Leonid A. Gavrilov, Ph.D. Natalia S. Gavrilova, Ph.D. Center on Aging

Early Life Biodemographic Influences on Exceptional Longevity: Parental Age at

Person's Birth and the Month of Birth Are Important Predictors

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

Center on Aging

NORC and The University of Chicago Chicago, USA

High Initial Damage Load (HIDL) Idea

"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.

Why should we expect high initial damage load in biological systems?

General argument:--  biological systems are formed by self-assembly without helpful external quality control.

Specific arguments:

1. Most cell divisions responsible for  DNA copy-errors occur in early development leading to clonal expansion of mutations

2. Loss of telomeres is also particularly high in early-life

3. Cell cycle checkpoints are disabled in early development

New Vision of Aging-Related Diseases

Approach

To study “success stories” in long-term avoidance of fatal diseases (survival to 100 years) and factors correlated with this remarkable survival success

How centenarians are different from their

shorter-lived sibling?

Within-Family Study of Exceptional Longevity

Cases - 1,081 centenarians born in the U.S. in 1880-1889 with known information about parental lifespan

Controls – 6,413 their own siblings

Method: Conditional logistic regression

Advantage: Allows researchers to eliminate confounding effects of between-family variation

Design of the Study

A typical image of ‘centenarian’ family in 1900

census

Multivariate Analysis:Conditional logistic

regression

For 1:1 matched study, the conditional likelihood is given by:

Where xi1 and xi0 are vectors representing the prognostic factors for the case and control, respectively, of the ith matched set.

101 ))(exp(1( i

ii xx

Maternal age and odds to live to 100 for siblings survived to age

50Conditional (fixed-effects) logistic regressionN=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 1.731.05-2.88

0.033

20-24 1.631.11-2.40

0.012

25-29 1.531.10-2.12

0.011

30-34 1.160.85-1.60

0.355

35-39 1.060.77-1.46

0.720

40+ 1.00Referenc

e

Results In smaller families (less than 9 children) the

effect of young mother is even larger (for siblings survived to age 50 and maternal age 20-24 years vs 40+ years):

Odds ratio = 2.23, P=0.013; 95%CI = 1.18 – 4.21

Compare to larger families (more than 9 children):

Odds ratio = 1.39, P=0.188; 95%CI = 0.85 – 2.27

Conclusion:"Young mother effect" is not confined to

extremely large family size

Question Families were quite large in the past,

particularly those covered by genealogical records (large family size bias).

Is the "young mother effect" robust to the family size, and is it observed in smaller families too?

Or is it confined to extremely large families only?

Approach:To split data in two equal parts by median family

size (9 children) and re-analyze the data in each group separately.

People Born to Young Mothers Have Twice Higher Chances to Live to 100Within-family study of 2,153 centenarians and their siblings survived to age 50. Family size

<9 children.

0.8

1

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

<20 20-24 25-29 30-34 35-39 40+

Odds

rati

o

Maternal Age at Birth

p=0.020

p=0.013

p=0.043

Being born to Young Mother Helps Laboratory Mice to Live

Longer 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.

Season-of-birth effect on longevity

Season-of-birth Study of Exceptional Longevity

Cases - 1,574 centenarians born in the U.S. in 1880-1895

Controls – 10,885 their own siblings and 1,083 spouses

Method: Conditional logistic regression

Advantage: Allows researchers to eliminate confounding effects of between-family variation

Distribution of individuals by month of birth in percent: centenarians, their shorter-lived siblings survived to age 30 and U.S. population born in our study window (1880-1895) according to the 1900 U.S. Census (IPUMS data)

Season of birth and odds to live to 100 Within-family study of

siblingsVariable All siblings Siblings survived to

age 30Siblings survived to age 50

Siblings survived to age 70

Month of birth:

January 1.13 (0.387) 1.11 (0.472) 1.11 (0.463) 1.09 (0.537)

February 1.25 (0.101) 1.25 (0.109) 1.24 (0.124) 1.16 (0.303)

March Reference Reference Reference Reference

April 1.15 (0.320) 1.15 (0.337) 1.16 (0.320) 1.09 (0.567)

May 1.20 (0.218) 1.17 (0.288) 1.19 (0.251) 1.15 (0.373)

June 1.20 (0.229) 1.00 (0.254) 1.18 (0.284) 1.11 (0.486)

July 1.03 (0.855) 1.19 (0.991) 1.01 (0.941) 1.00 (0.990)

August 1.25 (0.110) 1.24 (0.125) 1.27 (0.100) 1.21 (0.198)

September 1.44 (0.006) 1.43 (0.009) 1.45 (0.007) 1.39 (0.022)

October 1.43 (0.008) 1.37 (0.021) 1.37 (0.022) 1.27 (0.099)

November 1.51 (0.003) 1.48 (0.005) 1.47 (0.006) 1.41 (0.017)

December 1.17 (0.266) 1.13 (0.380) 1.17 (0.283) 1.11 (0.486)

Female sex 3.77 (<0.001) 3.82 (<0.001) 3.80 (<0.001) 3.41 (<0.001)

Pseudo R2 0.0811 0.0861 0.0871 0.0766

Number of observations

12,132 10,393 9,724 8,123

Siblings Born in September-November Have Higher Chances to

Live to 100Within-family study of 9,724 centenarians born in 1880-1895 and their siblings survived to

age 50

Spouses Born in October-November Have Higher Chances to Live to 100Within-family study of 1,800 centenarians born in 1880-1895 and their spouses survived

to age 50

Month of Birth

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

life

exp

ecta

ncy

at

age

80, y

ears

7.6

7.7

7.8

7.9

1885 Birth Cohort1891 Birth Cohort

Life Expectancy and Month of BirthData source: Social Security Death Master File

Published in:

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.

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.

AcknowledgmentsThis study was made possible thanks to:

generous support from the National Institute on Aging

grant #R01AG028620

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Final Conclusion

The shortest conclusion was suggested in the title of the New York Times article about this study