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Introduction

The aging state as reflected by the decline of functional capacity and stress resistance is different in every individual and has been referred to as the disablement process [1]. While many definitions for aging have been suggested, there is still no general agreement on the age at which a person becomes old. According to the World Health Organization WHO, senility is defined as the age of >60 years, while in the USA, it is considered as 65 years of age. However, gerontologists have distinguished three subsets of senility: younger older people (60–74 years of age), older people (75–85 years of age) and very old people (>85 years of age) [2]. It is known that the chronological age does not in general represent the “real” age of an individual, the so-called biological age; however, in view of the existing literature on aging for both females and males, individuals at 70 years or older can be considered among the aging population. Older age is considered to be a risk factor for many diseases, including cardiovascular disease (CVD) [3, 4]. Clinical studies have revealed that more than 80 % of all acute myocardial infarction (MI)-related deaths occur in persons aged 65 years or older [5–7] and with each 10-year increase in age, the odds for death in hospital following coronary artery event is augmented by 70 % [8]. In addition, the elderly account for more than 75 % of patients with heart failure and greater than 70 % patients with congestive atrial fibrillation [9]. These data imply that intrinsic cardiac aging per se is a major risk factor for CVD and is defined as slowly progressive age-dependent degeneration and decline in function that increases the vulnerability of the heart to stress [10].

It is estimated that by the year 2035, one in four of the global population will be 65 years of age or older. Thus, in view of the development of aging-associated cardiovascular complications, understanding how the aging process contributes to changes in cardiac structure and function is an enormous challenge for the cardiovascular research community. Indeed, it is difficult to study the exact mechanisms of effects of aging on the heart per se, because many comorbidities, including diabetes, hypertension, and dyslipidemia, exist in older individuals and thus can confound the aging process. In addition, factors that can contribute to the age-induced changes in cardiac structure and function such as ischemia and lack of physical activity should also be considered in defining the mechanisms for reduced function of the aging heart. Likewise, gender (sex hormones) may also have a significant impact on the progression of structural and functional changes in the aging heart. Therefore, distinguishing between the normal aging-induced changes and alterations due to disease is an important step in defining the mechanisms responsible for depressed function of the aging heart.

Aging-Induced Changes in Heart and Their Impact on Cardiac Function

A diverse range of aging-induced morphological and cellular changes has been identified in the senescent heart. Epicardial fat deposition and intracellular lipofuscin deposits appear to be symptomatic aging-induced changes without any overt adverse effects on heart function [11, 12]. On the other hand, aging-induced changes in myofilament activation, gene expression, lower capillary density, denervation, development of cardiac fibrosis, and reduced adrenoceptor sensitivity have been proposed as likely candidates for reduced function of the aging heart [10, 12–15]. Lakatta and Sollott [4] have suggested that changes in cardiac output are developed as an adaptive response to greater arterial stiffening. In the elderly, heart rate has been found to be lower, whereas left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVSV) are increased. These changes are accompanied by elevated left ventricular end-diastolic pressure (LVEDP), decreased maximal rate of pressure development (+dP/dt) and decay (−dP/dt), as well as blunted ejection fraction, indicating a significant impairment of cardiac contractile function and cardiac remodeling in the aging heart [7, 16–19]. It has also been shown that aging-induced cardiomyocyte hypertrophy occurs due to increased hemodynamic load and neurohumoral factors. Myocyte length and volume as well as the amount of collagen in the myocardial tissue progressively increase with senescence. On the other hand, the number of cardiomyocytes in the left ventricle of the aging heart has been reported to be reduced [16, 20] as a consequence of necrosis, apoptosis, impaired autophagic process, and reduced cardiomyocyte renewal [21].

Aerobic capacity in the heart declines with advancing age that is attributable to impaired redistribution of blood flow to working muscles, impaired oxygen extraction per unit muscle, a decrease in muscle mass and increase in body fat [4]. Interestingly, cardiac dysfunction due to aging has been reported to exhibit similar characteristics as of the failing heart due to MI [22]. Although abnormalities in mitochondrial function, oxidative stress, and loss of cytoprotective signaling have been implicated in the phenotype of the aging heart, altered Ca2+-homeostasis seems to play a crucial role in this process, and in fact both these aspects are closely related to each other. Indeed, increased production of mitochondrial reactive oxygen species (ROS) has been shown to result in defects in cardiomyocyte Ca2+-handling and subsequent disturbances in excitation–contraction coupling (ECC), excitation–metabolism coupling (EMC), and excitation–transcription coupling (ETC) (Fig. 26.1). The role of fluctuation of Ca2+ in the pathogenesis of cardiac dysfunction in the aging heart is supported by findings from studies investigating ischemia/reperfusion injury and heart failure, showing that intracellular Ca2+ overload results in mechanical and electrical dysfunction [23, 24]. Thus, impairment of Ca2+-homeostasis may be one of the mechanisms for reduced performance of the aging heart.

