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Lifestyle and Environmental Factors yAssociated with Telomere Length
an epidemiologic perspective
Dale P. SandlerEpidemiology Branchp gy
National Institute of Environmental Health Sciences
National Academy of SciencesNational Academy of SciencesOctober 4‐5, 2012
Telomere LengthTelomere Length
Telomeres ‐ non‐coding repeatTelomeres non coding repeat sequences of DNA; cap and protect chromosomes
– Telomeres shorten with cell division and DNA damageC iti ll h t t l– Critically short telomeres can lead to
• Cellular senescence• Genomic instability
– Implications for disease risk
Telomeres as a Biomarker f l h difor Human Health Studies
Alfred Stieglitz –Georgia O’Keeffe – Hands, 1919
…illustrating the power of th f t t ththe fragment to express the whole.
Telomere LengthTelomere Length
Telomere length determined by multiple factors– Shorten with age (~25 bp/year)
• Age‐related differences in rate of shortening• Shortening accelerated by oxidative stress and inflammation • Not a steady decline across the lifespan
– Telomerase‐related lengthening (compensation mechanisms)
Biological processes leading to telomere shortening are relevant mechanisms linking environmental exposures to diseasedisease
Telomeres an intermediary between exposures and disease?
General Biomarker or Causal Intermediate?General Biomarker or Causal Intermediate?
EnvironmentLifestyleStress
Telomere Length Changes
Health Effects
Changes
T l
EnvironmentLifestyle
Telomere Length Changes
Stress
Health Effects
Environment and Telomere Length Evidence in Twins
Twin studies can quantify genetic and environmentalTwin studies can quantify genetic and environmental contributions to disease or other outcomes
– Telomere length studied in 686 male US WWII and Korean Telomere length studied in 686 male US WWII and KoreanWar veteran monozygotic and dizygotic twins (mean age 77.5) including 181 MZ and 125 DZ complete pairs
– TL correlated in pairs, but no difference between MZ and DZ twins (N Huda, et al., Aging Cell 2007)
l l h l l f d h dTelomere length later in life due to shared environment rather than heritable effects
Environmental Factors d l hand Telomere Length
Most research focused on lifestyle factorsMost research focused on lifestyle factors– Shorter telomeres
• Smoking • Obesity and abdominal fatness• Alcohol
– Longer telomeresLonger telomeres • Greater physical activity• Multivitamin use• Dietary omega‐6 and omega‐3 fatty acids• Cereal fiber• Serum vitamin D levels
Alcohol and Telomere LengthAlcohol and Telomere Length
• Leukocyte telomeres ymeasured in random sample of older men (mean age 76) in The(mean age 76) in The Helsinki Businessmen Study (n=499)
• Alcohol at midlife associated with shorter telomeres; no associationtelomeres; no association with current drinking
• Lasting effects
TE Strandberg, et, al. Eur J Epidemiol 2012 (early epub)
Environmental Factors and Telomere LengthEnvironmental Factors and Telomere Length
Few studies of environmental toxicants– Shorter telomeres
• Traffic‐related air pollutants• Lead levels in Chinese battery workers• Lead levels in Chinese battery workers• N‐nitrosamines in Swedish rubber workers• PAH exposure in Polish coke‐oven workers• Some agricultural pesticides• Some agricultural pesticides
– Longer telomeres • Arsenic in drinking water
A i i d i h i d l i– Arsenic associated with increased telomerase expression• Acute exposure to metal‐rich PM in steel workers • PCBs and other organochlorines
Studies of Air Pollution and Telomere LengthStudies of Air Pollution and Telomere Length
Small studies; differing resultsSmall studies; differing results– Due to sample size, differences in exposures or exposure duration, other differences?
