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Lifestyle and Environmental Factors y Associated with Telomere Length an epidemiologic perspective Dale P. Sandler Epidemiology Branch p gy National Institute of Environmental Health Sciences National Academy of Sciences National Academy of Sciences October 4‐5, 2012 Telomere Length Telomere Length Telomeres ‐ non Telomeres non‐coding coding repeat repeat sequences of DNA; cap and protect chromosomes – Telomeres shorten with cell division and DNA damage – Critically short telomeres can C iti ll h t t l lead to • Cellular senescence • Genomic instability – Implications for disease risk Telomeres as a Biomarker f for Human Health Studies lh di Alfred Stieglitz – Georgia O’Keeffe – Hands, 1919 …illustrating the power of th f the fragment to express the tt th whole. Telomere Length Telomere 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 disease Telomeres an intermediary between exposures and disease? General Biomarker or Causal Intermediate? General Biomarker or Causal Intermediate? Environment Lifestyle Stress Telomere Length Changes Health Effects TTelomere l Length Changes Environment Lifestyle Stress Health Effects Environment and Telomere Length Evidence in Twins Twin studies can quantify genetic and environmental Twin studies can quantify genetic and environmental contributions to disease or other outcomes – Telomere Telomere length studied in 686 male US WWII and Korean length studied in 686 male US WWII and Korean War 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) Telomere length later in life due to shared l l hl lf d h d environment rather than heritable effects Environmental Factors and Telomere Length d l h Most research focused on lifestyle factors Most research focused on lifestyle factors – Shorter telomeres • Smoking • Obesity and abdominal fatness • Alcohol – Longer telomeres Longer telomeres • • • • • Greater physical activity Multivitamin use Dietary omega‐6 and omega‐3 fatty acids Cereal fiber Serum vitamin D levels Alcohol and Telomere Length Alcohol and Telomere Length • • • Leukocyte telomeres y measured 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 association telomeres; no association with current drinking Lasting effects TE Strandberg, et, al. Eur J Epidemiol 2012 (early epub) Environmental Factors and Telomere Length Environmental 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 – Arsenic associated with increased telomerase expression A i i d i hi d l i • Acute exposure to metal‐rich PM in steel workers • PCBs and other organochlorines Studies of Air Pollution and Telomere Length Studies of Air Pollution and Telomere Length Small studies; differing results Small 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 Study Boston, US1 Short Long‐term traffic pollution 77 traffic officers 57 office workers Milan, Italy2 Short 3‐day exposure to 3 day exposure to ambient PM 63 steel workers 63 steel workers Brescia, Italy Brescia Italy3 Long 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 2009 3. Dioni, EHP 2011; 4. Hou, Environ Int 2012 Telomere Length in the Sister Study Telomere Length in the Sister Study Sister Study Sister Study – prospective study of 50,884 sisters of 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 Data Lifetime Influences on Women’s Health Telomere Length in the Sister Study Telomere Length in the Sister Study Motivated by reports of psychological stress related y p py g telomere shortening (e.g. E Epel, PNAS 2004) – DoD grant, C Parks Cross‐sectional Cross sectional study using baseline Sister Study data 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 Study Telomere Length in the Sister Study Telomere length assay elomere length assay – quantitative PCR 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 Length Stress and Telomere Length All women Higher norepinepherine None PT FT OT Parks, et al., OEM 2011 0-2 >2 0 1-2 Stress Score Parks, et al. CEBP 2009 3-5 6-7 8+ 0 1 2 3 DeRoo, et al. AJE 2010 (abstract) Obesity and Telomere Length Obesity and Telomere Length <25 25-<30 30+ BMI now Kim, et al., CEBP 2009 <25 25-<30 30+ BMI 30-39 nml nml nml overwt nml obese overwt+ overwt+ Multivitamins and Telomere Length Multivitamins and Telomere Length Multivitamins 0 <3 4-6 Days per week Xu, et al., Am J Clin Nutrition 2009 daily Other Associations Other Associations Shorter telomeres – – – – – Increasing age (‐27 bp year) Current smoking Lower education Lower education Self‐reported poor health Cardiovascular or metabolic disease Factors not associated with telomere length d h l l h – – – – Clinical depression Average sleep duration Average sleep duration Regular exercise Use of HRT Telomere Length and Breast Cancer Telomere Length and Breast Cancer Case‐cohort study y – 385 incident cancers and random sample (n=770) of cohort enrolled by June 2007 by u e 00 No association of telomere length and breast cancer Associations between rTL and 5 (of 33) SNPs in genes involved in DNA histone methylation Epigenetic regulation of telomere length? telomere length? Kim, et al., PLoS One 2011 Quartile of Relative TL HR 95% CI ≥1 42 ≥1.42 10 1.0 Referent 1.18-<1.42 0.9 (0.6-1.3) 1.0 - <1.18 1.1 (0.8-1.6) <1.0 0.9 (0.6-1.4) Kim, et al., Cancer Causes Control 2011 Limitations • 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 p y, y g q ((Aviv 2011) – TL from single time point fairly represents average of multiple measurements over 12 months (Kim 2011) – Plate effects in qPCR l ff i C assay require technical replicates and careful i h i l li d f l balancing of case and control samples (Kim 2011) Limitations Most research cross‐sectional Most research cross sectional – Telomere length and rate of attrition vary across the lifespan – Heritable differences in telomere length may affect rate of change – Single 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 the complexity of an individual? h l i f i di id l? Nicholas Nixon The Brown Sisters 1975 Can a single image capture the complexity of an individual? h l i f i di id l? Nicholas Nixon The Brown Sisters 2011 The Brown Sisters 2011 Can a single image capture the complexity of an individual? h l i f i di id l? Nicholas Nixon Nicholas Nixon The Brown Sisters 1975‐2011 Acknowledgements Sister Study Telomere Collaborators Sister Study Telomere Collaborators – Honglei Chen – Lisa DeRoo Lisa DeRoo – Sangmi Kim – Christine Parks Ch i ti P k – Jack Taylor – Clarice Weinberg Cl i W i b – Qun Xu