Unraveling the Secrets of Human Longevity

Leonid A. GavrilovNatalia 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

ageFacts: 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

Aging starts early – at age 10

0.00001

0.0001

0.001

0.01

0.1

1

0 20 40 60 80 100

Age

log

(mor

talit

y ra

te)

MenWomen

Source: Swedish official life table, 2005

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

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

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.”

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

Age40 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

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

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.

Source: Westendorp, R. G. J., Kirkwood, T. B. L. Human longevity at the cost of reproductive success. Nature, 1998, 396, pp 743-746

Unfortunately Westendorp and

Kirkwood used very incomplete data source and did not check for

data quality

Antoinette de Bourbon(1493-1583)

Lived almost 90 yearsShe 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!

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

An example of incompleteness in dataset used by Westendorp and Kirkwood

Source:

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.

Childlessness Odds Ratio Estimatesas a Function of Wife's Lifespan

Multivariate logistic regression analysis of3,723 European aristocratic families

Wife's Lifespan<20 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90+

Chi

ldle

ssne

ss O

dds

Rat

io (N

et E

ffect

)

0

2

4

6

8

10

Childlessness and lifespan in aristocratic women

31 case

Our results were based on carefully checked data

(genealogies for European aristocratic families)

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

Charles IX d’Anguleme (1550-1574)

Henry VIII Tudor (1491-1547)

Marie-Antoinette von Habsburg-Lothringen

(1765-1793)

Daughter's Lifespan(Mean Deviation from the Birth Cohort Life Expectancy)

as a Function of Paternal Lifespan

Paternal Lifespan, years40 50 60 70 80 90 100

Dau

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r's L

ifesp

an (d

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tion)

, yea

rs

-2

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4

6

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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

Source: Gavrilova, Gavrilov, JAAM, 2001

Our Findings do not Agree with the Linearity Principle of Inheritance

in Quantitative Genetics

Dependence between parental traits and offspring traits is linear

“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

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

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

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.

An example of incredible vitality

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 Areas with high density of centenarians

Studies of centenarians require careful design and

serious work on age validation

There are two factors of longevity

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.

Month of BirthJan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

life

expe

ctan

cy a

t age

80,

yea

rs

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.

Household Property Status During Childhood and Survival to Age 100

Odds for household to be in a ‘centenarian’ group

A – Rented House

B – Owned House

C – Rented Farm

D – Owned farm(reference group)0

0.10.20.30.40.50.60.70.80.9

1

A B C D

MalesFemales

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: life-course 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 1880-1889Controls – 6,413 their shorter-lived brothers and sisters (5,778 survived to age 50)Method: Conditional logistic regressionAdvantage: Allows to eliminate between-family variation

Design of the Study

Age validation is a key moment in human longevity studies

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

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 1.73 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 100Within-family study of 2,153 centenarians and their siblings survived to age 50. Family size

<9 children.

0.8

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1.4

1.6

1.8

2

2.2

2.4

2.6

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

Odds

ratio

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.

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

age 50

Possible explanationsThese 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 DesignCases: 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 RegistrationRegistration 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

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

0

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70Pe

rcen

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Centenarians Controls

shortmediumtall

Body build and survival to age 100

0

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70Pe

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Centenarians Controls

slendermediumstout

Multivariate Analysis 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)

Statistical package Stata-10, command clogit

Results of multivariate study

Variable Odds Ratio

P-value

Medium height vs short and tall height

1.35 0.260

Slender and medium build vs stout build

2.63* 0.025

Farming 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 reference: tall height

1.02 0.967

‘Medium’ body height reference: tall height

1.43 0.212

Other variables include body build and farming

Having children by age 30 and survival to age 100

Conditional (fixed-effects) logistic regressionN=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%. 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.

Final Conclusion

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

Nutrition and longevity: Study of Okinawa

centenarians

Traditional nutrition in Okinawa island is strongly restricted in calories (Craig Willcox, Bradley Willcox)

109 years – still works in her field100-years-old karate

instructor

Japan has very high life expectancy, probably because of low calorie diet

Calorie Restriction with Optimal Nutrition Society «It is difficult only for

the first five years ...»

Roy Walford

Study of caloric restriction in monkeys showed no effect on

longevity 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 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, well-organized person, like a scientist-professor — somewhat obsessive and not at all carefree.” Howard S. Friedman and Leslie R. Martin, The Longevity Project

Genes and longevity 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

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

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

Improved lipid turnover and larger cholesterol particles, less oxidized lipids in plasma

High sensitivity to insulin, lower levels of glucose

Less expressed chronic inflammation

AcknowledgmentThis study was made possible thanks to:

generous support from the National Institute on Aging

grant #R01AG028620

stimulating working environment at the Center on

Aging, NORC/University of Chicago

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