JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO.

15, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.01.064

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

The Aging Cardiovascular System

Understanding It at the Cellular and Clinical Levels

Francesco Paneni, MD, PHD,a,b Candela Diaz Cañestro, MSC,a Peter Libby, MD, PHD,c Thomas F. Lüscher, MD,a,b
Giovanni G. Camici, PHDa,b

ABSTRACT

Cardiovascular disease (CVD) presents a great burden for elderly patients, their caregivers, and health systems.
Structural and functional alterations of vessels accumulate throughout life, culminating in increased risk of devel-
oping CVD. The growing elderly population worldwide highlights the need to understand how aging promotes CVD in
order to develop new strategies to confront this challenge. This review provides examples of some major unresolved
clinical problems encountered in daily cardiovascular practice as we care for elderly patients. Next, the authors
summarize the current understanding of the mechanisms implicated in cardiovascular aging, and the potential for
targeting novel pathways implicated in endothelial dysfunction, mitochondrial oxidative stress, chromatin remod-
eling, and genomic instability. Lastly, the authors consider critical aspects of vascular repair, including autologous
transplantation of bone marrow-derived stem cells in elderly patients. (J Am Coll Cardiol 2017;69:1952–67)
© 2017 by the American College of Cardiology Foundation.

A ge dominates risk factors for cardiovascular

disease (CVD) (1,2). Indeed, the advent of
contemporary treatments for acute coronary
syndromes and stroke have helped to extend life
expectancy (3). Although an enormous success from
an individual perspective, the resultant demographic
shift presents one of the greatest challenges for the
social and health care systems worldwide (4). The
population over 65 years of age will double from
12% in 2010 to 22% in 2040 (2). Indeed, by 2020, the
number of people 60 years of age and older will sur-
pass the number of children below 5 years of age.
The pace of population aging around the world is
increasing dramatically, particularly in low- and
middle-income countries (e.g., Chile, China, Iran,
and Russia).
Although aging presents an array of disorders (5),
CVD carries the greatest burden for the older popu-
lation, their care givers, and health systems (6). Cor-
onary heart disease (CHD) associates strongly with
age, and is the leading cause of death in Europe and
the United States (7–9). The prevalence of CVD in-
creases in people >65 years of age, especially in those
>80 years of age, and will increase by w10% over the
next 20 years (2). From 2010 to 2030, an additional
27 million people will have hypertension, 8 million

Listen to this manuscript’s
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aCenter for Molecular Cardiology, University of Zurich, Zurich, Switzerland; bUniversity Heart Center, Cardiology,
University Hospital Zurich, Zurich, Switzerland; and the cBrigham and Women’s Hospital, Division of Cardiovascular Medicine,
Boston, Massachusetts. The present work was supported by the Swiss National Science Foundation (Drs. Lüscher and Camici) and
the Alfred and Annemarie von Sick Grants for Translational and Clinical Research Cardiology and Oncology (Dr. Camici), an
unrestricted research grant by Pfizer, Inc. (Dr. Lüscher), the Foundation for Cardiovascular Research–Zurich Heart House and the
U.S. National Institutes of Health (RO1 HL080472), and from the RRM Charitable Fund (Dr. Libby). Drs. Paneni and Camici are
recipients of a Sheikh Khalifa’s Foundation Assistant Professorship at the Faculty of Medicine, University of Zurich. Dr. Libby has
been an unpaid consultant for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Merck
& Co., Novartis, Pfizer, Sanofi-Regeneron, Takeda Pharmaceuticals, and XBiotech; served as a scientific advisory board member
for Amgen, Athera Biotechnologies, Corvidia Therapeutics, DalCor Pharmaceuticals, Interleukin Genetics, Kowa Pharmaceuticals,
Medimmune, and Novartis; and has received lab funding from Novartis. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose.

Manuscript received July 12, 2016; revised manuscript received January 23, 2017, accepted January 24, 2017.
JACC VOL. 69, NO. 15, 2017 Paneni et al. 1953
APRIL 18, 2017:1952–67 The Aging Cardiovascular System

will have CHD, 4 million will have stroke, and 3 determinant of myocardial oxygen re- ABBREVIATIONS

million will have heart failure due to the rapid accu- quirements. Chronic exposure to increased AND ACRONYMS

mulation of elders (2). systolic pressure leads to LV hypertrophy,

BM = bone marrow
Increased CVD prevalence also interplays with causing a further rise in myocardial oxygen
CAC = circulating angiogenic
frailty, a condition of increased vulnerability to demand. Mediators, such as TGF-b , angio-
cell
stressors. A meta-analysis that included 54,250 tensin II, and the mineralocorticoid aldoste-
CHD = coronary heart disease
elderly patients associated CVD with an odds ratio rone, contribute mechanistically to
CI = confidence interval
(OR) of 2.7 to 4.1 for prevalent frailty and an OR of 1.5 hypertrophy and fibrosis in the pressure-
COX = cyclooxygenase
for incident frailty in those without frailty at baseline overloaded LV. Thus, the systolic hyperten-
CV = cardiovascular
(10). Current projections predict an increase in ex- sion and decreased diastolic pressure associ-
penditures for CHD and heart failure of w200% over ated with aging yield a “perfect storm” of CVD = cardiovascular disease

the next 20 years, with stroke expected to contribute decreased oxygen supply in the face of eNOS = endothelial nitric
oxide synthase
the largest relative increase in annual medical costs of augmented oxygen demand. As coronary
EPC = endothelial progenitor
238% (2). These considerations highlight the urgency atherosclerosis also advances with age, this
cell
of understanding why age contributes crucially to the additional limitation to oxygen supply often
HFpEF = heart failure with
development of CVD in order to enable us to cope compounds the increased oxygen demand preserved ejection fraction
with the aging of the population. This review pro- typically encountered in the aging CV system
LTL = leukocyte telomere
vides clinical and experimental evidence to support (Figure 1). In addition to altered large artery length
the established link between aging and CVD. function, chronic hypertension promotes LV = left ventricular
remodeling of the myocardial microvascula- MI = myocardial infarction
CLINICAL ASPECTS OF CVD IN ture. Thickening of the tunica media of
MMP = matrix
ELDERLY PATIENTS myocardial arterioles can further impede LV metalloproteinase
perfusion and impair vasomotion. These NF-kB = nuclear factor kappa-B
A number of age-related conditions present particular consequences of the increased systolic and OR = odds ratio
challenges to the clinical care of our cardiovascular decreased diastolic pressure that typically
PBMC = peripheral blood
(CV) patients. The accumulation of elderly in- accompany aging conspire to cause myocar- mononuclear cell
dividuals in our population underscores the growing dial ischemia. The regulation of arteriolar RAAS = renin-angiotensin-
importance of CV aging to practitioners. remodeling in the myocardium subjected to aldosterone system

