Kardiovaskuläre Medizin 2004;7:433–442

Cardiovascular Biology Prize SSC

David J. Kurz Telomere biology

Kardiovaskuläre Forschung,
Physiologisches Institut der Universität Zürich in cardiovascular disease
und Kardiologie,
Stadtspital Triemli,
Zürich

Summary Progression der atherosklerotischen Plaque

beitragen könnten, so zum Beispiel der Verlust
Advanced age brings about significant der regenerativen Kapazität oder die Expres-
changes to cardiovascular physiology, and is sion von pro-atherogenen Proteinen. In dieser
an independent risk factor for the development Übersichtsarbeit wird die Struktur und Funk-
of atherosclerosis. The basis for this associa- tionsweise des Telomers erläutert. Zudem
tion remains unclear, but it has been suggested wird die Evidenz zusammengefasst, welche
that atherogenesis may share common mech- für eine Beteiligung der seneszenz-assoziier-
anisms with the ageing process. Ageing at the ten Pathophysiologie vaskulärer Zellen in der
cellular level leads to a condition known as Entstehung von altersabhängigen kardiovas-
replicative senescence, which is triggered by kulären Erkrankungen sprechen. Dabei wur-
the shortening of chromosomal telomeres dur- den sowohl publizierte Arbeiten mit zell- und
ing repeated cell division. Senescent endothe- tierexperimentellen Modellen, als auch klini-
lial cells show a number of features, which sche Assoziationsstudien berücksichtigt.
could contribute to the initiation or progres-
sion of the atherosclerotic plaque, such as loss
of regenerative capacity and increased expres- Ageing and atherosclerosis
sion of pro-atherogenic proteins. This review
will outline the current understanding of In humans, the ageing process brings about a
telomere function and summarise the evidence wide array of changes to cardiovascular phys-
supporting a role for senescence-driven patho- iology, and even in the absence of established
physiology of vascular cells in age-related car- risk factors ageing is associated with major
diovascular disease. This will include pub- cardiovascular morbidity and mortality [1].
lished work from vascular cell culture, animal Advanced age is associated with hypertension
experiments and observational studies in hu- [1], endothelial cell dysfunction [2, 3], impair-
mans. ment of angiogenesis [4] and a decrease in an-
tithrombotic activity [5]. Furthermore, ageing
itself is one of the strongest independent risk
Zusammenfassung factors for the development of atherosclerosis
[1, 2]. The basis for this association remains
Mit zunehmendem Alter stellen sich beträcht- unclear, but it has been proposed that athero-
liche Veränderungen der kardiovaskulären sclerosis may share common biological mech-
Physiologie ein. Zudem ist das Alter ein wich- anisms with the ageing process [6]. This re-
tiger unabhängiger Risikofaktor für die Ent- view will summarise the evidence supporting
wicklung atherosklerotischer Erkrankungen. a role for telomere-driven replicative senes-
Die Ursachen dieser Zusammenhänge sind cence, one of the intrinsic cellular mechanisms
unbekannt, es wird aber vermutet, dass ge- implicated in the ageing process, in the devel-
meinsame Mechanismen der Atherogenese opment of age-related cardiovascular disease.
und dem Alterungsprozess zugrunde liegen
könnten. Auf zellulärer Ebene führt die Alte-
rung zur sogenannten replikativen Seneszenz, Correspondence:
ein physiologischer Zustand, welcher durch David J. Kurz, MD
Cardiology
die Verkürzung der Telomere (die Enden der
Triemli Hospital
Chromosomen) im Verlaufe wiederholter Zell-
Birmensdorferstrasse 497
teilungen herbeigeführt wird. Seneszente CH-8063 Zurich
Endothelzellen weisen charakteristische Ver- Switzerland
änderungen auf, welche zur Entstehung oder E-Mail: david.kurz@triemli.stzh.ch

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Cardiovascular Biology Prize SSC

