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12 PART | I Overview
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Adjusted
For? TL Assay
Age Q-PCR
No. of
Deaths
n = 53
deaths from
Follow-Up
(y)
CVD
Q-PCR
recruitment
site, assay
Age Q-PCR
n = 53 CVD
deaths
∼49 12 102 overall;
235 Range 70–79;
MacArthur
Details of
Result Sample n Age (Years) % ♂
Mortality from
M = 73.7
Health Aging
Study, USA
CVD associated
with baseline TL
for ♀ (OR = 2.3)
but not for ♂. No
associations with
∼43 to 52 10 975 Age, sex, race,
Range 70–79;
M ∼73.6 years
2721
(∼58%
white)
Health ABC
Study, USA
overall mortality
with survival or
specific causes of
death
46% 10 159 Unclear Q-PCR
M = 62.0
669 Baseline: 53–71;
Bruneck Study,
longitudinal,
Italy
at baseline for
those who subse-
quently died
27 ∼20 81 Age, sex Q-PCR
M age = 89.9
81 Range 85–101;
Leiden
85 + Study, The
Netherlands
over 3.7–12.9 y;
no association
∼49% 12 102 overall;
M = 73.7
235 Range 70–79;
MacArthur
Health Aging
Study, USA
over 2.5 y associ-
ated with CVD
mortality for ♂
only (OR = 3.0);
no associations
with overall
mortality
P
TABLE 1.2 Telomere Length and Mortality/Life Span Studies—cont’d
Value
<.05*
Study
Epel (2009)
for ♀
[173]
>.05 Not associated
Njajou
(2009) [174]
<.001*** Shorter telomeres
Ehrlenbach
(2009) [175]
Longitudinal Telomere Change
>.05 Change in TL
Martin-Ruiz
(2005) [167]
<.04* Change in TL
Epel (2009)
[173]
Studies used peripheral blood samples for TL estimation. CVD, cardiovascular disease; n.s., not significant; Q-PCR, quantitative real-time polymerase chain reaction; TL, telomere length; TRF, terminal/telomere restriction
fragment analyses. *P < .05; **P < .01; ***P < .001.
From Mather KA, Jorm AF, Parslow RA, Christensen H. Is telomere length a biomarker of aging? A review. J Gerontol A Biol Sci Med Sci February 2011;66(2):202–13 with permission.
Aging Aorta—Cellular Mechanisms Chapter | 1 13
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TABLE 1.3 Summary of Telomere Length Dynamic Studies in Vascular Surgical Disease and Healthy Vascular Tissue
Condition/
Tissue
Abdominal
aortic aneurysm (AAA)
Atherosclerotic
nonaneurysmal
aorta
Peripheral
vascular
disease (PVD)
Carotid disease Leukocytes TRF—Southern
Telomere
Source
Leukocytes Terminal
Leukocytes Telomere/
AAA proximal
sac versus
healthy aorta
Matched
aortic intimal
and medial
biopsies
Leukocytes Telomere to
Leukocytes TRF—Southern
Leukocytes TRF—Southern
Telomere
Measurement Main Findings
restriction fragment (TRF)—
Southern blot
analysis
genomic DNA
ratio—qPCR
TRF—Southern
blot analysis
single reference gene (T/S)
ratio—qPCR
blot analysis
blot analysis
blot analysis
Reduced telomere length
in AAA
Telomere shortening
correlated with
increasing AAA diameter
Reduced telomere
content in AAA
Telomere shortening in
AAA
Increased telomere
attrition rate in distal
aorta versus proximal
aorta for both tunica
intima and tunica media
Reduced telomere
length in patients with
chronic heart failure and
claudication versus those
without claudication
No association between
telomere length and
PVD-ankle-brachial pressure index (ABPI) <0.9
Reduced telomere length
in hypertensives with
carotid plaques versus
those without plaques
Reduced telomere length
in type 2 diabetics with
carotid and femoral
plaques versus those
without plaques
Cases/
Controls P Value References
190/183 .005 Atturu et al. [176]
20/12 <.001 Wilson et al. [177]
20/12 <.05
44/44 .003 Okuda et al. [178]
620/183 .001 Van Der Haarst
et al. [179]
22/n/a .51 Fitzpatrick et al.