SYSTOLIC HYPERTENSION AND WIDENED PULSE increased systolic and decreased diastolic ROS = reactive oxygen species

PRESSURE. With aging, the aorta stiffens due to pressure likely involves the same pathways RR = relative risk
increased collagen and decreased elastin (Figure 1). implicated in generation of aortic stiffness. TGF = transforming growth
Augmented transforming growth factor (TGF)-b We lack sufficient understanding of the pri- factor

activity favors the accumulation of collagen in the mary age-related triggers for these patho- TNF = tumor necrosis factor

aortic wall. The activity of various elastases, physiological processes that contribute VSMC = vascular smooth
including matrix metalloproteinases (MMPs), such as enormously to CV complications in the aging muscle cell

MMP-9 and MMP-12, as well as overexpression of the population. wtTTR = wild-type

cysteine proteinases cathepsins S, K, and L, and the
serine proteinase neutrophil elastase, elaborated by
inflammatory cells, can all contribute to depletion of
elastin (11). These alterations in the aorta’s extracel-
lular matrix contribute importantly to its loss of
distensibility. This increased stiffness raises reflected
waves and elevates systolic pressure. Yet diastolic
pressure tends to decline with age. As aortic pulse
wave velocity increases, pulse pressure rises (12).
Indeed, pulse pressure is an independent risk factor
for CV events (13). Isolated systolic hypertension ac-
counts for the majority of uncontrolled hypertension
in Americans over 50 years of age (14,15).
The fall in diastolic pressure decreases the drive for
coronary perfusion that occurs primarily during
diastole, favoring the development of myocardial
ischemia. The increased systolic pressure with age
increases left ventricular (LV) afterload, a major
transthyretin
Fortunately, some interventions can
improve outcomes in patients with isolated
systolic hypertension. The SHEP (Systolic
Hypertension in the Elderly), Syst-Eur (Systolic Hy-
pertension in Europe), Syst-China (Systolic Hyper-
tension in China), and other studies offer a rich
database affirming the ability of pharmacological
treatment of individuals in their 60s or 70s to reduce
substantially stroke and total mortality, with lesser
benefit for ischemic cardiac events (16). Avoiding
excessive sodium intake may provide an additional,
nonpharmacological intervention for control of hy-
pertension in older individuals (17,18). Some have
raised concerns regarding the safety of aggressive
lowering of blood pressure in elderly patients,
particularly those with concomitant coronary artery
disease (19). Indeed, a J-shaped curve relating CV
outcomes to blood pressure may pertain to this
1954 Paneni et al.
The Aging Cardiovascular System
F I G U R E 1 Pathophysiology of Aortic-LV Dynamics in the Aging CV System
Ang II ¼ angiotensin II; BP ¼ blood pressure; CV ¼ cardiovascular; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection
fraction; LV ¼ left ventricular; MMP ¼ matrix metalloproteinase; MVO2 ¼ myocardial oxygen consumption; TGF ¼ transforming growth factor.
population (20–22). Yet the HYVET (Hypertension in
the Very Elderly Trial) and SPRINT (Systolic Blood
Pressure Intervention Trial) studies confirmed the
relative safety and efficacy of antihypertensive
treatment in the older population, although recent
data suggest maintaining diastolic pressure above
70 mm Hg in those with established coronary artery
disease (21–25). Clinicians should tailor the aggres-
siveness of antihypertensive treatment of geriatric
patients on an individualized basis, depending on the
status of the coronary arteries, frailty, the integrity of
autonomic function, and other variables (26).
In addition to reducing stroke, a major impediment
to independent living and function in older patients,
antihypertensive therapy may limit the development
of dementing illnesses, as shown in the Syst-Eur
trial (27). Decreased dementia and cognitive decline
accrue with longer duration of antihypertensive
treatment (28). An asymmetric loss to follow-up of
individuals with impaired cognition may have biased
the results of dementia in the SHEP study to the
null (29).
VASCULAR AGING: DEFINITION, PATHOPHYSIOLOGY,
AND IMPACT. Alterations in the structure and function
of arteries accompany aging, and contribute to
increased risks of developing CVD (9,30). Accord-
ingly, understanding the mechanisms by which age
affects the vasculature should position us to prevent
JACC VOL. 69, NO. 15, 2017
APRIL 18, 2017:1952–67
or attenuate the increased risk of CVD in elderly
people.
Several recent (pre-)clinical studies have estab-
lished key vascular modifications occurring with
aging (31,32), identifying 2 main features: generalized
endothelial dysfunction and central arterial stiffness.
With regard to the former, vascular aging alters
the function of the endothelium, the cells that line
the lumen of blood vessels. Endothelial dysfunction
includes reduced vasodilatory and antithrombotic
properties, with an increase in oxidative stress
and inflammatory cytokines (33–35) favoring athero-
genesis and thrombosis, and predisposing to CVD
(36). Human and experimental studies concur
that diminished bioavailability of nitric oxide (NO), a
key mediator of vasorelaxation and antiatherogenic
processes, underlies age-dependent endothelial
dysfunction (37,38). Reduced NO bioavailability can
occur due to decreased synthesis or increased
degradation of NO. Under normal conditions, endo-
thelial nitric oxide synthase (eNOS) produces NO from
L -arginine in the presence of the cofactor tetrahy-
drobiopterin (BH4) (39). Although studies differ
regarding eNOS protein expression with age (34,40,41),
