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Aging Clinical and ExperimentalResearch ISSN 1720-8319Volume 25Number 5 Aging Clin Exp Res (2013) 25:487-497DOI 10.1007/s40520-013-0117-7

Molecular aspects of the cardioprotectiveeffect of exercise in the elderly

Giuseppe Rengo, Valentina Parisi,Grazia Daniela Femminella, GennaroPagano, Claudio de Lucia, AlessandroCannavo, Daniela Liccardo, et al.

1 23

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REVIEW ARTICLE

Molecular aspects of the cardioprotective effect of exercisein the elderly

Giuseppe Rengo • Valentina Parisi • Grazia Daniela Femminella • Gennaro Pagano • Claudio de Lucia •

Alessandro Cannavo • Daniela Liccardo • Francesco Giallauria • Oriana Scala • Carmela Zincarelli •

Pasquale Perrone Filardi • Nicola Ferrara • Dario Leosco

Received: 6 November 2012 / Accepted: 9 April 2013 / Published online: 15 August 2013

� Springer International Publishing Switzerland 2013

Abstract Aging is a well-recognized risk factor for sev-

eral different forms of cardiovascular disease. However,

mechanisms by which aging exerts its negative effect on

outcome have been only partially clarified. Numerous

evidence indicate that aging is associated with alterations

of several mechanisms whose integrity confers protective

action on the heart and vasculature. The present review

aims to focus on the beneficial effects of exercise, which

plays a pivotal role in primary and secondary prevention of

cardiovascular diseases, in counteracting age-related dete-

rioration of protective mechanisms that are crucially

involved in the homeostasis of cardiovascular system. In

this regard, animal and human studies indicate that exercise

training is able: (1) to improve the inotropic reserve of the

aging heart through restoration of cardiac b-adrenergic

receptor signaling; (2) to rescue the mechanism of cardiac

preconditioning and angiogenesis whose integrity has been

shown to confer cardioprotection against ischemia and to

improve post-myocardial infarction left ventricular

remodeling; (3) to counteract age-related reduction of

antioxidant systems that is associated to decreased cellular

resistance to reactive oxygen species accumulation.

Moreover, this review also describes the molecular effects

induced by different exercise training protocols (endurance

vs. resistance) in the attempt to better explain what kind of

exercise strategy could be more efficacious to improve

cardiovascular performance in the elderly population.

Keywords Aging � Exercise � Adrenergic receptors �Angiogenesis

Autonomic derangement occurring with aging

Aging parallels many alterations of cardiac autonomic

nervous system observed in heart failure (HF). Exposure to

high catecholamine levels has been shown to facilitate HF

progression and worse prognosis. In particular, cardiac

sympathetic hyperactivation has been shown to be one of

the earliest features of neurohormonal derangement in HF

and the sustained increase of adrenergic drive correlates

with an adverse outcome [1]. Although initially sympa-

thetic hyperactivity aims to preserve cardiac output, an

extensive body of evidence has demonstrated that sympa-

thetic nervous system (SNS) overdrive is, in the long term,

pro-arrhythmic, pro-ischemic, and pro-apoptotic. An

important molecular alteration related to chronic sympa-

thetic overstimulation is represented by cardiac b-adren-

ergic receptor (b-AR) dysfunction [2–7], due to b1-AR

downregulation/desensitization and b2-AR desensitization/

uncoupling. Several evidence indicate that increased levels

of cardiac G protein-coupled receptor kinase-2 (GRK2) are

crucially involved in both b1-AR and b2-AR dysregula-

tion. GRK2 is a serine-threonine kinase that phosphorylates

intracellular domains of activated receptors, leading to the

recruitment of arrestins to the receptors and the attenuation

of intracellular G protein-dependent signaling. Therefore,

GRK2 phosphorylates and uncouples receptors from the

G. Rengo and V. Parisi are co-first authors of this manuscript.

G. Rengo � V. Parisi � G. D. Femminella � G. Pagano �C. de Lucia � A. Cannavo � D. Liccardo � F. Giallauria �O. Scala � C. Zincarelli � P. Perrone Filardi � N. Ferrara �D. Leosco (&)

