15 / 48
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 12 NUMBER 2 • NOVEMBER 2015
57
A retrospective analysis of the Bogalusa Heart Study examined
the relationship between weight change and telomere dynamics
over a period of 10 to 12 years in 70 young adults. The study
showed that weight gain was associated with accelerated telomere
attrition and that a rise in insulin resistance accounted for the
relationship between the increase in body mass index (BMI) and
telomere attrition rate.
22
In the study by Valdes
et al
. of 1 122 healthy adult female twins
(45 monozygotic and 516 dizygotic pairs, mean age 47 years), it
was found that the telomeres of obese twins were 240 base pairs
shorter than those of the lean sibling. The difference in telomere
length between the lean and the obese corresponded to 8.8 years
of ageing.
19
The study also suggested that the mechanism by which
obesity affects telomere length is through increased leptin levels
rather than BMI
per se
.
Obesity is associated with high serum concentrations of leptin,
which is linked to NF-
κ
B activation, a mediating factor in the
production of ROS and inflammatory cytokines.
80
Nordfjall
et al
.
confirmed the negative association between BMI and telomere
length but in their study, this finding applied only to female
participants.
81
Insulin resistance
Insulin resistance is pro-atherogenic and increases the risk of CAD
even without the presence of hyperglycaemia.
82
The mechanisms
involved in atherogenesis include both systemic effects such as
dyslipidaemia, hypertension and a pro-inflammatory state as well
as direct effects on vascular endothelial cells, smooth muscle cells
and macrophages. These three cell types have insulin receptors
and effects are mediated via down-regulation of insulin signalling
pathways such as the Akt pathway.
In early atherosclerosis, insulin resistance causes decreased nitric
oxide production and an increase in VCAM-1, which are responsible
for impaired vasodilation and inflammation. In advanced plaques,
insulin resistance triggers apoptosis of cells via the Akt pathway.
83-86
Apoptosis of smooth muscle cells causes fibrous cap thinning,
whereas apoptosis of macrophages leads to plaque necrosis,
both being pathological processes that precipitate acute coronary
syndromes.
Diabetes
In the setting of type 2 diabetes, insulin resistance and
hyperglycaemia have additive effects that accelerate the process
of atherosclerosis. Hyperglycaemia is associated with the activation
of several molecular pathways that include the production of
advanced glycation end products (AGEs),
87,88
activation of protein
kinase C, increased activity of both the polyol as well as the
hexosamine pathways.
89,90
These pathways are interdependent and
induce cellular damage through the final common mechanism of
increased oxidative stress.
It is well established that hyperglycaemia, even in the pre-
diabetic state, induces oxidative stress
91-94
and ultimately leads to
cellular senescence. Cellular senescence and apoptosis occur not
only in vascular endothelial and smooth muscle cells but in multiple
cell lines, including endothelial progenitor cells.
95,96
Type 2 diabetes
can therefore be considered a premature-ageing syndrome.
In recent years several cross-sectional clinical studies have been
published that demonstrate anassociationbetween shorter telomere
length and type 2 diabetes (T2D).
23-26,97-99
The studies suggest that
there is a gradation in the severity of telomere shortening. Shorter
telomere lengths were noted in patients with impaired glucose
tolerance compared to controls, even shorter lengths in those
with diabetes, and the shortest lengths were observed in patients
with the combination of pre-diabetes/diabetes and atherosclerotic
vascular disease, compared to those with diabetes or cardiovascular
disease alone.
100
Satoh
et al
. showed that CAD patients with the metabolic
syndrome had shorter telomeres than CAD patients without the
metabolic syndrome.
97
Adaikalakoteswari
et al
. found that among
diabetic patients, those with atherosclerotic plaques had shorter
telomeres.
98
The study by Olivieri
et al
. demonstrated that diabetic
patients with myocardial infarction had shorter telomeres than
diabetic subjects without myocardial infarction,
99
and the study by
Salpea
et al
. showed that among diabetic subjects, those with CAD
had significantly shorter telomeres.
26
Based on these observations, it has been postulated that critically
shortened telomeres, due to a combination of inherited short
telomeres and oxidative stress-induced telomere attrition, caused
by the common risk factors between diabetes and cardiovascular
disease, indicates greater cellular ageing in vascular endothelial
cells and pancreatic beta-cells, and may be a useful biomarker of
tissue ageing and disease progression.
100
Atherosclerosis and coronary artery disease
Minamino
et al
. have shown that endothelial cells with characteristic
features of senescence are present in atherosclerotic regions
of human coronary arteries. They demonstrated that inhibiting
telomere function induced senescence in endothelial cells, whereas
introducing telomerase suppressed senescence and extended the
lifespan of these cells.
3
Ogami
et al
. have shown that the telomeres of coronary
endothelial cells were shorter in patients with CAD compared to
age-matched subjects without CAD and that in the CAD patients,
telomere length was shorter in endothelial cells at atherosclerotic
sites compared to non-atherosclerotic sites.
101
Chang and Harley
have shown that endothelial cells in regions of the vascular tree
that are subjected to greater haemodynamic stress demonstrated
more pronounced telomere attrition than endothelial cells from
areas with less shear stress. For example, telomere attrition rate
in the iliac arteries was –147 base pairs per year compared to the
internal mammary arteries at –87 base pairs per year.
102
Okuda
et al
. also demonstrated that telomere attrition was
higher in the intima of the distal abdominal aorta compared to
the proximal abdominal aorta, again indicating that areas of the
vasculature that undergo greater shear wall stress have higher
cellular turnover rates and consequently shorter telomere length.103
This variable telomere attrition rate indicates the significant impact
of environmental stress on telomere length.
Population studies have demonstrated a link between telomere
length and CAD.
104,105
In the pioneering study by Samani
et al
. of 10
cases and 20 control subjects, it was observed that mean telomere
length was significantly shorter in patients with severe triple-vessel
CAD compared with matched subjects who had normal coronary
angiograms.
106
A retrospective registry analysis of 383 patients (203 cases, 180
controls) showed that patients with premature myocardial infarction
had significantly shorter mean telomere lengths. In this study the
difference in telomere length between cases and chronologically
age-matched controls demonstrated a biological age gap in excess
of 11 years. Compared with subjects in the highest quartile for