recent data suggest an age-related alteration in
eNOS function, referred to as eNOS uncoupling (42).
This effect derives, at least in part, from a decrease in
BH4 availability, resulting in impaired NO release and
increased production of the highly pro-oxidant
JACC VOL. 69, NO. 15, 2017
APRIL 18, 2017:1952–67
superoxide anion (O 2) (33). Furthermore, the avail-
ability of the eNOS substrate, L -arginine, may also
restrict NO production. In this regard, the activity of
arginase, an enzyme that competes with eNOS for
L -arginine, increases with age, providing a plausible
mechanism for the decreased synthesis of NO (43).
Nevertheless, most of this mechanistic evidence has
emerged from animal studies, highlighting the need
for more human research regarding age-dependent
limitation of NO synthesis.
Additionally, aging may increase NO degradation
(34) due to elevated concentrations of reactive oxy-
gen species (ROS), mediated, in part, by chronic
inflammation, constituting a vicious cycle that de-
pletes NO (35). For example, age-dependent increases
in vascular and blood-borne tumor necrosis factor
(TNF)-a , associates with increased expression of
nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase (Figure 2). Augmented NADPH oxi-
dase activity yields overproduction of O 2, which, in
turn, reacts with NO to form peroxynitrite (ONOO ), a
powerful oxidant involved in nitrosylation of anti-
oxidant enzymes and eNOS (34). Besides inflamma-
tory cytokines, the renin-angiotensin-aldosterone
system (RAAS) may contribute to the age-associated
increase in NO inactivation. With aging, RAAS activ-
ity and the concentration of angiotensin II, a principal
RAAS effector, rise, increasing the production of ROS
by activating NADPH oxidase (44). In turn, age-
related increased ROS production may promote
vascular inflammation (45). Indeed, hydrogen
peroxide (H2O 2) activates nuclear factor kappa-B
(NF- k B), which augments the transcription of proin-
flammatory genes, leading to increased expression of
TNF- a , interleukin 6, chemokines, and adhesion
molecules implicated in atherogenesis (Figure 2).
Increased vasoconstrictor tone may compound age-
dependent impairment in endothelial-dependent
vasodilatation. Human aging associates with an in-
crease in circulating and arterial wall levels of
endothelin(ET)-1, a powerful vasoconstrictor impli-
cated in impaired endothelium-dependent dilation
(40,46). Moreover, evidence from rodent endothelial
cells indicates that concentrations of cyclooxygenase
(COX)-derived eicosanoids also change considerably
with age. With age, the COX-derived eicosanoids
associated with vasoconstriction and thrombosis rise
(i.e., prostaglandin H 2 [PGH2], thromboxane A 2
[TxA2]. and prostaglandin F2a [PGF 2a ]), whereas
prostaglandin I 2 (PGI 2, prostacyclin) falls (47,48).
Furthermore, impaired endothelial-dependent res-
ponsiveness to prostaglandins accompanies aging in
both humans and animals (49,50). Thus, aging asso-
ciates with a concerted impairment in endothelial
Paneni et al. 1955
The Aging Cardiovascular System
function that disrupts arterial homeostasis, favoring
chronic activation of pro-oxidant and proin-
flammatory pathways, and a shift toward a vasocon-
strictor profile, predisposing to CVD and adverse
events (51).
Increased stiffness of central arteries, particularly
of the thoracic aorta, also characterizes human
vascular aging (52) (Figure 1). Human and animal
studies suggest that the reduced distensibility of
large elastic arteries results primarily from the loss of
elastic fibers, as well as an increase in collagen (53).
Mechanistically, the age-related increase in elastin
degradation may result from augmented activity of
proteases with elastinolytic activity, including certain
MMPs and cysteinyl cathepsins, enzymes that, in
turn, are regulated by inflammatory mediators
(54,55). Collagen catabolism falls in aging arteries.
The accumulation of collagen modified by advanced
glycation end-products (AGEs) (condensates of
glucose produced by nonenzymatic reactions that
form cross-links between collagen molecules) may
contribute to this age-related increase in arterial
collagen. AGE-mediated cross-links can confer resis-
tance to enzymatic degradation, and thus interfere
with collagenolysis (56). In addition, increased ac-
tivity of TGF- b with aging stimulates the synthesis of
interstitial collagen by vascular smooth muscle cells
(VSMCs), and thereby augments arterial stiffness (57).
Likewise, increased activity of the RAAS may
augment collagen synthesis and heighten elastolysis
(58).
Endothelial dysfunction and arterial stiffness are
closely interconnected mediators of age-dependent
vascular dysfunction (59). The stiffer the artery, the
greater the exposure of the endothelium to hemody-
namic load, promoting endothelial activation,
inflammation, and damage (60). Age-related re-
ductions in NO bioavailability described earlier may
contribute to impaired arterial distensibility via
changes in smooth muscle tone (61). Novel therapies
aimed at attenuating age-related CVD could target
these features of vascular aging, with particular
emphasis on endothelial dysfunction and changes in
the arterial extracellular matrix that cause central
arterial stiffness.
HEART FAILURE WITH PRESERVED AND REDUCED
EJECTION FRACTION. Related etiologically to both
the acquisition of aortic stiffness and remodeling of
the myocardium, its extracellular matrix, and its
microvasculature, heart failure with preserved ejec-
tion fraction (HFpEF) plagues elderly patients,
particularly women. The risk of developing HFpEF
skyrockets with age (62,63). Indeed, hypertrophy
1956 Paneni et al. JACC VOL. 69, NO. 15, 2017

