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SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 12 NUMBER 2 • NOVEMBER 2015
53
Telomeres and atherosclerosis
SAJIDAH KHAN, ANIL A CHUTURGOON, DATSHANA P NAIDOO
Correspondence to: Sajidah Khan
Department of Cardiology, Nelson R Mandela School of Medicine, University
of KwaZulu-Natal, Durban, South Africa
e-mail:
sajidahkha@ialch.co.zaDatshana P Naidoo
Department of Cardiology, Nelson R Mandela School of Medicine, University
of KwaZulu-Natal, Durban, South Africa
Anil A Chuturgoon
Discipline of Medical Biochemistry, Nelson R Mandela School of Medicine,
University of KwaZulu-Natal, Durban, South Africa
Previously published in:
Cardiovasc J Afr
2012;
23
: 563–571
S Afr J Diabetes Vasc Dis
2015;
12
: 53–61
Abstract
In humans and other multicellular organisms that have
an extended lifespan, the leading causes of death
are atherosclerotic cardiovascular disease and cancer.
Experimental and clinical evidence indicates that these
age-related disorders are linked through dysregulation of
telomere homeostasis. Telomeres are DNA protein structures
located at the terminal end of chromosomes and shorten
with each cycle of cell replication, thereby reflecting the
biological age of an organism. Critically shortened telomeres
provoke cellular senescence and apoptosis, impairing
the function and viability of a cell. The endothelial cells
within atherosclerotic plaques have been shown to display
features of cellular senescence. Studies have consistently
demonstrated an association between shortened telomere
length and coronary artery disease (CAD).
Several of the CAD risk factors and particularly type 2
diabetes are linked to telomere shortening and cellular
senescence. Our interest in telomere biology was prompted
by the high incidence of premature CAD and diabetes in
a subset of our population, and the hypothesis that these
conditions are premature-ageing syndromes. The assessment
of telomere length may serve as a better predictor of
cardiovascular risk and mortality than currently available risk
markers, and anti-senescence therapy targeting the telomere
complex is emerging as a new strategy in the treatment of
atherosclerosis. We review the evidence linking telomere
biology to atherosclerosis and discuss methods to preserve
telomere length.
Keywords:
coronary artery disease, molecular and cellular
cardiology
Atherosclerosis is an age-related disorder.
1
Premature biological
ageing, an entity separate from chronological ageing, may
contribute to its pathogenesis. Cellular senescence, which is defined
as the finite replicative lifespan of cells leading to irreversible growth
arrest, plays a critical role in the pathogenesis of atherosclerosis.
2-4
A central feature of atherosclerosis is vascular endothelial cell
dysfunction.
The histology of atherosclerotic plaques has been
comprehensively studied and has demonstrated that endothelial
and vascular smooth muscle cells in atherosclerotic lesions display
changes of senescence.
5,6
In stable atherosclerotic plaques there are
few senescent cells, whereas in advanced, complicated plaques,
senescent cells accumulate because of high cell turnover and
increase the risk of acute coronary syndromes.
7
The biological mechanism that triggers the onset of cellular
senescence is thought to be telomere shortening. Telomeres
are DNA protein structures located at the extreme ends of the
chromosomes.They cap and protect the ends of chromosomes.
Whereas the DNA molecule carries the genetic code and is about
100 million base pairs long, the telomeric ends are non-coding and
are between 5 000 and 15 000 base pairs long: 15 000 at the time
of human conception and around 5 000 at the time of death.
8
During DNA replication, the very end sequences of the telomere
are not fully copied due to the inability of DNA polymerase to
completely replicate the chromosome to its very end. This is termed
the end-replication problem. As a result, between 50 and 200
nucleotides are lost with each cycle of cell replication, leading to
progressive telomere shortening.
9
When telomere length reaches a
critical threshold, the cell becomes incapable of further replication
and enters a phase of cellular growth arrest termed replicative
senescence. On average, cells reach senescence after 50 divisions.
The senescent phase may then progress to cell death or apoptosis.
Cellular senescence and the apoptotic cascade are mediated
by cell cycle checkpoint pathways, regulated mainly by p53/p21,
which are best recognised as tumour suppressor proteins.
2
This
process is responsible for physiological ageing and gives rise to the
morphological and functional changes that accompany the decline
in organ function seen with age, e.g. endothelial cell senescence
in atherosclerotic plaques or beta-cell senescence in diabetes
mellitus.
4,10,11
However, a limited number of cells (about one in 10 million)
are able to reactivate the enzyme telomerase. In the presence of
telomerase, cells are able to replicate and in this way telomere
integrity is maintained. Telomerase activity is lacking in somatic cells
but is preserved in reproductive and stem cells. High telomerase
activity has also been detected in about 90% of human cancer
samples. The high telomerase activity is thought to be responsible
for the indefinite cell proliferation and cellular immortalisation seen
with cancer.
12-15
Inducing cell senescence and apoptosis is therefore
an important mechanism for the suppression of cancer.
Studies have shown that telomere length is not only determined
by cell replication and lifespan, but is also influenced by heredity
and exposure to environmental risk factors. The healthy offspring
of parents with coronary artery disease have shorter telomeres
than the offspring of normal subjects.
16,17
The traditional risk factors
for atherosclerosis have been shown to lower the threshold for
cardiovascular disease by hastening biological aging.
18
Risk factors
such as smoking,
19,20
obesity,
19
insulin resistance,
21,22
and type 2
diabetes
23-26
are associated with accelerated telomere shortening.