3
4
0
Mortality Kinetics Long-Lived Mutants of Mouse and Drosophila
Mouse Snell dwarf mutant. Flurkey et al., PNAS, 2001.
Drosophila mutant methuselah. Lin et al., Science, 1998.
Mortality Kinetics for Progeny Born to Long-Lived (80+) vs Short-Lived Parents
Data are adjusted for historical changes in lifespan
Sons Daughters
Age
40 50 60 70 80 90 100
Lo
g(H
aza
rd R
ate)
0.001
0.01
0.1
1
short-lived parentslong-lived parents
Linear Regression Line
Age
40 50 60 70 80 90 100
Lo
g(H
aza
rd R
ate)
0.001
0.01
0.1
1
short-lived parentslong-lived parents
Linear Regression Line
Parental-Age Effects (accumulation of mutation load in
parental germ cells)
Does progeny conceived to older parents live shorter lives?
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.
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
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
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