Dipartimento di Scienze Mediche Traslazionali, Universita degli

Studi di Napoli Federico II, via Sergio Pansini, 5,

80131 Naples, Italy

e-mail: dleosco@unina.it

G. Rengo � C. Zincarelli

Fondazione Salvatore Maugeri, IRCCS, Telese (BN), Italy

123

Aging Clin Exp Res (2013) 25:487–497

DOI 10.1007/s40520-013-0117-7

Author's personal copy

adenylyl cyclase effector system. The overexpression of

this kinase in the heart has a pivotal role in HF patho-

genesis and progression. The relevance of cardiac GRK2

upregulation in failing myocardium is supported by the

observation that its inhibition reverses left ventricular (LV)

remodeling and improves myocardial contractility in the

failing heart [8–15]. It has been also demonstrated that

adrenal gland-specific GRK2 inhibition reverses a-2AR

dysregulation in HF, resulting in decreased plasma cate-

cholamine levels and improved cardiac b-AR signaling and

function [16–22].

Interestingly, myocardial GRK2 level and activity cor-

relate with expression of the kinase in peripheral white

blood cells, since it has been demonstrated that myocardial

GRK2 protein levels mirror those measured in circulating

lymphocytes in HF patients [23].

Noteworthy, similar deterioration of cardiac b-AR sys-

tem has been also described in the aging heart [24–26]

(Fig. 1a). With aging, systemic SNS activity is increased

and cardiac neuronal catecholamine uptake is decreased.

Although alterations in b-AR system are quite comparable

in the failing and aging human heart, a role for GRK2 in

age-related b-AR dysfunction has never been described

[27]. In this vein, animal studies indicate that both b1- and

b2-AR-dependent inotropic reserve are markedly

decreased in the myocardium of old rats as a consequence

of b-AR downregulation and desensitization. There are not

univocal data about the effect of age on cardiac inhibitory

G protein (Gi) levels in both humans and animal models. In

the human heart, Gi levels have been measured in atrial

samples and have been found to be increased with age [28].

Accordingly, age-dependent Gi upregulation has been

documented in animal models. This observation is partic-

ularly relevant, since b2-AR signaling couples to Gi pro-

teins as well as to stimulatory G proteins (Gs) [29]. In

contrast, some authors have reported that neither GRKs nor

Gi proteins appear to contribute to the age-related reduc-

tion in cardiac b-AR responsiveness [27]. This evidence

can be the consequence of a delayed progression of sym-

pathetic activity dysfunction in physiological aging com-

pared to HF [30, 31]. Thus, it is possible to speculate that

timing and intensity of SNS development can explain the

different behavior of GRK level/activity between aging and

failing human hearts.

Effects of exercise on autonomic derangement

occurring with aging

Animal studies

Exercise has been shown to modulate GRK2 levels/activity

by reducing levels of this kinase in the heart and,

consequently, inducing b-AR ‘‘resensitization’’. It has been

previously demonstrated in rats that both exercise and

b-blockers reverse b-AR dysfunction by restoring cardiac

receptor membrane density and G protein-dependent aden-

ylyl cyclase activation [32]. Of note, although cardiac GRK2

levels were not upregulated in old sedentary rats compared to

young sedentary rats, exercise resulted in a significant

reduction of GRK2 activity even at lower levels than those

observed in young controls (Fig. 1b). This latter phenome-

non represents a further demonstration of the beneficial

effects of physical activity on b-AR signaling [32]. Fur-

thermore, Bohm et al. [33] have demonstrated that exercise

can partially reverse depression in cAMP production due to

age-dependent Gi alpha increased expression. More

recently, it has also been demonstrated that exercise training

restores adrenal GRK2-a-2AR-catecholamine production

axis as a part of the mechanism, whereby this therapeutic

modality normalizes SNS overdrive in HF [34].

