Familial Factors in Longevity: Exploring Complex

Environmental and Genetic Effects

Leonid A. Gavrilov, Ph.D.Natalia S. Gavrilova, Ph.D.

Center on Aging

NORC and The University of Chicago Chicago, USA

Heritability of Longevity

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.

Parental Lifespan0 20 40 60 80

Off

sp

rin

g L

ifesp

an

0

10

20

30

40

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

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

“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

Heritability Estimates of Human Lifespan

Author(s) Heritability

estimate

Population

McGue et al., 1993 0.22 Danish twins

Ljungquist et al., 1998

<0.33 Swedish twins

Bocquet-Appel, Jacobi, 1990

0.10-0.30 French village

Mayer, 1991 0.10-0.33 New England families

Cournil et al., 2000 0.27 French village

Mitchell et al., 2001 0.25 Old Order Amish

Compensation Law of Mortality

Convergence of Mortality Rates with Age

1 – India, 1941-1950, males 2 – Turkey, 1950-1951,

males3 – Kenya, 1969, males 4 - Northern Ireland, 1950-

1952, males5 - England and Wales,

1930-1932, 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

Sons DaughtersAge

40 50 60 70 80 90 100

Log(

Haz

ard

Rat

e)

0.001

0.01

0.1

1

short-lived parentslong-lived parents

Linear Regression Line

Age

40 50 60 70 80 90 100

Log(

Haz

ard

Rat

e)

0.001

0.01

0.1

1

short-lived parentslong-lived parents

Linear Regression Line

Numerous studies showed that biological relatives of

centenarians have substantial survival

advantage compared to biological relatives of

shorter-lived individuals.

Who lives longer in centenarian families?

Siblings > Spouses > Siblings-in-law

Relatives:Men Women

N LS50* N LS50*

Parents 1590 76.2 1557 77.2

Spouses 877 75.4 283 81.4

Siblings 5324 77.6 4877 82.4

Siblings in law 2363 75.1 2410 79.5

1900 US birth cohort

73.3 79.4

*Mean lifespan conditional on survival to age 50

Relatives of 1,711 centenarians born in 1880-1895

Little is known about effects of centenarian’s

sex on longevity of relatives

In this study effects of centenarian’s sex were used to explore genetic and

environmental effects on longevity

Dataset

We have developed and analyzed a new computerized database on 1,711 validated centenarians born in 1880-1895 in the the United States, their parents and 13,185 shorter-lived siblings.

Methods

Gompertz multivariate regression models were used to model survival time between age 50 and death for centenarian siblings. Models for brothers and sisters were analyzed separately. Student t-test was used to compare mean life spans.

Steps of the study 23,127 records of centenarians born in

1880-1895 with known information about parents were identified using the Rootsweb genealogical website

2,834 centenarians having detailed information on their 21,893 siblings were selected

1,711 centenarians with their death dates verified using the Social Security Death Index were used for further analyses

Finally data on 398 male and 1,313 female centenarians, their 13,419 siblings, 1,307 spouses, and 7,924 siblings in law were used in the study

Having centenarian brother is ‘better’ than centenarian sister (for

males only)

Siblings of cente-narians

Male centenarians

Female centenarians

P-value

N LE50 N LE50

Brothers

1268 29.25 4056

27.09 <0.001

Sisters 1071 32.06 3806 32.45 0.328

Life expectancy of siblings at age 50 depending on the sex of centenarian

Survival of male siblings of centenarians, by sex of

centenarian

0.2

.4.6

.81

surv

ival

40 60 80 100 120age

Male cent. Female cent.

Male siblings

Male centenarians

Female centenarians

P-value

N LE50 N LE50

Fathers 374 27.22 1216

25.93 0.023

Mothers 362 27.97 1195 27.03 0.176Life expectancy of parents at age 50 depending on the sex of centenarian

Having centenarian son is ‘better’ than centenarian

daughter (for fathers only)

Male sex of centenarian is ‘better’ for brother’s longevity

Gomperz hazard regression model for survival of brothers of centenarians after age 50. N=5,287

CovariateHazar

d ratio

95% CIP-

value

Father lived 80+

0.8830.836-0.933

<0.001

Mother lived 80+

0.9300.881-0.982

0.009

Married 0.9130.843-0.988

0.025

Birth Year 1.0031.001-1.006

0.011

Female sex of centenarian

1.1721.100-1.249

<0.001

Sex of centenarian is not important for sister’s longevity

Gomperz hazard regression model for survival of sisters of centenarians after age 50. N=4,849

CovariateHazar

d ratio

95% CIP-

value

Father lived 80+ 0.978 0.924-1.035 0.443

Mother lived 80+

0.9310.879-0.985

0.013

Married 0.975 0.895-1.062 0.563

Birth Year 0.9960.994-0.999

0.013

Female sex of centenarian

1.019 0.952-1.091 0.590

Sex-specific Survival Threshold (SSST)

Hypothesis

Because of male and female centenarians have

different survival threshold to reach age

100, sex-specific effects are observed

Test of the SSST hypothesis

Compare siblings of male centenarians to siblings of

females survived to age 103 Probability of survival to 103 for females is similar to probability

of reaching age 100 for males (according to the 1900 U.S.