The Aging Cardiovascular System APRIL 18, 2017:1952–67

F I G U R E 2 Schematic Representation of Molecular Pathways Involved in Arterial Aging

Aged endothelial cells down-regulate JunD and SIRT1expression, leading to pro-oxidant and proinflammatory gene expression. Increased ROS and inflammatory
cytokines reduce NO availability. In parallel, age-related up-regulation of angiotensin II and COX-derived eicosanoids results in augmented vasoconstrictor
mediators, such as ET-1, TxA2, and PGF2a. This imbalance between dilator and constrictor factors prompts impaired vascular function. Furthermore, increased
MMP expression in VSMCs induces changes in structural components of the arterial wall (e.g., decreased elastin/collagen ratio), contributing to arterial
stiffness. AA ¼ arachidonic acid; ALDH-2 ¼ aldehyde dehydrogenase; AMPK ¼ 50 adenosine monophosphate-activated protein kinase; Arg II ¼ arginase II;
AT-1 ¼ angiotensin II receptor type 1; BH4 ¼ tetrahydrobiopterin; Ca2þ ¼ calcium ions; cGMP ¼ cyclic guanosine monophosphate; COX ¼ cyclooxygense; DP ¼
prostaglandin D2 receptor; ecSOD ¼ extracellular superoxide dismutase; EPI-4 ¼ prostaglandin E2 receptor 1-4; ETA ¼ endothelin receptor A; FP ¼ prosta-
glandin F receptor; GC ¼ guanylate cyclase; GTP ¼ guanosine triphosphate; ICAM ¼ intercellular adhesion molecule; IP ¼ prostacyclin receptor; MCP ¼
monocyte chemotactic protein; MnSOD ¼ manganese superoxide dismutase; NF-kB ¼ nuclear factor kB; NO ¼ nitric oxide; PGD2 ¼ prostaglandin D2; PGF2a ¼
prostaglandin F 2a; PGI2 ¼ prostacyclin; PKG ¼ protein kinase G; ROS ¼ reactive oxygen species; TNF- a ¼ tumor necrosis factor alpha; TP ¼ thromboxane
receptor; TxA2 ¼ thromboxane A2; VCAM ¼ vascular cell adhesion protein; VSMC ¼ vascular smooth muscle cell; other abbreviations as in Figure 1.
JACC VOL. 69, NO. 15, 2017
APRIL 18, 2017:1952–67
and fibrosis of the aged LV can impair lusitropy.
Practitioners generally acknowledge the increasing
prevalence of HFpEF, its accentuation in elderly pa-
tients, and its adverse outcomes in our aging patient
population, with regard, not only to morbidity, but
also to reduced quality of life and increased resource
utilization (64). Unfortunately, we possess few (if
any) evidence-based interventions to stem the
development or consequences of HFpEF. Studies in
progress of neurohumoral blockade may help to fill
this important gap in our therapeutic approach to
HFpEF in our elderly patients (65). However,
myocardial ischemia, due to either myocardial
infarction (MI) (ischemic cardiomyopathy) or sub-
endocardial ischemia in the hypertrophied LV, can
predispose to heart failure with reduced ejection
fraction. Thus, aging can promote the development of
both major forms of heart failure that constitute a key
challenge to quality of life of aging individuals, as
well as an enormous drain on health care resources
(Figure 1).
VALVULAR AND CARDIAC SKELETON CALCIFICATION. With
age, calcium in the axial skeleton particularly tends to
decline, while accumulating in CV structures.
Appreciation has increased that conditions such as
calcific aortic stenosis actually reflect a systemic
process (66). Evidence points to inflammation as a
potential physiological contributor to CV calcifica-
tion. Strong human genetic data also implicate lip-
oprotein(a) in the pathogenesis of aortic valve
calcification (67). Despite initial enthusiasm, clinical
trials have not substantiated that statin therapy can
limit progression of aortic valvular calcification.
Indeed, statins tend to accelerate coronary arterial
calcification (68,69). Given the pressing clinical
importance of calcific aortic stenosis in geriatric pa-
tients, we urgently need a greater understanding of
its pathophysiology and preventive measures to
mitigate its genesis, as once CV structures have
calcified, therapeutic reversal of this process may
prove elusive.
AMYLOIDOSIS AND THE AGING CV SYSTEM. Certain
forms of amyloidosis also particularly affect the older
population (70). The incidence of amyloid light-chain
amyloidosis rises in older patients, related to the
increase in multiple myeloma with age. Cardiac
amyloidosis associated with wild-type transthyretin
(wtTTR) particularly affects the older population,
especially men. Although many have regarded car-
diac amyloidosis as a rare condition, current data
using novel imaging modalities show that some 13%
of cases of HFpEF in individuals $60 years of age
associate with wtTTR amyloidosis (71). At least 20% of
Paneni et al. 1957
The Aging Cardiovascular System
people over 80 years of age have wtTTR amyloid de-
posits in their hearts at autopsy. Although the clinical
significance of this finding remains uncertain, it is
highly likely that with the aging of the population and
the advent of novel diagnostic modalities, wtTTR
amyloidosis will become better recognized as a
contributor to heart failure in the older population.
Amyloidosis due to wtTTR requires differentiation
from amyloid light-chain amyloidosis, because the
prognosis and treatment diverge substantially.
Although we currently lack effective therapy for
treating amyloidosis, promising imaging technologies
should provide evolving tools to evaluate novel
therapies currently in development or under inves-
tigation (72).
FRAILTY AND SARCOPENIA IN THE AGING
POPULATION. Frailty and loss of muscle mass and
function (sarcopenia) present a major challenge to
maintenance of independence, mobility, quality of
life, and the ability of our CV patients to undergo
surgery and other interventions (such as trans-
catheter valve procedures) successfully. Moreover,
the ability to tolerate CV therapies may decline with
frailty and sarcopenia, as discussed earlier for phar-
macological treatment of hypertension. We lack def-
inite criteria for defining sarcopenia and frailty
(73,74), which associate with both osteoporosis and
obesity (75). Potential pathophysiological pathways
that link these apparently disparate conditions
include proinflammatory cytokines. Further clarity in
diagnosis and pathophysiological mechanisms would
be highly desirable, given the increase in the elderly
population affected by CV disease, and the limita-
tions these conditions present to patients and their
management. Increased physical activity could pro-
vide a nonpharmacological preventive approach to
augmenting patient quality of life and function, and
could conceivably improve the ability to tolerate
pharmacological and interventional treatment of CV
conditions, hence improving CV outcomes.
MOLECULAR FEATURES OF
AGE-RELATED CVD
TELOMERES AND CELLULAR SENESCENCE. Accumulation
of senescent cells within the vascular wall and
heart can contribute to structural and functional
decline of the CV system with age (58). Considerable
evidence implicates telomere shortening in cellular
senescence. Telomeres consist of repetitive nucleotide
sequences (TTAGGG) at the ends of mammalian chro-
mosomes, that preserve chromosome stability and
integrity by preventing deterioration or fusion with
neighboring chromosomes (76) (Central Illustration).
1958 Paneni et al. JACC VOL. 69, NO. 15, 2017

The Aging Cardiovascular System APRIL 18, 2017:1952–67

C E NT R AL IL L U STR AT IO N Molecular Hallmarks of CV Aging (Cellular Senescence, Genomic Instability,

Chromatin Remodeling, and Mitochondrial Oxidative Stress)

Paneni, F. et al. J Am Coll Cardiol. 2017;69(15):1952–67.

These molecular events are strongly interconnected and contribute to vascular and cardiac dysfunction in elderly patients. A thorough understanding of these complex
processes may offer pharmaceutical targets to improve human health during aging. CV ¼ cardiovascular; CVD ¼ cardiovascular disease; eNOS ¼ endothelial nitric
oxide synthase; NADPH ¼ nicotinamide adenine dinucleotide phosphate; SIRT1 ¼ sirtuin 1; VSMC ¼ vascular smooth muscle cell.