Telomeres: the mitotic clock of cellular replicative capacity. Would chromo-

somes end with a “free” open tail, they would
Replicative senescence is a permanent non- falsely be identified by the cellular DNA dam-
dividing state, which ensues in most somatic age control machinery as a DNA break, which
cells following a pre-determined number of cell would result in the cell being blocked from en-
divisions [7]. Under ideal cell culture condi- tering the cell cycle. Apart from this chromo-
tions, human somatic cells proliferate for up to some capping function, telomeres play an im-
40–60 population doublings (ie 40–60 mitoses portant role in the maintenance of chromo-
per cell) before entering senescence [8]. Senes- some stability during DNA replication, as well
cent cells are blocked in the G1 phase of the as chromosomal positioning and segregation
cell cycle and thus cannot replicate, but re- during mitosis [12].
main viable and are metabolically active. How- The progressive shortening of telomeres
ever, senescent cells differ from their younger with each cell division occurs at a rate of about
ancestor cells in regard to morphological, gene 25–200 base pairs (bp) per mitosis. This is a
expression and functional characteristics. direct result of the so-called “end-replication
Replicative senescence is brought about by a problem”, which describes the inability of con-
progressive shortening of telomeres through- ventional DNA polymerases to replicate the
out a cell’s replicative life span [9]. Telomeres 3’ termini of the template strands, resulting in
build the physical ends (caps) of chromosomes. incomplete copying [13]. Thus, the presence of
They consist of non-coding, serial repeats of telomeres prevents the erosion of coding DNA
the nucleotide sequence TTAGGG, which in sequences at the ends of the chromosomes dur-
humans vary in length between 5000 and ing DNA replication. Telomere erosion with
15 000 base pairs, and end in a 3’ single- each cell division is cumulative, and a large
stranded DNA overhang. This DNA segment is body of evidence now suggests that once a crit-
complexed with a number of specialized telo- ical degree of telomere shortening is reached,
mere-associated proteins. Current evidence the telomere is unable to maintain its 3-dimen-
suggests that these proteins enable the telo- sional structure, which in turn is recognised by
meric DNA double helix to fold back upon it- the cell-cycle machinery as a signal to block
self to form a special loop structure (fig. 1) [10]. further replication (fig. 2). Thus, telomere
According to this model, the 3-dimensional in- length appears to act as a mitotic counting
tegrity of this so-called “T-loop”, in which the device, or “replicometer”, which counts cell
3’ single-strand overhang is thought to dis- divisions and limits replicative capacity by
place the complementary DNA-strand of the triggering entry into senescence [9].
double helix (“D-loop”) [11] and is thus “tucked
away”, is a prerequisite for the maintenance
Vascular cell senescence in vas-
Figure 1 cular ageing and atherosclerosis
Model of the 3-dimensional
superstructure of the hu- In vivo, the vascular endothelium is known to
man telomere. At the end undergo a low cellular turnover [14]. However,
of the chromosome, telo- during episodes of angiogenesis or following
meric DNA folds back upon
vascular injury, cells in the vessel wall may be
itself to form the t-loop
(telomere or terminal loop). required to carry out a considerable number of
The t-loop is thought to be cell divisions. It is also known that endothelial
stabilised by the 3’ single- cell replication rates are increased at “athero-
strand end of the telomere sclerosis-prone areas” such as vascular
(“overhang”) displacing the
branching points [15], most likely represent-
complementary DNA-strand
of the double helix (d-loop ing a response of the endothelium to the
= displacement loop), it chronic stress of shear and stretch at these
thus being “tucked away” sites [16]. This suggests that, in vivo, as
and hidden from recogni- chronological age advances, areas with high
tion by the DNA damage
machinery. A number of
endothelial cell turnover could be increasingly
telomere-associated pro- covered by clusters of senescent cells. Interest-
teins play essential roles in ingly, endothelial cells undergoing senescence
maintaining the integrity of in culture demonstrate a number of character-
this 3-dimensional structure
istic changes, which are typically also found in
and also contribute to
telomere length regulation. atherosclerotic lesions in vivo. These include
Figure adapted from [80]. both changes in morphology (an increase in

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Cardiovascular Biology Prize SSC

