the national institute on aging workshop on uses of survival data in research on factors affecting...

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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