Each cell division shortens telomeric DNA until, at a
critical length, the cells lose capping function at the
chromosomal ends, activating DNA damage check-
points, cell senescence, and eventually apoptosis.
Telomere shortening has particular relevance in the
setting of CVD. Leukocyte telomere length (LTL)
associates significantly with vascular cell senescence,
aortic valve stenosis, CV risk factors (i.e., hyperten-
sion, type 2 diabetes, obesity, and smoking), and risk of
atherothrombotic events. However, the causality of
JACC VOL. 69, NO. 15, 2017
APRIL 18, 2017:1952–67
these associations remains uncertain (77). Patients
with clinical and subclinical features of atherosclerosis
display reduced LTL compared with healthy
controls, even after adjustment for relevant con-
founders, such as age, sex, and race (78). In a recent
case-control study, individuals with shorter LTL
had a higher presence of ischemic (OR: 1.37; 95% con-
fidence interval [CI]: 1.06 to 1.77) and hemorrhagic
stroke (OR: 1.48; 95% CI: 1.08 to 2.02) as compared with
the highest tertile of telomere length (79). Moreover,
patients with reduced LTL had a significantly
increased risk for both incident plaque (hazard ratio:
1.49; 95% CI: 1.09 to 2.03) and plaque progression
(hazard ratio: 1.61; 95% CI: 1.26 to 2.07) (80). A recent
meta-analysis, including prospective and retrospec-
tive studies on the association between LTL and CHD
(43,725 participants of whom 8,400 had CVD),
revealed that patients with the shortest LTL had a
higher relative risk (RR) for CHD (RR: 1.54; 95% CI: 1.30
to 1.83) and cerebrovascular disease (RR: 1.42;
95% CI: 1.11 to 1.81) (81).
Critical aspects associated with cellular senescence
include age-dependent defects of adrenergic
signaling and calcium handling. Plasma levels of
norepinephrine significantly increase with age, as the
result of reduced plasma clearance and increased
spillover from the tissues (81). A reduction of the
catecholamine reuptake transporter localized in
sympathetic nerve terminals also contributes to
elevated catecholamine concentrations with aging.
Together, these alterations progressively impair
adrenergic responsiveness, resulting in b -adrenergic
desensitization. This phenomenon ultimately re-
duces the number, affinity, and internalization of
b-adrenergic receptors (namely the b 1-adrenergic re-
ceptor subtype), coupled with abnormalities in
membrane adenylate cyclase activity or cellular pro-
duction of cyclic adenosine monophosphate (82).
Such defects of autonomic modulation favor chrono-
tropic incompetence and reduced inotropic reserve of
the LV, thus affecting exercise tolerance.
Reduction of calcium reuptake by the myocardial
sarcoplasmic reticulum calcium adenosine triphos-
phatase (SERCA2a) is another key feature of car-
diomyocyte aging, yielding impaired early diastolic
LV filling and a compensatory increase in atrial
contraction (83). Calcium transient amplitude de-
creases gradually with age, being 3.2-fold smaller in
myocytes from patients $75 years of age than in those
younger than 55 years of age (84). An age-related
delay in propagation of the calcium transient from
the sarcolemma to the cell center may also occur (84).
Moreover, aged myocytes have reduced SERCA2
expression, limiting the amount of releasable
Paneni et al. 1959
The Aging Cardiovascular System
sarcoplasmic reticulum calcium, as well as calcium
release-induced I Ca calcium channel inactivation (84).
These changes dampen mechanical efficiency and
electrophysiological properties, and increase the risk
of arrhythmias (i.e., atrial fibrillation) in the older
population.
MITOCHONDRIAL OXIDATIVE STRESS. Mitochondrial
overproduction of ROS likely contributes to cellular
senescence (9). This process ultimately leads to for-
mation of the highly reactive products O 2 or H 2O 2,
whose accumulation and diffusion fosters senes-
cence, DNA mutations, inflammation, and multiple
cell death pathways (Central Illustration) (82).
The mitochondrial adaptor p66Shc gained
increasing attention due to its pivotal role in ROS
generation and cellular apoptosis (Central Illustration)
(83). Cells lacking the p66 Shc gene have reduced
intracellular free radicals, and mice lacking p66Shc
exposed to high oxidative stress have diminished
systemic and intracellular ROS (83). Additionally,
genetic deletion of p66Shc in the mouse extended
lifespan by 30% (84). Age-dependent alteration of
p66Shc signaling profoundly affects CV homeostasis.
Indeed, deletion of p66 Shc in mice protects from sys-
temic and cerebral age-dependent endothelial
dysfunction by virtue of decreased ROS production
and conserved NO bioavailability (83,85,86). Our own
recent work also underscored the relevance of this
gene in the pathogenesis of stroke. In fact,
p66Shc -deficient mice display decreased ROS produc-
tion in the brain, and have reduced stroke size
following ischemia-reperfusion brain injury (87). We
further demonstrated that even post-ischemic in vivo
silencing of p66Shc prevents ischemia-reperfusion
brain injury in mice, mainly through preservation of
blood-brain barrier integrity (88). The observation
that p66 Shc expression increases significantly in
stroke patients and correlates with neurological def-
icits supports the clinical relevance of these experi-
mental findings (88). Expression of p66 Shc also
increases in peripheral blood mononuclear cells
(PBMCs) of patients with acute coronary syndrome
and type 2 diabetes (89,90). The activation of this
protein by several CV risk factors, such as hypergly-
cemia, oxidized low-density lipoprotein, smoking,
and hypertension, further supports its contribution to
clinical CVD (9,83). Taken together, experimental and
clinical data strongly indicate p66 Shc as a potential
therapeutic target in the setting of age-related CVD
(Figure 2).
The Activated Protein-1 (AP-1) transcription factor
JunD has emerged as a mediator of oxidative stress in
aging (Figure 2). Dimeric complexes from 3 main
1960 Paneni et al.
The Aging Cardiovascular System
families of DNA-binding proteins (Jun, Fos, and
ATF/CREB) assemble to form AP-1 transcription fac-
tors with activities that depend critically on their
specific components and the cellular microenviron-
ment (91). JunD regulates cell growth and survival,
and protects cells against oxidative stress by modu-
lating genes involved in antioxidant defense and ROS
production (92). We recently reported that JunD falls
during aging both in the mouse aorta and in PBMCs
from old as compared with young, healthy humans
(93). Young mice lacking JunD display premature
endothelial dysfunction and vascular senescence
similar to aged wild-type mice (93). Aortas from
JunD / mice have augmentation of the aging
markers p53 and p16INK4a, reduced telomerase activ-
ity, and mitochondrial DNA damage. By contrast,
in vivo overexpression of JunD rescues vascular aging
features in old mice (93). Mechanistic experiments
revealed that age-associated reductions in JunD
cause an imbalance between oxidant (NADPH oxi-
dase) and scavenger enzymes (namely, manganese
superoxide dismutase and aldehyde dehydrogenase
2), leading to early redox changes, mitochondrial
dysfunction, and vascular senescence (93). In accord
with our findings, lack of JunD promotes pressure
overload-induced apoptosis of myocytes, hypertro-
phic growth, and angiogenesis in the heart (94).
Ongoing screening of chemical libraries aim to iden-