Figure 2 the discovery of a more reliable biomarker of

Telomere mechanism of cel- young
endothelial
senescent cells, the so-called “senescence-asso-
lular senescence. Senes-
cence ensues in normal so- cell ciated b-galactosidase activity” (SA-b-gal) [24],
matic cells following a pre- which has subsequently been used widely in
determined number of cell the scientific community. This cytochemical
Ch
divisions. Due to the inabil- ro
mo Telomeric DNA assay takes advantage of the propensity of
ity of conventional DNA so
ma
lD Sufficiently long telomere: senescent cells to vastly increase their number
polymerases to completely NA proliferation
D-loop of lysosomes, and thus also their content and
replicate the 3’ termini of
Telomere
the template strands, telo- T-loop
3í o related proteins
activity of the endogenous lysosomal enzyme
verh
meric DNA shortens with ang
b-galactosidase [25]. The assay distinguishes
each round of cell division. senescent from non-senescent cells by staining
Once a critical degree of
telomere shortening is
With each cell division: at a suboptimal pH of 6 (instead of pH = 4), at
telomere shortening
reached, the 3-dimensional Ch
rom
= mitotic clock which only the senescent cells have sufficient
integrity of the telomere is os
om
al
b-gal activity to convert the colourless enzyme
DN
lost, which is recognised by A substrate to the visible blue cleavage product
Loss of telomere integrity:
the cell-cycle machinery as a Telomeric DNA telomere uncapping [25] (fig. 3A–D). The SA-b-gal assay has been
signal to permanently block
further replication.
shown to be an excellent biomarker of vascu-
ATM lar cells in vitro [26], and was subsequently
p53 Activation of cell cycle
p21 check points used to demonstrate the emergence of senes-
pRB
(? p16)
cent vascular cells following vascular injury in
vivo [27]. In these experiments, rabbit carotid
senescent arteries were injured once or twice by balloon
Irreversable cell cycle exit::
endothelial senescence angioplasty at three-week intervals, and then
cell
histologically examined after SA-b-gal stain-
ing. In contrast to the uninjured contralateral
vessels, in which no senescent cells were
Figure 3 young senescent found, the neo-intima of the treated vessels
Biomarkers of senescence in contained isolated senescent cells after a sin-
human endothelial cells. gle angioplasty, and larger numbers of senes-
A, B. Bright field photomi- cent cells after repeated injury (fig. 4). These
SA-b-gal

crograph showing young

included both vascular smooth muscle cells
and senescent cultured hu-
man umbilical vein endothe-
and endothelial cells. In human pathology
lial cells (HUVEC) stained for specimens, SA-b-gal positive endothelial cells
senescence-associated b- have been demonstrated to overlay the ath-
galactosidase (SA-b-gal) ac- erosclerotic plaques in the aorta [28] and the
tivity (135҂ magnification).
coronary arteries [29], in contrast to the inter-
Note the lack of blue gran-
Acridine

nal mammary arteries [29]. Taken together,

orange

ula in the young cells, while

the senescent cells display these data implicate cellular senescence in the
in part intense blue stain- initiation and/or progression of atherosclero-
ing. Note also the increased sis, and support the concept that the number
cell size and polyploidy of
senescent cells.
of vascular cell replications that have taken
C, D. Same cultures as in place in the vessel wall increases not only as a
FISH telomeric

A and B, but stained with function of chronological age, but also as a

acridine orange identifying function of the haemodynamic or biochemical
probe

lysosomes in orange (Fluo-

stress to the vascular bed. This would link vas-
rescence micrograph 225҂
magnification). Note the
cular cell senescence to the “response to injury”
impressive increase in lyso- hypothesis of atherosclerosis [30].
somal content in the senes-
cent cultures.
E, F. Metaphase spreads
cell size, the presence of multiple nuclei, in- A role for telomere length in
of young and senescent
creased vacuolisation) [17, 18] and gene ex-
HUVEC. Fluorescence in situ age-related vascular pathologies
hybridisation with a telo- pression. Thus, both the atherosclerotic
meric probe (1000҂ magni- plaque and senescent endothelial cells over- Replicative senescence in its original form is
fication). Note the increased express interleukin-1a [19, 20], plasminogen triggered by the critical shortening of telo-
telomere signal (red) at the
ends of each chromosome
activator inhibitor-1 [5, 21], and the surface meres (fig. 2 and 3E, F). Therefore, comparing
arm in the young cell com- molecule ICAM-1 [22, 23]. More compelling telomere length in tissue specimens should
pared to the senescent cell. evidence suggesting a role for senescence in shed light on the replicative history of the cells
vascular pathology has become available with contained therein, making telomere length a