At vascular level, studies conducted in the aorta and

carotid arteries of old rats [35] have shown a reduced

b-AR-dependent vasorelaxation. Importantly, b-AR dys-

function observed in the aorta [36] and carotids of old rats

[37] is mainly due to GRK2 upregulation that seems to

have a crucial pathogenic role in age-related vascular b-AR

dysfunction. Importantly, exercise shows a therapeutic

effect on age-related impairment of vascular reactivity to

adrenergic stimulation and restores b-AR-dependent

vasodilatation by increasing vascular b-AR responsiveness

and reducing endothelial GRK2 activity [37].

Human studies

The mechanisms involved in the beneficial effects of

exercise on cardiac performance in the elderly are not

completely clarified. In old healthy subjects, it has been

demonstrated that physical training ameliorates age-related

deterioration of cardiac function in terms of enhanced left

ventricular inotropic response to catecholamines [38–40].

Contrasting data have been reported by other authors who

described unchanged left ventricular systolic performance

[41] in response to adrenergic stimulation after training in

the elderly. However, it is important to underline that

exercise training also enhances vagal tone [42], which

could mask the favorable effect of exercise on cardiac

b-adrenergic responsiveness.

Similarly, exercise training attenuates autonomic dys-

function in patients with HF [43] as demonstrated by the

significant reduction in plasma catecholamine levels [44,

45] and cardiac sympathetic nerve activation [46]. Thus,

exercise training is able to curb the detrimental effects of

sustained neurohumoral activation in HF patients, with

positive effects on cardiac function and peripheral vaso-

constriction, ultimately improving exercise tolerance.

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Effects of exercise on age-related impairment

of cardiac preconditioning mechanism

Cardiac preconditioning consists in brief episodes of

myocardial ischemia leading to reduced cellular damage

subsequent to a more prolonged ischemic injury and rep-

resents the strongest form of in vivo protection against

myocardial ischemic injury [47]. The integrity of ischemic

preconditioning in the aging heart is still under debate.

Animal studies

Experimental studies have demonstrated that ischemic

preconditioning is dysfunctional in the aging heart, thus,

Fig. 1 a Figure illustrates

b-AR signaling in

cardiomyocyte membrane of the

aging heart. The age-related

increase of norepinephrine (NE)

levels induces an

hyperstimulation of b-ARs that

activates protective mechanisms

through the cytoplasmic

recruitment of cardiac G

protein-coupled receptor kinase-

2 (GRK2) that phosphorylates

intracellular domains of

activated receptors, leading to

the recruitment of arrestins to

the receptors and the attenuation

of intracellular G protein-

dependent signaling.

Noteworthy, this phenomenon

induces different events

including b-AR endocytosis and

degradation (downregulation)

and uncoupling from the

adenylyl cyclase effector

system. The reduced Protein

Kinase A (PKA) activation from

cyclic AMP leads to blunted

cardiomyocyte contractility.

b Exercise induces a significant

reduction of GRK2 levels in

cardiomyocytes with

consequent reduction of

receptor phosphorylation,

attenuation of b-AR

endocytosis, and restoration of

the normal membrane

transduction signaling to the

downstream molecular

pathways

Aging Clin Exp Res (2013) 25:487–497 489

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resulting in abnormal left ventricular remodeling after

myocardial infarction. In particular, ex vivo experiments

have shown that the beneficial effects of preconditioning

following ischemia and reperfusion injury are not func-

tional in senescent hearts [48]. It has been hypothesized

that the age-related loss of ischemic preconditioning is

caused by a dysfunction of calcium-sensitive potassium

channel in the mitochondria and/or its upstream signaling

pathway represented by protein kinase A [49]. Thus, age-

related impairment of mitochondrial energy production

could contribute to the attenuation of preconditioning

mechanisms observed with aging.

Several studies indicate that exercise is able to coun-

teract the progressive loss of the cardioprotective effect of

ischemic preconditioning partially restoring this mecha-

nism in the heart [50–53]. In this regard, it has also been

reported that exercise training might restore ischemic

preconditioning mechanism in the aging heart by increas-

ing norepinephrine release in response to preconditioning

stimuli [51]. These data confirm previous observations

indicating that exogenous administration of norepinephrine

is able to restore ischemic preconditioning in the aging

heart [49].

