CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
AFRICA
563
Telomeres and atherosclerosis
SAJIDAH KHAN, ANIL A CHUTURGOON, DATSHANA P NAIDOO
Abstract
In humans and other multicellular organisms that have an
extended lifespan, the leading causes of death are atheroscle-
rotic 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 repli-
cation, 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 assess-
ment 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 telo-
mere 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
Submitted 11/4/12, accepted 4/7/12
Cardiovasc J Afr
2012;
23
: 563–571
DOI: 10.5830/CVJA-2012-056
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.
Department of Cardiology, Nelson R Mandela School of
Medicine, University of KwaZulu-Natal, Durban, South Africa
SAJIDAH KHAN, MB ChB, FCP (SA),
;
DATSHANA P NAIDOO, MD
Discipline of Medical Biochemistry, Nelson R Mandela
School of Medicine, University of KwaZulu-Natal, Durban,
South Africa
ANIL A CHUTURGOON, PhD