Exposure Subjects Location TL
1‐year exposure levels to black carbon
165 never‐smoking men in the Normative Aging St d
Boston, US1 Short
Study
Long‐term traffic pollution 77 traffic officers57 office workers
Milan, Italy2 Short
3 day exposure to 63 steel workers Brescia Italy3 Long3‐day exposure to ambient PM
63 steel workers Brescia, Italy3 Long
Long‐term PM 60 truck drivers 60 indoor office workers
Beijing, China4 Long (2‐day exposure) Short (14‐day exposure)
1. McCracken, EHP 2010; 2. Hoxha, Environ Health 20093. Dioni, EHP 2011; 4. Hou, Environ Int 2012
Telomere Length in the Sister StudyTelomere Length in the Sister Study
Sister Study – prospective study of 50,884 sisters ofSister Study prospective study of 50,884 sisters of women who have had breast cancer
– Recruited 2004 – 2009– US and Puerto Rico– Age 35‐74– Never had breast cancer– 16% minority
Sister Study Design
Sister Study DataLifetime Influences on Women’s Health
Telomere Length in the Sister StudyTelomere Length in the Sister Study
Motivated by reports of psychological stress related y p p y gtelomere shortening (e.g. E Epel, PNAS 2004) – DoD grant, C ParksCross‐sectional study using baseline Sister Study dataCross sectional study using baseline Sister Study data
– Questionnaire data on self‐perceived stress and other factors– Measured height and weight
Stress hormone levels in urine– Stress hormone levels in urine– Leukocyte telomere length
Sample of early participants (N=647)– Exclusions: Current shift work, recent surgery/chemotherapy,
missing data, breast cancer within 12 months of enrollment– Enriched for higher perceived stress, nonwhite race, smoking
Telomere Length in the Sister StudyTelomere Length in the Sister Study
Telomere length assay – quantitative PCR*Telomere length assay quantitative PCR– DNA from leukocytes (frozen whole blood)– Ratio of relative amplification of telomere sequence (t) to p q ( )a single copy (s) gene
– QC – duplicates (8.7% CV, adj. for plate)
Average t/s ratio values normally distributed; mean = 1.32 (SD 0.25)Transformed (some results) into base pairs (1 t/s ratio unit=4270 bp); mean = 5,618 (SD 1,069)
*RM Cawthon, Nucl Acids Res 2002
Stress and Telomere LengthStress and Telomere Length
All Higher women norepinepherine
None PT FT OTParks, et al., OEM 2011
0-2 >2 0 1-2 3-5 6-7 8+Stress Score
Parks, et al. CEBP 2009 0 1 2 3
DeRoo, et al. AJE 2010 (abstract)
Obesity and Telomere LengthObesity and Telomere Length
nml nml nml overwt+nml overwt obese overwt+
<25 25-<30 30+ <25 25-<30 30+
BMI now BMI 30-39
Kim, et al., CEBP 2009
Multivitamins and Telomere LengthMultivitamins and Telomere Length
MultivitaminsMultivitamins
0 <3 4-6 daily
Days per weekXu, et al., Am J Clin Nutrition 2009
Other AssociationsOther Associations
Shorter telomeres– Increasing age (‐27 bp year)– Current smoking– Lower education– Lower education– Self‐reported poor health– Cardiovascular or metabolic disease
d h l l hFactors not associated with telomere length– Clinical depression– Average sleep durationAverage sleep duration– Regular exercise– Use of HRT
Telomere Length and Breast CancerTelomere Length and Breast Cancer
Case‐cohort study y– 385 incident cancers and random
sample (n=770) of cohort enrolled by June 2007
Quartile of Relative TL HR 95% CI≥1 42 1 0 Referentby u e 00
No association of telomere length and breast cancer
≥1.42 1.0 Referent1.18-<1.42 0.9 (0.6-1.3)1.0 - <1.18 1.1 (0.8-1.6)
Associations between rTL and 5 (of 33) SNPs in genes involved in
<1.0 0.9 (0.6-1.4)
Kim, et al., Cancer Causes Control 2011
DNA histone methylationEpigenetic regulation of telomere length?telomere length?
Kim, et al., PLoS One 2011
LimitationsLimitations
• Small sample sizes p• Inconsistent or unconfirmed results – possibly due to different study designs or population factors
• Limited data on reproducibility and validity of assays, inter‐laboratory differences
– Good reproducibility, but inter‐assay CV higher for qPCR (Aviv p y, y g q (2011)
– TL from single time point fairly represents average of multiple measurements over 12 months (Kim 2011)l ff i C i h i l li d f l– Plate effects in qPCR assay require technical replicates and careful
balancing of case and control samples (Kim 2011)
LimitationsLimitations
Most research cross‐sectionalMost research cross sectional– Telomere length and rate of attrition vary across the
lifespan – Heritable differences in telomere length may affect rate of
changeSingle measure at one time point may misclassify telomere– Single measure at one time‐point may misclassify telomere characteristics
Need longitudinal studies
Can a single image capture h l i f i di id l?the complexity of an individual?
Nicholas NixonThe Brown Sisters 1975
Can a single image capture h l i f i di id l?the complexity of an individual?
Nicholas NixonThe Brown Sisters 2011The Brown Sisters 2011
Can a single image capture h l i f i di id l?the complexity of an individual?
Nicholas NixonNicholas NixonThe Brown Sisters1975‐2011
AcknowledgementsAcknowledgements
Sister Study Telomere CollaboratorsSister Study Telomere Collaborators– Honglei ChenLisa DeRoo– Lisa DeRoo
– Sangmi KimCh i ti P k– Christine Parks
– Jack TaylorCl i W i b– Clarice Weinberg
– Qun Xu