Human studies

It is known that aging is associated with high rates of

morbidity after acute myocardial infarction [54, 55]. A

progressive loss in the efficacy of ischemic preconditioning

has been proposed as one of the mechanisms responsible

for worse prognosis after acute coronary syndromes in the

elderly [56–58]. Pre-infarction angina is considered one of

the most reliable clinical equivalents of ischemic precon-

ditioning being associated with both reduction in infarct

size and attenuation of left ventricular dysfunction [59, 60].

However, there are conflicting results on the loss of the

protective effect of pre-infarction angina with age [61, 62].

In fact, some human studies have not found an age-

dependent alteration in ischemic preconditioning with age,

reporting that pre-infarction angina is associated with a

lower rate of in-hospital death, heart failure progression,

and also arrhythmias in elderly patients [63, 64]. In con-

trast, other studies report that in elderly patients, differently

from adult patients, pre-infarction angina does not exert a

protective effect against in-hospital outcomes such as

mortality, cardiogenic shock and the combined end-points.

Nevertheless, in patients with high level of physical

activity, the protective role of pre-infarction angina against

these in-hospital outcomes seems to be preserved [65, 66],

thus indicating another potential explanation for the car-

dioprotective effect of exercise.

Noteworthy, there are numerous evidence suggesting

that other mechanisms may also be involved in the

exercise-induced cardioprotection. In this regard, the

favorable action of exercise on those cellular and molecular

phenomena associated with aging, such as increased oxi-

dative stress and reduced efficiency of mechanisms related

to cellular damages reparation, could play an important

role in restoring a cardioprotective phenotype in elderly

trained subjects [67].

Effects of exercise on age-impaired angiogenesis

Impaired angiogenesis and endothelial dysfunction are rec-

ognized to increase the prevalence of cardiovascular diseases

in the elderly. Adult angiogenesis represents an essential

adaptive response to physiological stress and an endogenous

defence to ischemic injury. In addition, stimulation of

angiogenesis is a promising therapeutic approach for cardiac

and peripheral ischemic diseases. For these reasons, a deeper

understanding of the molecular mechanisms involved in the

age-related impairment of angiogenesis and endothelial

function might have relevant implications for cardiovascular

diseases management and therapy.

Animal studies

It has been demonstrated that several factors involved in

neo-vessel formation, such as hypoxia-inducible factor-1

(HIF-1), peroxisome proliferator-activated receptor-ccoactivator (PGC)-1, and endothelial nitric oxide synthase

(eNOS), interact with multiple age-related pathways, such

as telomerase, sirtuins, and the p16/p19 regulators of cell

senescence [68]. Angiogenesis stimuli increase the

expression of transcription factors or co-activators such as

HIF1 and PCG-1 that, in turn, induce the production of

angiogenic growth factors [69]. In particular, PGC-1-dri-

ven angiogenesis appears to be particularly important in

exercise-induced angiogenesis [70]. Aging is associated

with altered angiogenesis responses to ischemia [68].

Although the link between age and reduced angiogenesis is

not completely clarified, this phenomenon can be explained

by the concurrence of different events: reduced prolifera-

tion of senescent endothelial cells that limits the capacity to

form new functional vascular structures [71]; age-related

increased activity of the cyclin-dependent kinase inhibitors,

p16(Ink4a) and p19(Arf) [72, 73], that is responsible for

decreased VEGF-A production; increased oxidative stress

which negatively affects blood vessel growth and induces

telomere exhaustion [74]. Indeed, redox imbalance can

lead to both telomere-dependent and telomere-independent

cellular senescence, reducing proliferative capacity and

altering endothelial cell function. Superoxides inhibit

angiogenesis acting as nitric oxide scavengers [75],

impairing both endothelium-dependent vasodilation [76]

and collateral vessel formation [77].