Fig. 26.1
figure 1

Defects in cardiomyocyte Ca 2+-handling and subsequent disturbances in excitation-coupling mechanisms leading to heart dysfunction. It is proposed that changes in membrane lipid composition as well as the development of oxidative stress lead to Ca2+-handling abnormalities in the aging heart. Thus, the occurrence of intracellular Ca2+-overload plays a critical role in inducing alterations in gene expression, myocardial metabolism, and cardiac function in the aging heart. ECC excitation–contraction coupling, EMC excitation–metabolism coupling, ETC excitation–transcription coupling

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Altered Ca2+-Homeostasis in the Aged Heart

The kinetics of cellular reactions, which are involved in ECC in the aging heart, has been shown to be reduced. As a consequence, the action potential duration and contraction are prolonged. An increase in the magnitude of L-type Ca2+-current (I Ca) and Ca2+-transient amplitude in the aging heart [25, 26] can contribute to the prolonged relaxation time of cardiomyocytes in the senescent heart. A slower inactivation of I Ca in addition to the reduction in peak transient outward K+ current can provide an explanation of prolonged action potential observed in the aging heart [27, 28]. Interestingly, unlike in male mice, no age-related changes in cardiomyocyte I Ca characteristics were observed in female mice [29]. In contrast, the peak I Ca and integrated Ca2+ entry were significantly greater in aged than in younger cardiomyocytes isolated from female sheep [25]. In addition, molecular studies have also revealed a reduction in the density of L-type Ca2+ channels in the sarcolemmal (SL) membrane of the aging heart [30].

The prolonged relaxation time of the senescent heart may also be related to a transient increase in cytosolic Ca2+ due to diminished sarcoplasmic reticulum (SR) storage that prolongs contractile protein activation. Prolongation of Ca2+ elevation can occur due to the lower protein levels of SR Ca2+-pump (SERCA2) [3, 31] reflecting decline in expression of SERCA2 gene along to a reduced SR Ca2+-pump activity [32–35]. These changes suggest that the lower SR Ca2+-uptake may, in part, explain the impaired relaxation of the senescent heart. In support of this contention, overexpression of SERCA2a in the aging heart has been shown to improve cardiac function [36]. However, it should be pointed out that data regarding the changes in SERCA2 due to aging are not consistent. Although reduced SERCA activity has been reported, the protein levels were found to be unchanged in the aged heart [34, 35]. In addition, recently published data have revealed that despite no changes in SERCA2 protein expression in aged cardiomyocytes, diastolic dysfunction was still evident in C57BL/6 mice [26]. These changes in gene and protein expression of SERCA2 are unlikely to be related to species. Moreover, inconsistencies in SERCA2 density have also been seen in different mice strains (FVB versus C57BL/6). Although similar features were detected in the failing cardiomyocytes from different strains of mice, Western blot analysis revealed different results regarding protein contents [26, 31]. Importantly, Ca2+-calmodulin kinase II (CaMKII)-mediated phosphorylation of phospholamban (PLB), which leads to release of the inhibitory action on the SERCA2, was also significantly decreased by 25–40 % in the aged compared with adult rat hearts. In addition, CaMKII-mediated phosphorylation of Ca2+-release channel or ryanodine receptor (RyR2) was also downregulated with senescence. The total amount of CaMKII was also approximately 50 % lower and the stimulatory effect of calmodulin on Ca2+ uptake was also reduced in the aging heart [34]. This suggests that not only intrinsic properties of the SR Ca2+ regulatory proteins are changed, but their activation by CaMKII is also impaired in the senescent heart.

In addition to SERCA, the Na+–Ca2+ exchanger (NCX) at the SL membrane is considered to be another mechanism for lowering the cytoplasmic concentration of Ca2+. As with other Ca2+-handling proteins, changes of NCX protein in the senescent heart are conflicting. In rats, the cardiac mRNA level for NCX has been found to be initially decreased and then increased with the progression of age [37]. On the other hand, the NCX protein levels have been observed to be downregulated in the hearts failing due to aging [18, 38, 39]. No differences in the gene and protein expression of NCX between young and aged hearts have been reported [15, 31, 33]. A recent study has revealed an age-related increase in NCX (forward mode activity) that may provide an explanation for the late action potential prolongation [40]. From the information available in the literature, it appears that the increase in SL NCX may serve as an adaptive mechanism for lowering the cytoplasmic concentration of Ca2+ at initial stages of aging myocardium, whereas depression in its activity may contribute in the development of intracellular Ca2+-overload at late stages of the aging heart.

