Lifestyle and Environmental Factors Associated with Telomere Length an epidemiologic perspective

Transcription

1 Lifestyle and Environmental Factors Associated with Telomere Length an epidemiologic perspective Dale P. Sandler Epidemiology Branch National Institute of Environmental Health Sciences National Academy of Sciences National Academy of Sciences October 4 5, 2012

2 Telomere Length Telomeres non coding repeat sequences of DNA; cap and protect chromosomes Telomeres shorten with cell division and DNA damage Citi Critically short ttl telomeres can lead to Cellular senescence Genomic instability Implications for disease risk

3 Telomeres as a Biomarker for Human Health lhstudies Alfred Stieglitz Georgia O Keeffe Hands, 1919 illustrating the power of the fragment tto express the whole.

4 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?

5 General Biomarker or Causal Intermediate? Environment Lifestyle Stress Telomere Length Changes Health Effects Environment Lifestyle Stress Tl Telomere Length Changes Health Effects

6 Environment and Telomere Length Evidence in Twins Twin studies can quantify genetic and environmental contributions to disease or other outcomes Telomere length studied in686maleuswwiiandkorean and 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) l l hl lf d h d Telomere length later in life due to shared environment rather than heritable effects

7 Environmental Factors and Telomere Length Most research focused on lifestyle factors Shorter telomeres Smoking Obesity and abdominal fatness Alcohol Longer telomeres Greater physical activity Multivitamin use Dietary omega 6 and omega 3 fatty acids Cereal fiber Serum vitamin D levels

8 Alcohol and Telomere Length Leukocyte telomeres measured in random sample of older men (mean age 76) in The Helsinki Businessmen Study (n=499) Alcohol at midlife associated with shorter telomeres; no association with current drinking Lasting effects TE Strandberg, et, al. Eur J Epidemiol 2012 (early epub)

9 Environmental Factors and Telomere Length Few studies of environmental toxicants Shorter telomeres Traffic related air pollutants Lead levels in Chinesebatteryworkers N nitrosamines in Swedish rubber workers PAH exposure in Polish coke oven workers Some agricultural pesticides Longer telomeres Arsenic in drinking water Arsenic associated with ihincreased telomerase expression Acute exposure to metal rich PM in steel workers PCBs and other organochlorines

10 Studies of Air Pollution and Telomere Length Smallstudies; 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 Long term traffic pollution 165 never smoking men in the Normative Aging Study 77 traffic officers 57 office workers Boston, US 1 Milan, Italy 2 Short Short 3 day exposure to 63 steel workers Brescia, Italy 3 Long ambient PM Long term PM 60 truck drivers 60 indoor office workers Beijing, China 4 Long (2 day exposure) Short (14 day exposure) 1. McCracken, EHP 2010; 2. Hoxha, Environ Health Dioni, EHP 2011; 4. Hou, Environ Int 2012

11 Telomere Length in the Sister Study Sister Study prospective study of 50,884 sisters of women who have had breast cancer Recruited US and Puerto Rico Age Never had breast cancer 16% minority

12 Sister Study Design

13 Sister Study Data Lifetime Influences on Women s Health

14 Telomere Length in the Sister Study Motivated by reports of py psychological stress related telomere shortening (e.g. E Epel, PNAS 2004) DoD grant, C Parks Cross sectional 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 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

15 Telomere Length in the Sister Study Telomere length assay quantitative PCR* DNA from leukocytes (frozen whole blood) Ratio of relative amplification of telomere sequence () (t) to 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

16 Stress and Telomere Length All Higher women norepinepherine None PT FT OT Parks, et al., OEM > Stress Score Parks, et al. CEBP DeRoo, et al. AJE 2010 (abstract)

17 Obesity and Telomere Length <25 25-< <25 25-< BMI now BMI nml nml nml overwt+ nml overwt obese overwt+ Kim, et al., CEBP 2009

18 Multivitamins and Telomere Length Multivitamins Xu, et al., Am J Clin Nutrition <3 4-6 daily Days per week

19 Other Associations Shorter telomeres Increasing age ( 27 bp year) Current smoking Lower education Self reported poor health Cardiovascular or metabolic disease Factors not associated with telomere length Clinical depression Average sleep duration Regular exercise Use of HRT

20 Telomere Length and Breast Cancer Case cohort study 385 incident cancers and random sample (n=770) of cohort enrolled by June 2007 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? Quartile of Relative TL HR 95% CI Referent 1.18-< ( ) < ( ) < ( ) Kim, et al., Cancer Causes Control 2011 Kim, et al., PLoS One 2011

21 Limitations Small sample sizes 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 2011) TL from single time point fairly represents average of multiple measurements over 12 months (Kim 2011) Plate effects in qpcr assay require technical replicates and careful balancing of case and control samples (Kim 2011)

22 Limitations Most research cross sectional sectional Telomere length and rate of attrition vary across the lifespan Heritable differences in telomere length may affect rate of change Singlemeasure at one time point maymisclassify misclassify telomere characteristics Need longitudinal studies

23 Can a single image capture the complexity of an individual? id Nicholas Nixon The Brown Sisters 1975

24 Can a single image capture the complexity of an individual? id Nicholas Nixon The Brown Sisters 2011

25 Can a single image capture the complexity of an individual? id Nicholas Nixon Nicholas Nixon The Brown Sisters

26 Acknowledgements Sister Study Telomere Collaborators Honglei Chen Lisa DeRoo Sangmi Kim Christine Parks Jack Taylor Clarice Wib Weinberg Qun Xu