tify compounds capable of restoring JunD activity in
the vasculature and the heart.
The family of nicotinamide adenine dinucleotide-
dependent proteins termed sirtuins have an estab-
lished role in human aging (Figure 2) (9). A recent study
found that endogenous SIRT1 expression in VSMCs
correlated inversely with donor age (95). Age-related
loss of SIRT1 correlated with functional deficits,
diminished stress response, reduced capacity for
migration/proliferation, and increased senescence
(95). Moreover, activation of SIRT1 may promote
preservation of endothelial cell function during aging.
Hypercholesterolemic mice with endothelial-specific
SIRT1 overexpression or those exposed chronically to
a SIRT1 activator exhibit attenuated atherogenesis,
whereas reduced SIRT1 activity results in greater foam
cell formation and atherosclerosis (96–98). The
observation that immunosuppressant drugs (i.e.,
sirolimus and everolimus) cause endothelial senes-
cence via SIRT1 inhibition supports these results (99).
SIRT1 blockade also impairs eNOS functionality,
whereas its activation improves endothelial NO avail-
ability (100). Moreover, microRNA-217, an endogenous
SIRT1 inhibitor, triggers endothelial senescence by
suppressing SIRT1-dependent eNOS functionality
(101). Recent work identified SIRT1 as a master
JACC VOL. 69, NO. 15, 2017
APRIL 18, 2017:1952–67
regulator of p66 Shc transcription, controlling acetyla-
tion of histone H3 bound to the p66Shc promoter (102).
Impaired SIRT1 activity also favors acetylation of
NF- kB p65, leading to its nuclear translocation and
transcription of inflammatory genes, as described
earlier (103). Moreover, SIRT1 represses detrimental
pathways of arterial aging, such as Forkhead box O
(FOXO) 1, 3, and 4, thus preventing DNA damage, cell
cycle arrest, and oxidative stress (104). SIRT1 deace-
tylates LKB1, leading to activation of the final effector
enzyme 5 0 adenosine monophosphate-activated pro-
tein kinase, a central energy regulator involved in
glucose homeostasis, maintenance of cellular adeno-
sine triphosphate levels, and endothelial integrity
via regulation of eNOS activity and autophagy
(Figure 2) (105).
Klotho has also emerged as an important antiaging
gene (106). Klotho protein functions as a circulating
hormone that binds to a cell-surface receptor, and
represses intracellular signals of insulin and insulin-
like growth factor 1, key molecules preserving
longevity (107). Genetic deletion of Klotho in mice
associates with premature aging features, including
vascular calcification, altered calcium/phosphate
metabolism, and reduced lifespan (108). By contrast,
Klotho overexpression prolongs lifespan in mice and
protects against age-related CV and renal impairment
(109). Of clinical relevance, higher plasma Klotho
levels associate independently with a lower likeli-
hood of CVD in humans, whereas low serum Klotho
concentrations independently predict coronary artery
disease and arterial stiffness (106). Validation of
Klotho as a clinically useful biomarker and a thera-
peutic target to counteract age-related CVD requires
further study.
GENOMIC INSTABILITY. Accumulation of genetic
damage through the course of life likely contributes
importantly to aging (Central Illustration). Genome
alterations fall into 3 main categories: 1) chemical
damage to genomic DNA; 2) mutations (e.g., addition,
deletion, or substitution of bits of genetic code); and
3) epigenetic alterations, which modify gene activity
without affecting DNA sequence. To cope with ge-
netic lesions, organisms have evolved highly profi-
cient DNA repair systems that can, in most cases,
restore the correct base pair sequence (110). Defects in
DNA repair nonetheless occur, and can contribute to
cellular senescence and organ dysfunction (111).
Genomic instability particularly affects the CV system
(112). Hutchinson–Gilford progeria syndrome, char-
acterized by massive nuclear DNA damage, associates
with premature atherosclerosis and CVD, which lead
to fatal MI or stroke by an average age of 13 years
JACC VOL. 69, NO. 15, 2017
APRIL 18, 2017:1952–67
(113). Similarly, mice with genomic instability result-
ing from defective nucleotide excision repair genes
ERCC1 and XPD recapitulate aging features, such as
endothelial cell senescence, vascular stiffness, and
hypertension, at a very young age (114). CV aging in
this setting results mostly from eNOS and sirtuin
deregulation, as well as augmented NADPH oxidase
(114).
Beyond genetic diseases, a growing body of evi-
dence indicates that sporadic genomic mutations
accumulated across the lifetime represent a major
underpinning of CVD (115). Several studies have shown
the presence of DNA damage in both circulating cells of
patients with atherosclerosis and in the plaques
themselves (116). PBMCs from patients with CHD have
chromosomal damage and mitochondrial DNA de-
letions that correlate with disease severity (117).
Similarly, data from the AortaGen Consortium showed
that genetic variation in the nucleotide excision repair
components (namely, a single-nucleotide poly-
morphism [rs2029298] in the promoter region of the
DNA damage-binding protein 2 [DDB2] gene) associ-
ated strongly with carotid-femoral pulse wave velocity
(114). Genomic instability in senescent VSMCs in-
creases phosphodiesterase type 1 (PDE1) expression,
with subsequent impairment of NO/cyclic guanosine
monophosphate signaling and endothelial dysfunc-
tion. Human genetic studies consistently reveal sig-
nificant associations of PDE1A single-nucleotide
polymorphisms with diastolic blood pressure and ca-
rotid intima-media thickness (118). Overall, extensive
evidence shows that genomic damage accompanies CV
aging. With age, humans can accumulate somatic
mutations that give rise to hematopoietic clones
associated not only with myelodysplastic syndromes
and hematologic malignancies, but surprisingly, even
more strongly with CV risk (119). Future research in
this area should unveil new interventions aimed at
preserving genome stability to alleviate age-related
CVD.
CHROMATIN MODIFICATIONS. Although many
studies have focused on the genes that influence ag-
ing, nongenomic regulation of aging has gained
increasing attention. Growing evidence suggests that
epigenetic modifications can derail transcriptional
programs implicated in oxidative stress, inflamma-
tion, angiogenesis, and cellular metabolism, thus
fostering maladaptive pathways and features of
vascular aging (Central Illustration) (120). Epigenetic
modifications acquired during life appear durable and
relatively stable, thus providing a molecular frame-
work through which the environment interacts with
the genome to alter gene expression. Indeed,
Paneni et al. 1961
The Aging Cardiovascular System
epigenetic modifications caused by environmental
stimuli can be inherited, thus contributing to early
senescent traits and CVD in young adults (121).
Chromatin modifications include DNA methylation
and post-translational histone modifications (Central
Illustration). DNA methylation, which involves the
addition of a methyl group to DNA nucleotides, re-
presses gene transcription by affecting chromatin
accessibility to the transcriptional machinery. DNA
methylation progressively decreases with age in mice
and humans, whereas the rate of demethylation as-
sociates inversely with age (122,123). Large-scale
analysis revealed unmethylated or partially methyl-
ated CpG islands in atherosclerotic plaques and leu-