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Cardiovascular Biology Prize SSC

Figure 4
Identification of senescent
cells in vivo following
carotid artery injury. Pho-
tomicrographs showing SA-
b-gal staining in representa-
tive carotid artery cross-sec-
tions from rabbits having
undergone sham (A, D),
single (B, E) and double
(C, F) denudations. D, E and
F show high-power micro-
graphs of areas close to the
vessel lumen within A, B
and C, respectively. The ar-
row in panel E indicates a
single positively stained cell
in the neointima of a single
denudation vessel. Scale
bars = 160 mm (A, B, C) and
20 mm (D, E, F). Reproduced
with permission of the pub-
lisher. legitimate marker of senescence. In one of the as “human telomerase reverse transcriptase”
first papers looking into a possible role for en- (hTERT) and an RNA template (human telo-
dothelial senescence in the aetiology of athero- merase RNA, hTR). This enzyme enables cells
sclerosis, Chang and Harley found that the undergoing sustained proliferation to escape
telomere length of intimal cells collected from senescence by maintaining telomere length
post-mortems was significantly shorter in the and chromosomal integrity despite repeated
iliac arteries than in the iliac veins [31]. Fur- cell divisions. However, in most human so-
thermore, the telomere length in the intima of matic cells telomerase activity is down-regu-
the iliac artery was shorter than in the inter- lated to a very low level. In post-natal life, sub-
nal thoracic artery of the same donor, and this stantial telomerase activity can be detected in
difference increased with advancing age of the germ line cells, which obviously must main-
donor. In contrast, cells from the media of these tain their original telomere length and “youth-
arteries had similar telomere lengths [31]. fulness” through endless cell divisions [36],
This inverse relationship between chronologi- and in the stem cells of some normal somatic
cal age and telomere length in the endothelium tissues that undergo sustained proliferative
was subsequently confirmed in tissues sam- renewal, such as haematopoietic lineages and
pled from the human aorta [32, 33]. A recent the epidermis [37]. Telomerase has become
paper examined the relationship between well known among medical professionals due
telomere length and coronary artery disease to its infamous role in the development of can-
(CAD). The authors demonstrated that the cer: maintenance of telomere length through
telomeres in the coronary endothelium from vast numbers of cell divisions is one of the
autopsy specimens of patients with CAD were barriers that normal cells need to transcend
shorter than in age-matched specimens from in their path to malignant transformation. In
donors without CAD [34]. Taken together, about 85% of human malignancies, this is
these papers support the hypothesis that focal achieved by the loss of transcriptional control
replicative senescence and telomere shorten- over telomerase and its pathological up-re-
ing of the endothelium contribute to the age- gulation [38], while the remaining 15% use a
related development of atherosclerosis. recombinatorial strategy of telomere mainte-
nance known as “alternative lengthening of
telomeres” (ALT) [39].
Telomerase
The ribonucleoprotein telomerase is one the Telomerase activity in the
components of the telomere superstructure,
vasculature
and it plays a key role in the control of telo-
mere length and cellular replicative capacity. In the vasculature, telomerase activity can be
Telomerase is a specialized reverse transcrip- detected in cultured vascular smooth muscle
tase that adds the sequence TTAGGG to the cells [40] and endothelial cells [41–43], al-
3’ ends of nuclear DNA [35]. Its two main com- though the level of activity found in proliferat-
ponents are a catalytic protein subunit known ing endothelial cells is about 40-fold lower