490 Aging Clin Exp Res (2013) 25:487–497

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Age-related impairment of angiogenesis could be a

pivotal mechanism explaining the abnormal cardiac

remodeling after acute ischemia observed with aging. In

this regard, impaired macrophage migration inhibitory

factor-AMPK activation has important functional conse-

quences in the post-ischemic senescent hearts, including

reduced recovery of LV contractile function and larger

infarcts [78]. It is also known that HIF-1, a crucial mole-

cule regulating angiogenesis, delays premature senescence

through the activation of migration inhibitory factor (MIF)

in murine embryonic fibroblasts [79]. An age-dependent

decrease in HIF-1 expression has been reported in the

brain, liver, kidney of mice [80], and in hindlimb muscles

of old rats [81].

Altered VEGF/AKT/eNOs pathway, which has an

established key role in the regulation of angiogenesis [82,

83], has also been described as a potential mechanism

leading to blunted angiogenesis with aging. Iemitsu et al.

[84] confirmed previous results indicating an age-related

decrease in VEGF mRNA and protein levels, and reduced

Akt and eNOS activation in the heart. The same authors

have demonstrated that exercise training is able to restore

this pro-angiogenic signaling, thus increasing capillary

density in aging rat hearts. Similarly, in a rat model of post-

ischemic HF, exercise reactivated the cardiac VEGF-

dependent pro-angiogenic pathway and increased coronary

vascular network [85].

Human studies

It is well-established that a relevant role in the angiogenesis

process can be attributed to circulating endothelial pro-

genitor cells (EPCs) number and function. A decline in

circulating EPCs function has been suggested to participate

to the etiology of age-related vascular dysfunction [86, 87].

Exercise increases the number of EPCs in bone marrow,

peripheral blood, and spleen in mice, and upregulates cir-

culating EPCs in patients with coronary artery disease,

probably through enhanced endothelial NO and VEGF

production [88, 89].

Taken together, these results indicate that exercise is

able to restore angiogenic signaling and to increase new

vessels formation in the failing and aging myocardium, as

well as in the skeletal muscle. This effect can induce a

more favorable cardiac remodeling after coronary events,

thus improving cardiovascular outcome in the elderly [90–

94].

Effects of exercise on age-related decrease of cardiac

tolerance to oxidative stress

Aging is a complex process characterized by chronic

damage of molecules, cells, and tissues with important

pathophysiological consequences and characterized by

altered regulation of some genes involved in stress resis-

tance and tissue repair and regeneration. Experimental and

clinical data have demonstrated that aging is characterized

by impaired responsiveness to stress and reduced efficiency

of endogenous protective mechanisms against exalted

oxidative insult [95–97].