cohort)

It is ‘better’ to have the same sex as your centenarian-sibling

Male centenarians

Females survived to age 103

P-value (diff.in LS)

N LE50 N LE50

Brothers

1268 29.25 990 27.65 0.0009

Sisters 1071 32.06 963 33.85 0.0008

Fathers 374 27.22 294 25.82 0.112

Mothers 362 27.97 291 26.96 0.276Life expectancy of siblings at age 50 depending on the sex of centenarian

SSST Hypothesis is confirmedfor brothers of centenarians

Gomperz hazard regression model for survival of male centenarian brothers and brothers of females

lived 103+ years after age 50. N=2,243

CovariateHazar

d ratio

95% CIP-

value

Father lived 80+

0.8990.826-0.978

0.013

Mother lived 80+

0.9100.837-0.990

0.027

Married 0.926 0.822-1.043 0.209

Birth Year 1.0051.001-1.009

0.025

Female sex of centenarian

1.064 0.978-1.157 0.147

SSST Hypothesis is NOT confirmed for sisters of

centenarians: sex is still important

Gomperz hazard regression model for survival of male centenarian sisters and sisters of females

lived 103+ years after age 50. N=2,022

CovariateHazar

d ratio

95% CIP-

value

Father lived 80+ 0.984 0.901-1.075 0.727

Mother lived 80+

0.8950.820-0.978

0.014

Married 1.028 0.896-1.179 0.695

Birth Year 0.996 0.991-1.001 0.113

Female sex of centenarian

0.8580.786-0.937

0.001

Using siblings-in-law as a control group

Siblings-in-law do not share genetic background and living conditions with centenarians

On the other hand, they usually come from a similar socio-

economic background, so may be a good control group

Sex of centenarian is important for siblings but not for siblings-

in-law

Married relatives:

Male centenarians

Females centenarians

P-value

N LE50 N LE50

Brothers 784 29.53 2437 27.12

<0.001

Sisters 650 31.36 2378 32.40

0.045

Brothers in law

492 24.95 1857 25.06 0.846

Sisters in law 611 29.22 1796 29.55 0.539

Life expectancy of relatives at age 50 depending on the sex of centenarian

Only women benefit from having centenarian spouse

Centenarian spouses

Sibling spouses

P-value

Sex of spouse

N LE50 N LE50

Men 875 25.40 2349 25.04 0.411

Men (married to 103+ centenarians)

214 25.36 2349 25.04 NS

Women 283 31.40 2407

29.46 0.007

Life expectancy of spouses at age 50 depending on the sex of centenarian

For sisters of centenarians father’s longevity becomes

unimportant

Gomperz hazard regression model for survival of centenarian sisters after age 50.

N=3,141

CovariateHazar

d ratio

95% CIP-

value

Father lived 80+ 1.005 0.933-1.081 0.902

Mother lived 80+

0.9230.858-0.993

0.032

Spouse lived 80+

0.9050.832-0.985

0.020

Birth Year 0.9940.990-0.997

0.001

Female sex of centenarian

0.975 0.893-1.065 0.577

For brothers of centenarians father’s longevity is still

important

Gomperz hazard regression model for survival of centenarian married brothers after age 50.

N=3,141Covariate

Hazard

ratio95% CI

P-value

Father lived 80+

0.9180.855-0.986

0.019

Mother lived 80+

0.9190.857-0.987

0.020

Spouse lived 80+

0.8680.806-0.935

<0001

Birth Year 1.002 0.999-1.006 0.178

Female sex of centenarian

1.1831.090-1.284

<0001

Conclusion

Familial factors in human longevity are likely to be sex-specific.

Exploring complex environmental and genetic effects in longevity could be facilitated by further analysis of sex-specific effects

AcknowledgmentsThis study was made possible thanks to:

generous support from the National Institute on Aging

grant #R01AG028620

For More Information and Updates Please Visit Our Scientific and Educational

Website on Human Longevity:

http://longevity-science.org

And Please Post Your Comments at our Scientific Discussion Blog:

http://longevity-science.blogspot.com/

Exceptional longevity in a family of Iowa farmers

Father: Mike Ackerman, Farmer, 1865-1939 lived 74 years

Mother: Mary Hassebroek 1870-1961 lived 91 years

1. Engelke "Edward" M. Ackerman b: 28 APR 1892 in Iowa 101

2. Fred Ackerman b: 19 JUL 1893 in Iowa 1033. Harmina "Minnie" Ackerman b: 18 SEP 1895 in Iowa 1004. Lena Ackerman b: 21 APR 1897 in Iowa 1055. Peter M. Ackerman b: 26 MAY 1899 in Iowa 866. Martha Ackerman b: 27 APR 1901 in IA 957. Grace Ackerman b: 2 OCT 1904 in IA 1048. Anna Ackerman b: 29 JAN 1907 in IA 1019. Mitchell Johannes Ackerman b: 25 FEB 1909 in IA 85