[170]
73/90 .03 Benetos et al.
[180]
30/30 .0001 Adaikalakoteswari
et al. [181]
From Butt HZ, Atturu G, London NJ, Sayers, RD, Bown, MJ. Telomere length dynamics in vascular disease: a review. Eur J Vasc Endovasc Surg July 2010;40(1):17–26
with permission.
process that causes telomere decay because of higher rates of leukocyte production; (4) decreased telomerase activity;
and (5) increased blood homocysteine that is linked with shorten telomeres.
Certainly, prospective longitudinal studies looking for the correct explanation of shortening of telomere length are
required. Telomere increase by telomerase oversecretion does not influence stress-induced senescence [188] but restrains
replicative senescence [189–191]. Last, telomere shortening is strongly related with severe atherosclerosis [185].
ATHEROGENESIS
The theory of cellular aging was first used by Hayflick during the 1960s [46,192] and assumes decreasing or stopping of
cell division from the structure of arterial wall. In these conditions, VSMCs and elastin are replaced by connective tissue
(collagen) that because of its reduced elasticity causes stiffness of aortic wall, conditions in which atherogenesis and calcification are favored and occur frequently in the arteries of elderly patients. The Russell Ross hypothesis on atherosclerosis
development has been modified three times and established as being a “response to injury hypothesis” [193–195]. This
theory states that reactive oxygen species has a significant task in the initiation and progression of atherosclerosis [196].
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FIGURE 1.8 Atherosclerosis in the aged artery. Aged endothelial cells express various adhesion molecules (AM), which facilitate the binding as well as
transportation of various inflammatory cells, including monocytes (M) and lymphocytes (L) into the intima. OxLDL plays a major role in the formation
of foam cells (F). The foam cells secrete several growth factors (GF) and cytokines (C) that lead to increased proliferation of vascular smooth muscle cells
(VSMCs). Increased expression of endothelin-1 facilitates atherosclerosis through ET-A receptor activation. The lymphocytes also play a critical role in
causing inflammation in the endothelium. Altogether, these changes facilitate the plaque formation in the blood vessels of aged populations [198]. It is an
open access chapter under Attribution 3.0 Unported (CC BY 3.0).
Cellular senescence is involved in vascular disorders, mainly atherosclerosis. It is also established that the initiation of
premature senescence through the p53/p21-dependent pathway in human VSMCs [197]. Aging alterations of aortic wall are
the result of the concomitantly or sequentially degenerative process, which comprise endothelium, intima, tunica media, and
tunica adventitia, and produce: stiffness, calcifications, atheroma, and deformation. The main factor of aging aorta is that atherosclerosis undoubtedly starts with endothelium alteration by the adhesion of the molecules that attract inflammatory cells
(lymphocytes, monocytes) and penetrate both the tunica media and intima. As a consequence, oxidized low density lipoproteins by (OxLDL) arise from the foam cells (F). Conversely, these foam cells produce growth factors (GFs) and cytokines (C).
Further, these determine the proliferation of VSMCs, activation of endothelin, and lymphocyte infiltration [198,199] (Fig. 1.8).
As already described, atherosclerosis development is reduced by NO [200] that also has an antioxidant effect [201].
The basal NO secretion was examined with NO synthase inhibitor such as N(G)-monomethyl l-arginine and superoxide
dismutase [202]. Also, the expression of p22phox is an important element of nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase, when atherosclerosis is increased [203]. To summarize, NO works by numerous processes to stop the
development of atherosclerosis [204].
Senescent endothelial cells exist in human atherosclerosis but not in nonatherosclerotic pathology [205] and support
that cellular senescence causes atherogenesis [206]. MMP9 (gelatinase B) is expressed in atherosclerotic lesions [207].
Further, Blankenberg et al. (2003) [208] showed that the C−1562T polymorphism increased promoter activity, adjusted
plasma MMP9 levels in patients with CVD, and prognosticated CV events. Finally, vascular inflammation is coordinated
by multiple cytokines and chemokines secreted by a plethora of vascular cells and immune cells [209].
