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REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
58
VOLUME 12 NUMBER 2 • NOVEMBER 2015
telomere length, the risk of myocardial infarction was increased
between 2.8- and 3.2-fold in subjects with shorter-than-average
telomeres.
107
In another study of 143 normal blood donors over the
age of 60 years, it was shown that subjects with shorter telomeres
had poorer survival, with a 3.18-fold higher mortality rate from
heart disease.
108
In a sub-study of the West of Scotland Primary Prevention Study
(WOSCOPS) that compared telomere lengths at recruitment in 484
individuals who went on to develop coronary heart disease events
with those from 1 058 age-matched controls who remained free of
CAD, it was shown that subjects with shorter telomere length at
the time of recruitment had a significantly higher risk of developing
subsequent coronary heart disease.
109
In a case-control sub-study of
the Cardiovascular
Health Study that examined 419 older subjects, it was found
that individuals 73 years or younger had a threefold increased risk
of myocardial infarction and stroke for each one kilobase decrease
in telomere length.
110
Farzaneh-Far
et al
. measured telomere length in 780 patients
with stable angina in a prospective cohort study. During a mean
follow up of 4.4 years, shorter telomere length was significantly
associated with all-cause mortality, independent of age, clinical and
echocardiographic variables.
111
Zee
et al
. using samples collected at
baseline in the prospective Physician’s Health Study from a cohort
of 14 916 initially healthy men, of whom 337 went on to develop
myocardial infarction, demonstrated that participants with shorter
telomere length at baseline had a significantly increased risk of
incident myocardial infarction compared to age- and smoking-
matched controls who remained free of vascular disease over a
mean follow up of 3.85 years.
112
Finally, in the prospective population-based Bruneck study,
baseline telomere length was a significant risk predictor for
subsequent myocardial infarction and stroke, independent of
standard risk factors. Of note in this study was that telomere
length was strongly associated with advanced pathology and acute
vascular syndromes but not early atherosclerosis.
7
Mechanisms to preserve telomere length
Telomerase has been shown to be activated by lifestyle choices that
include a healthy diet, stress relief through meditation, chronic high-
intensity aerobic physical exercise as well as by pharmacological
agents.
113,114
Exercise has been associated with improved cardiovascular
health and longevity. La Rocca
et al
. in a recent study have shown
that maintaining high levels of aerobic fitness preserved telomere
length.
115
They examined young and old individuals and compared
sedentary subjects who exercised fewer than two days per
week for less than 30 min per day with active ones who had
exercised five days per week for more than 45 min per day for
five years. Telomere length was preserved in the older adults
who performed chronic, vigorous exercise and was positively
correlated with maximum aerobic capacity as assessed by higher
VO2
max
levels.
The molecular mechanisms exploring the protective effects of
exercise on the heart has been studied in experimental animals.
Exercise has been shown to promote cell survival by increasing
the activity of telomerase and the expression of TRF2. The
up-regulation of telomerase was mediated via insulin-like growth
factor 2 and endothelial nitric oxide synthase. Exercise was also
shown to decrease levels of markers of cellular growth arrest and
apoptosis, such as p16, cell cycle-checkpoint kinase 2 and p53.
Molecules that enhance low residual telomerase activity or
re-express silenced telomerase may help preserve telomere length.
Natural products such as derivatives from the Chinese Astragalus
plant,
Ginko biloba
and resveratrol have been shown to activate
telomerase, the latter two via PI3k/Akt signalling pathways. The anti-
oxidants N-acetylcysteine and
α
-tocopherol enhance telomerase
activity.
116,117
Farzaneh-Far
et al
. demonstrated in a prospective
study of patients with stable CAD, an inverse relationship between
baseline blood levels of marine omega-3 fatty acids and the rate of
telomere shortening over five years.
118
Aspirin, ACE inhibitors and particularly statin therapy have
been shown to positively impact on the vascular endothelium via
anti-senescence effects. Over and above its anti-thrombotic and
anti-inflammatory effects, aspirin has been shown to decrease the
formation of dimethylarginine, an endogenous inhibitor of nitric oxide
synthase, thereby reducing oxidative stress and delaying endothelial
cell senescence.
119
ACE inhibitors, particularly those containing the
sulfhydryl group, havebeenshown todelayendothelial cell senescence
by activating Akt phosphorylation, increasing the expression of nitric
oxide synthase and up-regulating telomerase.
120
Several studies have suggested that the survival benefit attributed
to statin therapy may be linked to its effects on telomere biology.
Spyridopoulos
et al
. have shown that statins enhance the migratory
capacity of endothelial progenitor cells by up-regulation of TRF2,
the telomere-binding protein that stabilises telomere structure at
the t-loop.
121
Satoh and co-workers demonstrated that intensive
statin therapy over 12 months, through its anti-oxidant effects,
prevents endothelial progenitor cell telomere erosion in patients
with CAD.
122
A recent publication by Saliques
et al
. who studied
patients presenting with acute myocardial infarction, showed that
prior statin therapy was independently associated with significantly
longer telomere length in subjects below the age of 64 years.
123
Conclusion
Our interest in telomere biology stems from the high incidence
of both premature CAD and type 2 diabetes mellitus witnessed
in the population that we serve. Patients with CAD who have
diabetes have worse outcomes than those without diabetes. This,
coupled with the fact that the initial presentation in a substantial
majority of our young patients is with myocardial infarction, which
carries a worse prognosis than stable CAD, further contributes to
adverse long-term outcomes. Indications are that revascularisation
procedures are not as efficacious in this population.
The availability of quantitative polymerase chain reaction, which
is a simpler, less labour-intensive and cheaper method requiring
smaller quantities of DNA compared to the standard method of
southern blot analysis, has made it feasible for us to determine
telomere length in our patients.
124,125
The study of telomere dynamics may serve several functions.
Firstly, measuring telomere length in the early years of life may
indicate a genetic predisposition and help target susceptible
individuals. Studies on the genetic contribution to premature
CAD with genome-wide association scans have yielded little thus
far, whereas an assessment of telomere length provides a more
universal insight into the genetics of CAD.
Secondly, telomere length is ameasure of cumulative DNA damage
from multiple environmental risk factors over an individual’s lifespan