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Cardiovascular Biology Prize SSC

than that of a typical human cancer cell line fects of telomerase-inhibiting drugs. Clinical
[43]. In human somatic cells, telomerase activ- trials to assess the value of such compounds as
ity is tightly regulated at multiple levels, pri- anticancer agents are currently being
marily by factors related to the proliferative planned, and potential strategies include long-
status of the cell. Thus, in growth-arrested en- term maintenance therapy of patients in clin-
dothelial cells in culture, as well as in the in- ical remission. In view of the newly discovered
tact endothelium in vivo, telomerase activity physiological role of telomerase in somatic
is down-regulated to a very low level [43]. Sim- cells, one might imagine a number of vascular
ilar findings have also been reported for vas- side effects resulting from such therapies, in-
cular smooth muscle cells [44]. A number of cluding atherothrombotic events after loss of
stimuli have been shown to induce or restore endothelial integrity or loss of atherosclerotic
this activity in endothelial cells, including ni- plaque stability and impaired formation of
tric oxide [42] and basic fibroblast growth fac- collaterals to ischaemic tissues [53, 54].
tor (bFGF), a potent angiogenic growth factor
[43]. Both transcriptional regulation of hTERT
[43], post-transcriptional phosphorylation by Do ageing mechanisms act
the protein kinase Akt [45], and active trans-
in synergy?
port of hTERT to and from the telomere [46,
47] have been implicated in the regulation of The progressive oxidative damage of macro-
its activity. Genetic manipulation of human molecules resulting from the continual expo-
endothelial and vascular smooth muscle cells sure of cellular components to oxidative stress
forcing them to overexpress hTERT enabled is a process that has long been implicated in
these cultures to escape senescence and dra- ageing and age-related pathologies [6]. It has
matically extend their life span [40, 48]. To- become known as the “free radical theory of
gether with the original reports of this gene ageing”. Interestingly, a large body of evidence
transfer experiment in human fibroblasts [49, now indicates that oxidative stress can also
50], these findings have been of critical impor- induce or accelerate the onset of replicative
tance in supporting the telomere hypothesis of senescence [55]. This phenomenon has been
cellular senescence. It is important to empha- collectively termed “stress-induced premature
size that endothelial cells telomerised in this senescence” [56]. Earlier studies, primarily in
fashion are not malignantly transformed and fibroblasts, demonstrated that culture con-
display a normal cell culture phenotype [48]. ditions with a high level of oxidative stress
Furthermore, telomerised endothelial cells rapidly induced growth arrest and a senescent
create capillaries in vivo at least as efficiently cellular phenotype, which was not associated
as their primary parental cells, indicating that with telomere loss [56]. However, other exper-
high levels of telomerase activity are able to iments using milder and more physiologically-
maintain a youthful microvascular phenotype ranged oxidative stress were found to induce
[51]. premature senescence which could be attrib-
On the other hand, increasing evidence uted to accelerated telomere erosion [57], most
now indicates that telomerase plays a more likely resulting from the generation of single
complex role in the control of the cell cycle, in- strand breaks in the telomeric DNA. More re-
volving functions beyond telomere mainte- cently, evidence has been accumulating that
nance. Inhibition of telomerase in vascular oxidative stress can also accelerate the loss of
cells rapidly impairs their proliferative capac- telomere integrity and the onset of senescence
ity in a manner which is independent of telo- in endothelial cells [58–60]. These effects have
mere shortening [43, 44]. Thus, endothelial been induced by a variety of oxidant stressors,
cell cultures stimulated to grow with vascular including homocysteine [58], pharmacological
endothelial growth factor (VEGF), which in inhibition of endogenous antioxidant defence
the absence of bFGF does not restore telo- [59], and genetic manipulation inducing the
merase activity, undergo senescence after only activation of mitochondrial NAD(P)H-oxidase
10 population doublings, about a quarter of the by rac1 [60]. An additional effect observed in
life span achieved by cultures growing under endothelial cells even during mild oxidative
bFGF stimulation [52]. These findings are in stress was a rapid down-regulation of telome-
agreement with work in other cell types [53], rase activity [59]. This was in agreement with
showing that telomerase activity is essential other work, showing that oxidant substances
to the upkeep of cellular proliferation in hu- with known pro-atherogenic properties such
man somatic cells. This concept has important as oxidized LDL or tumour necrosis factor a
implications with regard to potential toxic ef- also reduced telomerase activity in endothelial