Animal studies

Old animals show increased release of glutathione and

decreased release of oxidized glutathione, suggesting that

cardiac oxidative tolerance decreases with age. Ferrara

et al. [97] demonstrated that impairment of left ventricular

systolic and diastolic function, induction of arrhythmias,

release of glutathione, and other abnormalities caused by

oxidant exposure can be prevented through antioxidants

administration. The protective systems involved in anti-

oxidant cellular defence are represented by peroxidase,

superoxide dismutases (SOD), and heat shock proteins

(HSPs). The SOD catalyzes the dismutation of superoxide

into oxygen and hydrogen peroxide during physiological

and pathological conditions, including aging. It has been

demonstrated that the expression and activity of the SOD

system are modified with aging, with reduced cellular

ability to counteract the oxidant molecules, resulting in

increased reactive oxygen species (ROS) accumulation

[98]. Obviously, cytotypes with limited replication ability,

such as brain and heart, are particularly vulnerable to this

phenomenon that could contribute, at least in part, to the

high prevalence of cardiovascular and neurological disor-

ders in the elders. Physical activity increases the expression

and the activity of antioxidant enzymes, with consequent

reduction of ROS accumulation. The favorable effects of

exercise on the aging heart, in terms of antioxidant activity,

could be in part ascribed to a greater expression and

activity of SOD and HSPs. Rinaldi et al. [98] showed that

physical training induced higher levels of SOD and

increased HSP70 and HSP27 expression in trained old rats

compared to sedentary old and young rats. Accordingly,

other studies have reported that training is able to increase

SOD activity in sedentary old rats [99–102]. Physical

activity has been shown to reduce generation of oxidants

during ischemia–reperfusion damage and to exert a pro-

tective role through the activation of the MnSOD scaven-

ger. The relation between aging and accumulation of

oxidatively damaged proteins, lipids, and nucleic acids

explains how a higher resistance to oxidative stress is

associated with increased lifespan [103]. A recent study has

reported the effects of aging and exercise training on Sir-

tuin 1 (SIRT1) activity identifying a pathway linking

SIRT1 to antioxidant response and cell cycle regulation in

rats [104]. In this study, SIRT1 activity was significantly

Aging Clin Exp Res (2013) 25:487–497 491

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reduced in aged rat hearts, together with decreased Mn-

SOD and catalase expression and increased lipid peroxi-

dation. Exercise training significantly increased cardiac

SIRT1 activity, and Mn-SOD and catalase levels, thus,

indicating its ability to promote a recovery in the antioxi-

dant system efficiency of the aged heart.

Human studies

Several evidence indicate that both aerobic and anaerobic

training enhance the antioxidant enzyme activity in various

tissues [105–107]. This adaptive process takes place

because free radicals, produced during muscle contraction,

act as signaling molecules that stimulate gene expression,

increase antioxidant enzymes production, and modulate

other oxidative stress protection pathways [105, 108]. The

type and duration of training are crucial for a significant

upregulation of the endogenous antioxidants, with long-

duration high intensity endurance training being more

effective [109]. Niess et al. [110] reported that trained

individuals present less DNA damage after an exhaustive

bout of exercise compared to untrained men. Other evi-

dence for training adaptation was reported by Miyazaki

et al. [111], which showed that free radicals production was

reduced after 12 weeks of endurance training.

Although the positive effects of exercise in terms of

antioxidant activity are well-established, conflicting results

have been reported on the use of antioxidant vitamins in

older individuals. In several non-randomized observational

studies in different populations, dietary intake or plasma

concentrations of antioxidant vitamins, such as vitamin E,

b-carotene, and vitamin C, were inversely associated with

vascular disease incidence and mortality [112–117]. Sim-

ilar results on atherosclerosis progression [118, 119] and

incidence of vascular disease [120, 121] have been reported

from small randomized trials. However, larger randomized

trials on vitamin E, vitamin C and b-carotene, did not

indicate any benefit ([122–127] Heart protection study).

The results of the heart protection study, that included a

total of 20,536 individuals (with 5,806 aged at least

70 years at study entry), clearly indicated that 5 years of

daily supplementation with 600 mg vitamin E, 250 mg

Table 1 Type of exercise and molecular remodeling with aging

References Study

design

Type of exercise Molecular effects Functional effects

Hambrecht et al. [66] Human MIT : pENOS, : PKB : Endothelial function

Laufs et al. [88] Human MIT ? strength/

resistance

: Circulating EPCs Not explored

Sandri et al. [89] Human MIT : CXCR4, : EPCs : Exercise performance

Giallauria et al. [93] Human MIT ? strength/

resistance

: HMGB1 : LV post-MI remodeling

Leosco et al. [32] Animal MIT Cardiac recovery of b-AR density

and adenylate cyclase activity

: Cardiac inotropic reserve

Bohm et al. [33] Animal MIT : Adenylate cyclase activity Not explored

Leosco et al. [37] Animal HIT ; Endothelial GRK2, : vascular

b-AR density

: Vasorelaxant responses to

adrenergic stimulation

Abete et al. [51] Animal HIT : Cardiac norepinephrine release ; Cardiac post-ischemic

dysfunction

Chinsomboon et al. [70] Animal MIT : PGC-1alpha : Muscle angiogenesis

Iemitsu et al. [84] Animal HIT : eNOS, : PKB, : VEGF : Cardiac angiogenesis

Rinaldi et al. [98] Animal MIT : SOD, : HSP : LV performance

Navarro-Arevalo et al. [99] Animal HIT : SOD Not explored

Gunduz et al. [101] Animal Long-term MIT : SOD Not explored

Ferrara et al. [104] Animal MIT : SIRT1, : Mn-SOD, : Catalase : Cardiac function

Atherton et al. [131] Animal MIT Resistance : Muscle AMPK-PGC-1alpha

: Muscle PKB-TSC2-mTOR

: Muscle mitochondrial

biogenesis

: Muscle growth

Gibala et al. [129] Animal HIT : AMPK-p38 MAPK- PGC-1alpha : Muscle mitochondrial

