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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