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Cardiovascular Biology Prize SSC

cells [45]. Completing this picture of synergis- the same cell are very heterogeneous (inter-
tic inter-dependency of ageing mechanisms, chromosomal heterogeneity of telomere length).
the metabolism of senescent cells seems to pro- However, the pattern of chromosomal telomere
duce increased levels of reactive oxygen heterogeneity is consistent between cells of the
species [61]. In summary, these findings show same species [62]. At the next level, mean
that the ageing mechanisms of replicative telomere length varies between different cells
senescence and oxidative stress promote each of the same tissue, reflecting differences in the
other, suggesting that they might contribute replicative history (degree of clonal expansion)
both to the ageing process in general and the of each cell (inter-cellular heterogeneity of telo-
development of age-related cardiovascular mere length). Finally, mean telomere length
pathologies in a synergistic fashion (fig. 5). varies considerably between individuals of the
same age, both in neonates and in adults
(inter-individual heterogeneity of telomere
Is telomere length a hereditary length). Genetic studies performed in twins
have demonstrated that these inter-individual
determinant of age-related
differences in mean telomere length found in
cardiovascular disease? peripheral white blood cells (WBC) are to a
Telomere lengths in humans of the same age large extent genetically determined, with 78%
vary widely, with this variability being found of inter-individual heterogeneity being due to
at a number of levels. First, individual telo- hereditability [63]. Recent evidence suggests
mere lengths of different chromosomes within that the inheritance of telomere-length is X-
linked, and therefore not conferred from fa-
thers to their sons [64]. Apart from age, addi-
Figure 5
Synergistic contributions young endothelial cell tional factors which have been shown to be
of ageing mechanisms to associated with shorter WBC telomere length
endothelial cell senescence. include male sex, smoking and high pulse
Endothelial cell renewal in pressure [64, 65].
response to chronic oxida-
tive (and other) injury as
It is known from human cells that both the
well as oxidative stress in replicative capacity (ex vivo) and the telomere
itself both contribute to length of these cells declines with increasing
Cell Reactive
telomere shortening and age of the donor [66]. Does this mean that in-
loss of telomere integrity. proliferation oxygen species
dividuals with shorter telomeres have a re-
Oxidative stress can further Replication
induce a senescent pheno-
Replication duced capacity to regenerate their tissues in
dependent independent
type independently of response to life long wear and tear? Observa-
telomere damage, probably tional studies seem to support this concept. In
by activating DNA damage loss of telomere patients with severe coronary disease, WBC
cell cycle checkpoints integrity telomere length was shown to be shorter than
(stress-induced premature
senescence). Downstream age-matched controls [67]. The same re-
effector pathways are most searchers also found a significant association
likely independent of the ATM and other between shorter WBC telomere length and the
initial stimulus. Finally, risk of premature (<50 years of age) myocar-
senescent cells have in- effector signals
creased production of
dial infarction [68]. Similarly, carotid athero-
reactive oxygen species
? sclerosis has been associated with shorter
(red arrow). telomeres, when hypertensive patients with
p16INK4A p53 and without carotid artery plaques were com-
pared [69]. Looking beyond atherosclerosis, we
have recently demonstrated that patients with
p21 degenerative calcific aortic valve stenosis, an
archetypal age-related disorder, have shorter
WBC telomeres than controls matched for age,
sex, and the presence or absence of coronary
disease [70]. Shorter telomeres have also been
associated with vascular dementia [71]. Until
now, only one study has been able to examine
the prognostic relevance of telomere length in
a longitudinal fashion. In this study of 143
healthy individuals >60 years of age, shorter
senescent endothelial cell telomeres in WBC were associated with a 3.2