biogenesis

MIT endurance moderate intensity training, HIT high intensity training, b-AR b-adrenergic receptor, GRK2 G protein-coupled receptor kinase-2,

pENOS phosphorylated endothelial nitric oxide synthase, PKB protein kinase B, PGC-1alpha peroxisome proliferator-activated receptor-ccoactivator-1alpha, VEGF vascular endothelial growth factor, EPCs endothelial progenitor cells, HMGB1 high-mobility group box-1, SOD

superoxide dismutases, HSP heat shock proteins, SIRT1 sirtuin 1, AMPK AMP kinase

492 Aging Clin Exp Res (2013) 25:487–497

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vitamin C, and 20 mg b-carotene, were not associated to

any substantial reduction in heart attacks and strokes [128].

Effects of different exercise protocols on age-related

molecular alterations in the cardiovascular system

(Table 1)

It is known that different kinds of training programs, based

on low or high intensity endurance or strength-resistance

exercise protocols, are associated to different cellular and

molecular responses which are specific for the type of

exercise adopted [129, 130]. In the skeletal muscle,

endurance training activates signaling pathways related to

mitochondrial biogenesis, such as AMP-activated protein

kinase, while resistance training affects mainly the muscle

growth via activation of protein kinase B-Akt signaling

cascade [131]. High intensity interval training is associated

with the activation of the peroxisome proliferator-activated

receptor-coactivator-1, a transcriptional coactivator that

regulates mitochondrial biogenesis [129]. It has been

shown that exercise-related activation of angiogenesis in

striated ischemic muscle is typically related to the intensity

and duration of training. In old rats, a 3-month endurance

exercise program induces cardiac SIRT1 activity increase

and causes a decrease in cyclin D(2) expression, thus

activating antioxidant systems and DNA repair [104].

It is important to underline that most of the data on the

effects of exercise training on cardiovascular performance

in the elderly come from studies in HF patients. The

intensity of exercise training showing the greatest benefi-

cial effects in these patients is still debated. As for car-

diovascular effect, aerobic interval training was found to be

superior to moderate continuous training in a randomized

study [132] and was associated with reverse left ventricular

remodeling and decreased pro-brain natriuretic peptide

levels. A growing body of evidence suggests that resistance

training prevents age-related skeletal muscle mass and

function decline [133] and regular vigorous resistance

training results in a shift from fatigue-prone type II fibers to

fatigue-resistant type I fibers in patients with cardiovas-

cular disease with skeletal muscle myopathy [134].

However, also regular leisure-time physical activity,

such as regular walking and weekend recreation, produces

benefits in the elderly. Reports from the British Regional

Heart Study have shown that light to moderate physical

activity in men aged 60 and over results in a significant

decrease in cardiovascular mortality [135].

Conclusions

This review has focused on the mechanisms underlying the

effects of exercise training at counterbalancing age-related

loss of cardiovascular homeostasis. Recovery of cardiac b-

AR signaling and function, myocardial ischemic precon-

ditioning, more efficient angiogenesis responses to ische-

mia, and oxidative stress reduction represent all putative

mechanisms by which exercise may contribute to increase

defences to stressors in the senescent cardiac and vascular

system. Obviously, most of the data on cellular and

molecular effects of exercise come from studies conducted

in aged animals, thus extrapolations to humans need criti-

cal and cautious evaluations. To this aim, further studies

exploring the type and levels of physical activity required

to obtain an adequate cardioprotection in the elderly are

needed. In this way, it will be possible to develop primary

and secondary prevention strategies based on the imple-

mentation of exercise training programs in this high-risk

population.

Conflict of interest None.

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