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Initiative to Study Exceptional Longevity. Advisory Panel on Exceptional Longevity (APEL) ... factors that contribute to exceptional longevity (EL) and reduce risks across major ...

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The Utah Study of Fertility

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The Utah Study of Fertility, Longevity & Agingand the Utah Population DatabaseKen R. Smith(ken.smith@fcs.utah.edu)

Supported by NIA grants AG00767, AG14495, and AG13478.


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How Long Will You Live?… in Good Health?Is there a way to know?Is there a way to change it?


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Longevity Game – Northwestern Mutual

Gender

Age

Family History

BMI

Blood Pressure

Stress

Exercise

Diet

Seat Belt

Driving Style

Alcohol

Smoking

Illicit Drug Use

http://www.nmfn.com/tn/learnctr--lifeevents--longevity_end


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Longevity Calculator - New England Centenarian Study

Tobacco

Diet

Alcohol

Air pollution

Coffee/tea

Aspirin

Flossing

History of CVD

Tanning

Social Support

Stress

Family Hx

of Longevity

Exercise

Vitamins

Gender

Age


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Traditional Method

  • Life Tables

  • Gender

  • Age

  • Place

  • Year


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Years of Life Remaining:Utah Males 2001

Years

Age


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Years of Life Remaining: Utah Females 2001

Years

Age


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Difference in Remaining Years of Life: Female Advantage over Males 2001, Utah

Years

Age


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Years of Life Remaining:US and Utah Males 2001

Years

Age


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Years of Life Remaining: US and Utah Females 2001

Years

Age


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Objectives

  • Why study exceptional familial longevity?

  • NIA support

  • Utah Longevity Study

  • Measures

  • Importance of the Utah Population Database

  • Research Highlights

  • Final thoughts


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What is Possiblefor Achieving a Healthy Life Span?Look to the record-holders.


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LONGEST LIVED

HUMAN WITH

AUTHENTICATED

RECORDS

Jeanne Louise Calment,

Paris

Died 1997 at age 122

LONGEST LIVING

HUMAN WITH

AUTHENTICATED

RECORDS

116-year-old

Elizabeth “Lizzie” Bolden.

Memphis, Tenn.


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What allowed these individuals to live so long?

Aged slowly & thus avoided serious fatal diseases

Science, 2-28-2003


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National Institute on AgingInitiative to Study Exceptional Longevity

  • Advisory Panel on Exceptional Longevity (APEL)

    • Find genetic & environmental factors that contribute to exceptional longevity (EL) and reduce risks across major age-related diseases

    • Find homogenous subgroups that comprise the long-lived population (e.g., familial patterns of longevity)


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Utah Study of Fertility, Longevity, and Aging (USFLAG) (National Institute on Aging)

2

Resistance to chronic diseases and environmental stressors

Rank UPDB pedigrees

in terms of family pattern of longevity past 65

Psycho-social, biological, genetic markers associated with exceptional survival among relatives around age 90+

3

1

  • Do offspring of long-lived parents age more slowly than controls

4


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Utah Study of Fertility, Longevity, and Aging (USFLAG) (National Institute on Aging)


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Demographic Factors

Risk/Lifestyle Factors

Medical History

Reproductive History

Cognitive Functioning

Instrumental/Activities of

Daily Living

Depression

Stress Resiliency

Blood Measures

Serum Cholesterol

Glycosylated Hemoglobin

C-reactive protein

DHEA/DHEAS

Albumin

Uric Acid

Creatinine

WBC

DNA

Immortal cell lines

Genome Wide Scan

Telomere Length

Mutations in mtDNA

APOE

Clinical Measures

Grip Strength

Blood and Pulse Pressure

Heart Rate

Lung Function

Body Mass Index

Body Temperature

Morbidity

(CMS Medicare claims)

Mortality (cause of death)

Selected Measures


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UPDB and FLAG


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Aging Research Advances ThroughNovel Linkages to UPDB

Centers for Medicare &

Medicaid Services

1991-2002

400,000 Utahns

age 65+

Cache County Study on

Memory, Health & Aging

Ron Munger, JoAnn Tschanz, Maria Norton

USU

Kathleen Welsh-Bohmer

Duke


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Research Highlights:A Sampler


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Does Exceptional Survival Run in Families?Does a Family History of Extreme Longevity Protect Against Major Age-Related Diseases?


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Recurrence Risks of Extreme Longevity (Lived Past 99th Percentile of Excess Longevity) in Various Classes of Relatives (UPDB)

Extreme Longevity Runs in

Families

Parent, Sibling

Gparent, Gchild, Aunt, Uncle,

Niece, Nephews

1st Cousin

Once Removed

1st Cousins

Kerber, O’Brien, Smith and Cawthon, 2001, J of Gerontology


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Relative Risk of Mortality:Top 25% vs. Bottom 25% of Familial Longevity (UPDB)

Extreme Familial Longevity

Reduces Risk at Most Ages

Worse

Cancer

Cerebrovascular

Diabetes

Better

Heart

Age

O’Brien, Kerber, Smith, Mineau, submitted, 2006


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Are there factors that we can observe in midlife (age 50) in UPDB that predict lower mortality in later years?The case of late female fertility(or if you can measure it, late natural menopause)


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Relative Risk of Living to 100