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fold higher mortality rate from cardiovascular drome are normal at birth, but get shorter
disease [72]. much quicker than usual. Progeria Hutchin-
The results of studies investigating the as- son-Gilford is an extremely rare disease, in
sociation of telomere length in peripheral which children of kindergarten age have a wiz-
WBCs with cardiovascular disease states and/ ened old appearance and usually die of coro-
or its’ risk factors are summarised in Table 1. nary disease by the age of 10. The defect in-
Although these data appear to delineate a con- volves the gene Lamin A (lmna), although it
sistent line of evidence, it needs to be empha- remains unclear how this results in the pheno-
sized that these studies show only an associa- type. These children are born with telomeres
tion, without actually demonstrating that which are only about half as long as age-
telomere shortening is a primary abnormality matched controls [75].
rendering organisms more susceptible to ath- In contrast, two other well characterised
erosclerosic risk factors. It has been argued inherited disorders associated with short
that the shorter WBC telomere length found in telomeres and features of premature ageing,
atherosclerotic vascular disease might instead dyskeratosis congenita and ataxia teleangi-
reflect the life-long increased turnover of ectasia, do not feature accelerated develop-
WBCs associated with the chronic systemic in- ment of atherosclerosis. Two different genetic
flammatory state in this disease [73]. Accord- variants of dyskeratosis congenita exist. The
ing to this hypothesis, for which further evi- x-linked form has a mutation in the dyskerin
dence is equally lacking, shorter WBC telo- gene, which is involved in ribosomal DNA pro-
meres in age-related vascular disease would cessing and telomerase function, while the au-
be a secondary epiphenomenon without any tosomal dominant form has a defect in the gene
causal involvement. for the telomerase RNA component. Dysker-
atosis congenita patients have reduced telome-
rase activity and short telomeres, and usually
Evidence from human genetic die in young adulthood of bone marrow failure,
cancer or pulmonary complications [76]. Pa-
mutations
tients with the autosomal recessive disorder
A number of inherited disorders in humans are ataxia teleangiectasia have mutations in the
associated with a phenotype displaying fea- atm (ataxia teleangiectasia mutated) gene,
tures of premuture ageing. Patients with which encodes a protein involved in DNA dam-
Werner syndrome, a rare autosomal recessive age repair. They suffer from neurological de-
disease caused by mutations in the wrn gene generation, premature ageing and increased
(encoding a DNA helicase involved in DNA neoplasia. Cells from these patients display ac-
damage-repair), suffer from ageing of the skin, celerated telomere shortening in vitro, proba-
cataracts, diabetes and severe premature ath- bly due to dysfunctional repair of oxidative
erosclerosis in young adulthood [74]. These pa- damage to telomeric (and other) DNA [77]. The
tients have an average life expectancy of 40–50 absence of atherosclerosis in patients with
years. Telomeres in patients with Werner syn- either of these disorders has been used to

Table 1
Conditions or diseases associated with short telomere length in peripheral white blood cells.

Condition / disease n age control population p-value author ref.

(patients) (mean or
range)
Cardiovascular mortality 143 >60 N/A (supra- vs 0.008 Cawthon [72]
submedian groups)
Coronary atherosclerosis 10 42–72 normal coronary arteries (n = 20) 0.002 Samani [67]
Premature myocardial 203 47 vs 47 healthy controls (n = 180) <0.0001 Brouilette [68]
infarction (<50 years)
Vascular dementia 41 18–98 healthy controls (n = 73) <0.001 von Zglinicki [71]
Hypertensives with 73 60 vs 64 hypertensives with no carotid 0.03 Benetos [69]
carotid atherosclerosis atherosclerosis (n = 90)
Age-related calcific aortic 30 77 vs 77 no aortic stenosis (n = 30) 0.002 Kurz [70]
stenosis
Increased pulse pressure 98 18–44 N/A (correlation) 0.0032 Jeanclos [65]
Smokers 82 15–80 non-smokers (n = 189) 0.014 Nawrot [64]
Men 119 15–80 females (n = 152) 0.028 Nawrot [64]

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Cardiovascular Biology Prize SSC

argue against a role for telomere-based cell therapy will always need to be balanced
senescence in atherogenesis. against the risk of giving up the protection of-
fered by the mitotic counter of senescence
against the development of cancer.
Cellular senescence
Acknowledgments
and organismal ageing
David J. Kurz gratefully receives financial sup-
The concept that telomere-based senescence port from the Swiss National Science Founda-
may be a main player in the actual ageing tion and the Swiss Heart Foundation.
process of multicellular organisms remains The Cardiovascular Biology Price of the SSC was
highly controversial. However, a role for this sponsered by Pfizer.
process in age-related degenerative disorders
in humans, who as a species now outlive their
evolution-driving life span by decades, seems References
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known as “antagonistic pleiotropy” suggests shareholders in cardiovascular disease enterprises: Part I:
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