kocytes from both patients and atherosclerosis-prone
mice (124). Changes in DNA methylation localize at
the promoters of several genes, including NOS, es-
trogen receptors, collagen type XV alpha 1 (COL15A1),
and the vascular endothelial growth factor receptor
(VEGFR). Hence, aberrant DNA methylation during
the lifetime results in altered transcription of critical
regulatory genes for the induction of proatherogenic
and senescent cellular functions (125).
Together with DNA-related changes, post-
translational histone modifications, among them
methylation, acetylation, ubiquitination, and phos-
phorylation, may cluster in different patterns to
regulate chromatin architecture. Histone methylation
may result in different chromatin states, depending
on the methylated residue and the number of methyl
groups added (120). Methylation marks on histone
H3 regulate lifespan, as well as vascular homeostasis
(126,127). For example, histone methylation by the
mammalian methyltransferase Set7 regulates endo-
thelial NF- kB signaling, a pivotal modulator of
inflammation and longevity (128,129). In addition,
methylation by Set7 fundamentally regulates key
lifespan determinants heavily involved in the modu-
lation of CV homeostasis, namely SIRT1, FoxO3, and
p53 (130). Set7 expression increases in PBMCs of pa-
tients with type 2 diabetes, and significantly corre-
lates with NF-k B–mediated inflammation, oxidative
stress, and endothelial dysfunction, supporting the
clinical relevance of these observations (131). Histone
deacetylation by SIRT1 may also influence age-related
CV disease. Transgenic overexpression of SIRT1 im-
proves metabolic efficiency and endothelial function
in aged mice (103). SIRT6 can prevent endothelial
dysfunction and atherosclerosis by epigenetic mod-
ulation of multiple atherosclerosis-related genes,
including the proatherogenic gene, tumor necrosis
factor superfamily member 4 (TNFSF4) (132). These
results shed light on how chromatin modifications
may regulate aging-related features, and identify
1962 Paneni et al.
The Aging Cardiovascular System
reversal of epigenetic modifications as an attractive
therapeutic target.
AGE-ASSOCIATED DEFECTS IN
VASCULAR REPAIR
IMPAIRMENT OF ANGIOGENESIS. Elderly individuals
not only have increased incidence of stroke, periph-
eral artery disease, and MI, but also display worsened
outcomes than younger patients. Aged patients with
acute limb ischemia have higher mortality and an
increased rate of limb amputation (133). Moreover,
about 35% to 40% of elderly patients experience
inadequate myocardial reperfusion post-MI, eventu-
ally leading to adverse LV remodeling, heart failure,
and CV death (134). Available evidence strongly
indicates an association of aging with several defects
in angiogenesis. Elderly men display reduced capil-
lary density, which is associated with microvascular
disease, defective eNOS functionality, and impaired
insulin sensitivity (135). Furthermore, senescent
endothelial cells have lower proliferative capacity,
decreased telomerase activity, and reduced produc-
tion of angiogenic growth factors, such as VEGF-A.
Endothelial migration is also impaired, leading to
reduced tube formation (133). Reduced hypoxia-
inducible factor 1 a (HIF1 a ) activity, mainly due to
increased degradation and reduced nuclear trans-
location by importin a , significantly contributes to
age-related impairment of angiogenesis after
ischemia. Interestingly, adenoviral delivery of a
constitutively active form of HIF1 a improved neo-
vascularization and rest pain in patients with critical
limb ischemia, whereas it failed to improve walking
performance in patients with intermittent claudica-
tion (136,137). The activity of PGC-1a , an emerging
transcriptional coactivator that plays an essential role
in hypoxia-driven angiogenesis, also declines with
age (133). Dysregulation of angiogenic pathways is
associated with an age-dependent reduction in the
number and functionality of stem and progenitor
cells (i.e., circulating angiogenic cells [CACs] and
bone marrow [BM]-derived cells) (133). Understand-
ing how aging deteriorates stem cell functionality is
of paramount importance to develop new therapeutic
approaches in this area.
MECHANISMS OF STEM CELL AGING. Recent data
obtained in hematopoietic stem cells (HSCs) indicate
that, by the age of 70 years, clonal diversity collapses,
resulting in the dominance of 1 HSC clone (138). Such
collapse of highly polyclonal into quasi-monotypic
hematopoiesis may influence stem cell competency
during ischemia or infarction. In addition, several
JACC VOL. 69, NO. 15, 2017
APRIL 18, 2017:1952–67
studies have documented a reduced number of BM-
derived cells and CACs in aged patients, as well as
in subjects exposed to modifiable CV risk factors
(139). Features of senescence, such as telomere
shortening, genomic instability, and subsequent cell
cycle arrest, accompany this reduced cell number
(140) (Figure 3). Kushner et al. (141) showed an
approximately 60% decline in telomerase activity in
CACs of older men (56 to 67 years of age). Over-
expression of human telomerase reverse transcrip-
tase in CACs preserved telomerase activity, delayed
cell senescence, and improved age-related CAC
dysfunction in mice with ischemic hind limbs (142).
Increased production of ROS and decreased expres-
sion of antioxidant enzymes also produces senescent
cell changes. Early endothelial progenitor cells (EPCs)
from elderly subjects show reduced activity of the
antioxidant enzyme glutathione peroxidase-1 in
association with enhanced cell apoptosis (143).
Increased angiotensin II may also stimulate ROS
production and cellular senescence in early EPCs
(144). The mobilization of progenitor cells from the
BM, and their homing and engraftment depend upon
a number of angiogenic factors, SDF1/CXCR4 inter-
action, and VEGF (145). We recently showed profound
dysregulation of the aging and longevity genes p66Shc
and JunD in old (as compared with young) EPCs,
promoting mitochondrial oxidative stress and
impairing SDF-1 secretion (146). This study indicates
that altered gene expression trajectories during life
strongly affect stem and progenitor cell functions.
ROLE OF EPIGENETICS. Time-dependent accumula-
tion of adverse epigenetic modifications has emerged
as a potential underpinning of stem cell dysfunction
in aging (Figure 3). Transfer of epigenetic information
(i.e., noncoding RNAs [ncRNAs]), which may occur
either by direct cell-to-cell contact or from the
bloodstream into the cell, may strongly influence
phenotype and cell fate decisions (139). More recent
studies showed that extracellular vesicles, including
microparticles, exosomes, and apoptotic bodies, can
mediate intercellular communication of BM-derived
cells with other cell types, with modification of the
transcriptional profile mediated by ncRNAs (147).
MicroRNA profiling in BM cells from young and aged
mice revealed that miR-10A* and miR-21, and their
common target gene Hmga2, can drive EPC senes-
cence (148). Suppression of those microRNAs in aged
EPCs increased Hmga2 expression and blunted
expression of the senescence genes p16 INK4a/p19 ARF ,
thus ameliorating angiogenic properties. In another
study, miR-34a induced EPC senescence by sup-
pressing SIRT1 (149). These novel data illustrate how
JACC VOL. 69, NO. 15, 2017 Paneni et al. 1963
APRIL 18, 2017:1952–67 The Aging Cardiovascular System