Increasing evidence suggests an important role of miRNAs as epigenetic regulators of age-related diseases, including
vascular and metabolic diseases [210,211]. Gene expression, cell-type–specific function, and cell–cell communication are
regulated by miRNAs, which emerge as important regulators of the cardiovascular system. Because miRNA controls the
fate of many genes modulating signaling networks and cell function, targeting a miRNA might be a promising strategy to
treat atherosclerotic disease (Fig. 1.9).
CONCLUSIONS
Strategies to prevent the premature senescence of VSMCs could be an effective approach for reducing vascular disease.
Therefore, the prevention of arterial aging and its side effects could be made by regular exercise, drugs therapy, or the debatable newly benefits effects of nutraceuticals.
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FIGURE 1.9 miRNAs implicated in atherosclerotic processes. Positive/atheroprotective (in green frame) or negative/atherogenic (in red frame) effects
of miRNAs on the atherosclerotic process are shown. Question marks next to miRNAs indicate controversial or contradictory evidence. miRNAs in
bold are those reported to be regulated by blood flow/shear stress. Low-density lipoprotein (LDL) diffuses from the blood into the intima and undergoes
oxidative modification. Oxidized LDL triggers the expression of leukocyte adhesion molecules by endothelial cells. The initial steps of atherosclerosis
include adhesion of blood monocytes to the activated endothelium, their migration into the intima, their maturation into macrophages (or dendritic cells),
and their uptake of lipid yielding foam cells. Although fewer in number than macrophages, other leukocyte subsets, such as T cells, also enter the intima
and regulate cellular and humoral immune responses. Lesion progression involves the proliferation and migration of SMCs into the intima, as well as
increased extracellular matrix protein synthesis, including collagen. Advanced lesions also exhibit intraplaque neovascularization and outward remodeling. Abbreviations: LDL, low-density lipoprotein; SMC, smooth muscle cell. From Andreou I, Sun X, Stone PH, Edelman ER, Feinberg MW. miRNAs in
atherosclerotic plaque initiation, progression, and rupture. Trends Mol Med May 2015;21(5):307–18 with permission.
Exercise enhances endothelial function in muscular arteries [213] and decreases the magnitude of reflected waves that
come back to the heart [214].
In case of drugs administration for aging prevention, the proportion of elastin fracture could be decreased by therapy
with beta-blockers. In monogenic disorders such as Marfan’s syndrome, beta-blockers efficiently decreased arterial stiffness [215]. Moreover, the use of statins improves endothelial function, raises NO systemic availability, and raises antioxidant and antiinflammatory outcomes [216–218].
Understanding of new molecular therapies that influence the vascular aging mechanisms has important scientific
consideration. miRNAs are emerging as new therapeutic targets [219]. As already described, miR-34a is defined
as p53-regulated tumor suppressor miRNA, effective in regulating cell cycle ending, apoptosis, and senescence
[220–222].
Moreover, NO decreases atherosclerosis. Therefore, eNOS may have an important function in the control of endothelial
cells senescence, being an important aim for a new therapeutic strategy of vascular aging disorders [223].
Phosphodiesterase 1 (PDE1) inhibitors may represent novel therapeutic agents for treating CVDs [224]. Recent studies also identify nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) as underlying an aging suppression
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pathway in smooth muscle cells, with potential relevance to controlling atherosclerosis and possibly other diseases of aging
[225,226]. Moreover, the beginning of endothelial senescence can be anticipated or stopped by some growth factors, as well
as PF/VEGF, TGF-β, IGF, or IL-1α [227–229].
During this decade, nutraceuticals received significant consideration from the part of researchers in aging prevention.
Resveratrol (3,5,4′-trihydroxystilbene), a polyphenol from red wine has antiaging abilities (preservation of telomere length)
could be a helpful nutraceutical therapy in CVD [226]. Furthermore, from the same group of polyphenol, the plant flavonoids [230–232] showed antiaging properties. For instance, grape seed proanthocyanidin extracts have higher antioxidant
properties in comparison with vitamin C, vitamin E, or any other antioxidant [233] and decreases atherosclerosis too [234].
To summarize, CVD is the principal etiology of worldwide mortality and early arterial stiffening is a major promoter to
this risk. Increased data of studies underline that arterial stiffness is an independent predictor of cardiovascular disorders.
Unfortunately, the accurate molecular pathways managing stiffness are unsuccessfully comprehended and further studies
are obviously required.
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