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REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
56
VOLUME 12 NUMBER 2 • NOVEMBER 2015
may activate Ras signalling, which has also been shown to
participate in the divergent processes of both cell proliferation
and senescence.
66
Oxidative stress and telomere shortening
Exposure of DNA to oxidative stress produces higher levels of stress
biomarkers in telomere sequences than in non-telomere sequences.
8-oxodG (8-oxo-7,8-dihydro-2-deoxyguanosine) is a sensitive
biomarker for oxidative stress on DNA. Progressive increases in
8-oxodG have been shown to correlate with decreasing telomere
length. The high guanine (-GGG) content of telomeres makes them
particularly sensitive to damage by oxidative stress.
47,67
This site specificity for guanine is due to several reasons. Firstly,
guanine is the most easily oxidised DNA base as its oxidation
potential is lower than that of the other three bases (adenine <
cytosine < thymine). A second factor is the distribution of electrons
on the DNA base. The highest occupied molecular orbital that
accommodates electrons with the greatest energy determines the
reactivity of DNA bases. Many of these electrons are located on the
5
′
-G of the GG sequence and therefore this guanine is more likely
to be oxidised.
A third reason is that the ROS have different redox potentials,
which may determine site specificity. For example, the free hydroxyl
radicals cause DNA damage without a marked site specificity,
whereas the benzoyloxyl radicals specifically cause damage to the
5
′
-G in GG sequence.
68-70
In addition to the direct effects of ROS,
telomeres, unlike the rest of the genome, appear less efficient
in repairing oxidative damage.
71
An important consequence of
oxidative stress is the initiation of an inflammatory response.
Inflammation and telomere shortening
Chronic systemic inflammation is responsible for an increase in
peripheral white blood cell turnover, which in turn leads to an
exaggerated telomere attrition rate.
55
The increased white cell
consumption induces haematopoietic stem cells to divide, thereby
shortening their telomere length as well. Exposure to TNF-
α
also
reduces telomere length by negative regulation of telomerase
activity.
57
DNA sampling for telomere length quantification is generally
sourced from circulating white blood cells rather than human
vascular tissue. It has been suggested that white blood cell telomere
attrition is a consequence of systemic inflammation rather than
being indicative of vascular endothelial cell ageing. The study by
Wilson
et al
. demonstrated that telomere attrition in circulating
blood leucocytes reflects similar changes in the vasculature and is an
acceptable surrogate for vascular ageing in population studies.
72
Mechanisms of repair: stem cells and endothelial
progenitor cells
The atherosclerotic process is characterised by endothelial cell
dysfunction. Repair of the endothelium is dependent on the
presence of endothelial progenitor cells, which migrate to sites
of vascular injury to initiate repair. Endothelial progenitor cells are
produced by haematopoietic stem cells, which, due to their higher
telomerase activity, have a greater proliferative capacity. Exhaustion
of the progenitor cell or stem cell pool is an important factor in
endothelial cell dysfunction. Telomere length in haematopoietic
stem cells (HSC) is a reflection of progenitor cell reserves, and
shortened telomere length in these cells is indicative of diminished
reparative capacity.
41,42
The onset of atherosclerotic disease is therefore dependent on
the balance between injury and repair of the endothelium – injury
from oxidative stress and inflammation, and repair, which depends
on haematopoietic stem cell reserves, as reflected by HSC telomere
length.
41
Telomeres and atherosclerosis risk factors
Smoking
Cigarette smoking is associated with increased oxidative
stress.
73
Although there is variability in the findings of different
epidemiological studies, the following studies recorded an
association between smoking and telomere shortening. Nawrot
et al
., reporting on the Flemish study on environment, genes and
health outcomes, found shorter telomeres in smokers compared
to non-smokers.
45
The study by Valdes
et al
. showed that women
who had never smoked had longer telomeres than former smokers,
and both had longer telomeres than current smokers (531 never
smokers, 369 ex-smokers and 203 current smokers).
They also demonstrated a dose-dependent relationship between
smoking and telomere shortening. Each pack-year smoked was
equivalent to the lossof anadditional fivebasepairsof telomere length,
or 18% of the average annual loss in telomere length, compared
to the rate in the overall cohort.
19
The dose-effect relationship was
subsequently replicated by Morla
et al
. who studied a cohort of male
smokers with and without chronic obstructive pulmonary disease (50
smokers, 26 never smokers) in whom telomere shortening correlated
with cumulative exposure to tobacco smoking.
20
Hypertension
Since systolic blood pressure rises with age, and diastolic blood
pressure plateaus, Jeanclos
et al
. postulated that arterial pulse
pressure may correlate with biological age. Among 49 twin pairs
(mean age 37 years) in the Danish Twin Register, they showed a
significant inverse correlation between pulse pressure and telomere
length, i.e. wider pulse pressure was associated with shorter
telomere length.
74
The Framingham Heart Study found shorter telomere lengths in
hypertensive males (
n
= 171) compared to their normotensive peers
(
n
= 156) but the shorter telomere length was largely due to insulin
resistance.
21
Benetos
et al
. examined the relationship between
telomere length and carotid artery atherosclerosis in 163 treated
hypertensive males and found that telomere length was shorter in
hypertensive men with carotid plaques compared to hypertensive
men without plaques.
75
Obesity
Increased caloric intake and obesity are recognised to shorten
lifespan. Adipose tissue is not only a source of ROS and pro
inflammatory cytokines but also secretes a host of bioactive
molecules including angiotensinogen, leptin, resistin, adiponectin
and PAI-1, which influence the function and structural integrity
of the cardiovascular system.
76,77
These adipocytokines influence
glucose metabolism, blood pressure regulation, lipid metabolism,
the coagulation system and endothelial function to accelerate the
process of atherosclerosis.
Obesity is strongly associated with cardiovascular disease and
promotes the clustering of risk factors such as dyslipidaemia,
hypertension, diabetes and the metabolic syndrome. Obese
individuals experience substantially elevated morbidity and mortality
from all forms of cardiovascular disease.
78,79