Vs. Dying Before Age 85 Among Women By Age at Last Birth

(Among Women Surviving to Age 60; Born <=1900) (UPDB)

Late Fertile Women

More Likely to be Centenarians

Relative Risk

Age at Last Birth

Controls for Mormon/Non-Mormon status, birth year, parity, age at first birth

Reference group: Women whose Age at Last Birth is 37 to 42 years of age

Smith, Mineau, Bean, Social Biology, 2002


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Reduced Risk of Mortality from Leading Causes of Death Among Females (60+) with Very Late Fertility (>age 45) vs. Controls (UPDB)

Late Fertile Women

Less Prone to Major

Causes of Death


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Relative Risk for Late vs. Average Age (<=41) at Last Birth Between Female Members 55 or Older of Lineages Selected for Exceptional Longevity & Control Lineages

>=3 Probands per Lineage

8.9

Women from LL Pedigrees are

More Prone to be Late Fertile

Adjusts for birth date, age at first birth, LDS affiliation; Bars represent 95% CI; N=440; All subjects lived to age 55.


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Relative Risks for Mortality for Brothers Living to Age 50 byMaximum Age at Last Birth of Sisters Who Survived to Age 50(Reference Group: Sisters’ with Max Age at Last Birth below 50th Pct)

Brothers of Late Fertile Women Live Longer

Relative Risk

UT = Utah Population Database (n=29,445 males)


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Telomeres and Longevity

As cells divide, telomeres shorten with increasing age due to a decline in the enzyme telomerase

Short telomeres trigger cell death & cellular senescence (possibly as a protection against cancer) and are associated with aging and death

UGRP (Utah Genetic Reference Project) families linked to UPDB


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Those with longer telomeres in blood DNA live longer among the elderly, controlling for age

Years Since Blood Draw

Cawthon, Smith, O’Brien, Sivatchenko, Kerber, Lancet, 2003


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Women

Men

Years Since Blood Draw

Cawthon, Smith, O’Brien, Sivatchenko, Kerber, Lancet, 2003


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Age 60-74

Age 75+

Cawthon, Smith, O’Brien, Sivatchenko, Kerber, Lancet, 2003


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How are the Middle-agedand Young Elderly of the Exceptional Survivors Doing?


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Relative Risk of Disease: Offspring of Proband vs. Controls

Odds Ratio

69 offspring

1569 NHANES controls

Controls for age, gender, education, marital status


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Cache County Study on Memory, Health & Aging

Cache Co.


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Genetic Markers Associated with Aging and Survival that are Linked to the UPDB

  • ε4 allele:

    • Risk of cardiovascular disease

    • Alzheimer’s Disease

  • ε2 allele

    • More frequent in centenarians

  • Association between APOE genotype and cause-specific mortality

    • Modified by indicators of rates of aging

    • Possible because of record linkage to UPDB


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Mortality Rate Ratios for APOE Genotypes (ε33 is reference)

All-Cause

Cardiovascular (633)

ε22 ε23ε24 ε34 ε44

ε22 ε23ε24 ε34 ε44

Respiratory (176)

Cancer (249)

ε22 ε23ε24 ε34 ε44

ε22 ε23ε24 ε34 ε44


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Mortality Rate Ratios for APOE Genotypes (ε33 is reference)

Nervous (AD, Parkinson) (84)

Endocrine (Diabetes) (62)

ε22 ε23ε24 ε34 ε44

ε22 ε23ε24 ε34 ε44

Digestive System (57)

Mental Disorders (42)

ε22 ε23ε24 ε34 ε44

ε22 ε23ε24 ε34 ε44


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Effects of APOE Genotype on All-Cause Mortality by Familial Longevity

Pedigrees of Average Longevity

Long-Lived Pedigrees

ε22 ε23ε24 ε34 ε44

ε22 ε23ε24 ε34 ε44

Interaction between FEL and ε34 & ε44, p<.05


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Medicare Claims

  • 65-69 year olds (n=28,000)

  • 1998-2002

  • Medicare Claims in Utah

  • Compare top 10% for familial longevity to the rest

    • 11.2 fewer claims

    • 8 fewer claims for heart disease, stroke, cancer, and diabetes combined

    • 40% more likely to have made no claims for these four leading conditions


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Final Thoughts

  • Study not designed with personalized medicine in mind

  • Potential for identifying measures that capture rates of aging that predict risks from multiple diseases

  • Long-lived as a source of information about low disease risk

  • Value of deep family history of longevity to supplement family medical history

  • Value of UPDB


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Genetics and Genetic Epidemiology

Richard Cawthon

Richard Kerber

Elizabeth O’Brien

Demography

Geri Mineau

Ken Smith

Biostatistics

Ken Boucher

Gilda Garibotti

Psychology

Cindy Berg

Project Manager

Diana Lane Reed

Database Manager

Alison Fraser

Project Coordinators

Heather Anderson

Jahn Barlow

Database Linkage/Programmers

Richard Pimentel

Heidi Hanson

Study Coordinator

Michelle Robinson

Phlebotomists

Kellie Littlefield

Jayci Bash

Layah Steinberg-Moss

Informatics

Dinny Berry

Research Administration

Camille Phillips

CRC

Sayed Ahmed

USFLAG Team


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