F I G U R E 3 Features of Age-Related Stem Cell Dysfunction and Approaches to Boost Their Therapeutic Potential in Elderly
Patients With CVD

elderly patient
with CVD (MI, HF)
epigenetic changes
“Dysfunctional
BM-derived cells” genomic instability

clonal diversity

telomere shortening

oxidative stress
“aged” bone marrow
inflammation

ex-vivo reprogramming in situ reprogramming

(epigenetic signals, gene therapy) (cardiomyocyte dedifferentiation,
stimulation of endogenous CSC)

intracoronary stem cell reinfusion

Future strategies to ameliorate the efficiency of autologous transplantation may include ex vivo reprogramming of maladaptive pathways, in
situ reprogramming by stimulating cardiomyocyte dedifferentiation, or in situ stimulation of endogenous cardiac stem cells. BM ¼ bone
marrow; CSC ¼ cardiac stem cell; CVD ¼ cardiovascular disease; HF ¼ heart failure; MI ¼ myocardial infarction.

editing the epigenetic landscape of aged EPCs can
furnish a novel mechanism-based approach to pro-
moting vascular repair in elderly patients with CVD.
STEM CELL–BASED THERAPIES. Available evidence
on the CV effects of stem cell-based therapies is
overall very difficult to interpret due to heteroge-
neous populations, and different
approaches. The ACCRUE study (meta-Analysis of
Cell-based CaRdiac stUdiEs), which included ran-
domized trials in patients with a recent acute MI,
revealed that intracoronary cell therapy provided no
benefit, in terms of clinical events or changes in LV
function (150). However, the PreSERVE-AMI trial (A
Prospective Randomized Double Blind
Controlled Phase II Trial of Intra-coronary Infusion of
AMR-001, a Bone Marrow Derived Autologous CD34þ
Selected Cell Product, in Patients With
Myocardial Infarction), the largest study of cell-based
therapy for ST-segment elevation MI completed in
the United States, showed that intracoronary infusion
of autologous CD34 þ cells in patients with ischemic
LV dysfunction may exert favorable, albeit small, cell
dose-dependent effect on LV ejection fraction, infarct
size, and survival after discharge (151). By contrast, in
the SWISS AMI trial (Swiss Multicenter Intracoronary
Stem Cells Study in Acute Myocardial Infarction),
which recruited a similar number of patients, treat-
ment with BM-derived mononuclear cells for either 5
to 7 days or 3 to 4 weeks after acute MI failed to
improve LV function (assessed by cardiac magnetic
resonance imaging) at 12 months (152). Furthermore,
technical a very recent meta-analysis in patients with re-
fractory angina showed that cell-based therapy im-
proves anginal episodes, reduces the use of
antianginal medications, ameliorates exercise toler-
ance and myocardial perfusion, and reduces the risk
of major adverse cardiac events and arrhythmias
compared with maximal medical therapy (153). The
Placebo explanation behind these conflicting and highly
debated results lies in the fact that, in most cases,
“aged” BM cells, which have already traveled down
Acute the aforementioned senescence pathways, are rein-
fused. Moreover, the older recipient organ presents a
diseased milieu whereby activation of several patho-
physiological pathways may hamper the healing po-
tential of stem cells. In this regard, new-generation
approaches should include identification of compe-
tent cells from the BM aspirate, as well as ex vivo
reprogramming of maladaptive pathways and
1964 Paneni et al. JACC VOL. 69, NO. 15, 2017

The Aging Cardiovascular System APRIL 18, 2017:1952–67

epigenetic signals. Of clinical relevance, the growing
understanding of chromatin architecture and meta-
bolism has led to the design of specific compounds
(some already approved by the Food and Drug
Administration and tested in clinical trials) that can
modulate epigenetic modifications, and thereby
restore gene expression.
CONCLUSIONS AND FUTURE PERSPECTIVES
More than 2 decades of dedicated research have
firmly established the concept that increased oxida-
tive stress and inflammation promote CV aging.
However, generalized antioxidant supplementation,
including vitamin E and b-carotene, failed to reduce
CV events in asymptomatic individuals, as well as in
patients at high CV risk (154,155). Anti-inflammatory
interventions, such as anti-TNF a treatments, did
not demonstrate beneficial effects on morbidity
and mortality in patients with chronic heart failure
(156). Despite these disappointing results, emerging
innovative strategies that target ROS, either by
inhibiting specific pro-oxidant enzymes or by aug-
menting endogenous antioxidants, have yielded
some promising preclinical results. Other efforts seek
to develop selective anti-inflammatory agents that
might reduce CVD without disturbing metabolic ho-
meostasis. New molecular targets, such as p66Shc,
JunD, and SIRT1, have gained increasing attention
due to their involvement in essential pathways
regulating ROS production and/or scavenging and
proinflammatory cytokines. Indeed, the SIRT1 acti-
vator SRT2104 has already undergone clinical study
(157). These more targeted and selective in-
terventions merit attention, given the disappoint-
ments encountered with the application of blunt
approaches to limit oxidative stress in humans.
Recent clinical trials have shown that therapeutic
targeting of oxidative stress using ROS scavengers not
only lacks efficacy, but can even prove harmful (82).
Ultimately, from a lifestyle perspective, regimens
such as caloric restriction or regular endurance exer-
cise may attenuate signs of vascular aging by
increasing SIRT1 levels, PGC-1a –dependent mito-
chondrial biogenesis, eNOS functionality, and anti-
oxidant response via enhanced activity of the
transcription factor Nfr-2 (41,158). Translation of the
basic and clinical science reviewed here should pre-
pare us better to confront the burden of CVD in our
growing older population.
ADDRESS FOR CORRESPONDENCE: Prof. Giovanni G.
Camici, Center for Molecular Cardiology, University
of Zurich, Wagistrasse 12, Schlieren CH-8952, Zurich,
Switzerland. E-mail: giovanni.camici@uzh.ch.

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KEY WORDS arterial stiffness,
endothelium, epigenetics, stem cells