Ca2+-release from the SR is mediated by the RyR as well as through the inositol trisphosphate receptor (InsP3R); any changes in their expression and function can cause systolic and diastolic dysfunction. The protein content of the total RyR [41] and its CaMKII-mediated phosphorylated form [34] have been reported to be reduced in the aging heart. In accordance, in senescent rat cardiomyocytes lower Cai 2+-transient amplitude has been observed, which was also correlated with a reduced Ca2+ content in the SR [42]. Likewise, frequency of spontaneous Ca2+ sparks in cardiomyocytes isolated from senescent hearts has been shown to be increased [42, 43]. This would seem to suggest that the increased Ca2+ leak from the SR may explain both systolic and diastolic dysfunction due to a lower Ca2+content available for release and a slower decrease of the Cai 2+ transient, respectively. Although an impaired function of RyR in the aging heart has been reported, it appears to be independent of any age-related differences in gene transcription [33] and protein expression levels [34]. Aging causes an increase in InsP3R mRNA level that has been suggested to account for the age-related enhanced susceptibility of InsP3R to proteolytic degradation that is compensated for by increased synthesis of InsP3R protein through increased InsP3R mRNA [35].

The myocardial abundance of other Ca2+-handling proteins, which regulate Ca2+ homeostasis within the SR (calsequestrin and PLB), is reported to be unchanged during the aging process [34]. On the other hand, the Na+–K+ -ATPase activity and number of ouabain-binding sites in the SL membrane have been found to be decreased in the senescent heart, which was also found to be related to a lower threshold for onset of arrhythmias [44]. Furthermore, the number of ventricular and supraventricular premature beats and the incidence of atrioventricular block are increased in the senescent heart [45]. Although Na+–K+ -ATPase does not directly influence cytosolic Ca2+ levels, inhibition of Na+–K+ -ATPase by cardiac glycosides leads to Ca2+ influx and produces positive inotropic effects. Thus, decreased density of SL Na+–K+ -ATPase could explain cardiac dysfunction and a higher arrhythmogenicity of the aging heart. From the foregoing discussion, it is evident that intrinsic cardiac aging is a complex of Ca2+-dependent events that can underlie impaired mechanical function, increased sensitivity to arrhythmias, and cell death.

Mechanisms Causing Disturbances in Ca2+-Homeostasis due to Advancing Age

Cardiomyocytes of senescent hearts exhibit a reduced threshold for abnormalities due to Ca2+ loading under conditions known to increase Ca2+-influx such as excessive production of catecholamines, reperfusion of postischemic tissue, and oxidative stress [24, 46]. The relative Ca2+ intolerance in the aging heart is mainly caused by changes in the Ca2+ regulatory proteins, which may, in part, be due to altered gene expression, activity, and changes in the membrane composition. It has been shown that with age, the n − 6 polyunsaturated fatty acid (PUFA) content of rat cardiac cell and inner mitochondrial membrane is increased, whereas n − 3 PUFA content is decreased. However, it remains to be demonstrated whether alterations in mitochondrial membrane with respect to PUFA content are responsible for inducing changes in mitochondrial function. Nonetheless, these changes are associated with abnormal cell Ca2+ balance that results in increased Ca2+-dependent arrhythmogenesis during reperfusion following ischemia [47]. In addition to changes in membrane composition, intracellular generation of ROS is likely to contribute to impaired Ca2+-homeostasis as a consequence of alterations in the membrane composition of both SL and SR. In fact, perfusion of isolated rabbit hearts with hydrogen peroxide has been shown to increase cytosolic Ca2+ levels [48]. With respect to the aged hearts, it has been reported that increased ROS formation by mitochondrial electron transport chain or NADPH oxidase promotes a pro-oxidative shift in redox balance [49, 50]. In fact, the content of thiol groups, as a marker of oxidative damage of proteins, has been found to be decreased, while lipid peroxidation measured as conjugated diene formation has been shown to increase in the hearts of senescent rats [51]. On the other hand, it has been shown that lifelong constitutive overexpression of antioxidative enzymes prevents age-dependent diastolic dysfunction indicating that oxidative stress is involved in the pathogenesis of cardiac dysfunction of the aging heart [10, 52]. Thus, it can be postulated that increased production of ROS in the aging heart may interact and damage various cellular components, including Ca2+ regulatory proteins, and thereby contribute to alterations in Ca2+-homeostasis and subsequent Ca2+-dependent events including proteolysis, energy depletion, and cellular necrosis.

Aging-induced ROS production has been associated with depression of SERCA2 activity [53, 54]. Likewise, Rueckschloss et al. [15] have shown increased NADPH oxidase activity and expression, decelerated shortening/relengthening, and the increased amplitude of Ca2+-transients in the aged cardiomyocytes. These changes were accompanied by a reduced Ca2+ sensitivity of myofilaments, but not by altered density of RyR2, PLB, calsequestrin, nor L-type Ca2+-channel, indicating that aging changes the contractile phenotype of cardiomyocytes involving altered Ca2+-homeostasis and myofilament function. Of note, reduced Ca2+ sensitivity of myofilaments of aged cardiomyocytes was reversed by the superoxide scavenger tiron. In addition, pharmacological inhibition of NADPH oxidase by apocynin normalized deceleration of shortening/relengthening of aged cardiomyocytes, clearly indicating a link between superoxide formation, age-dependent alterations in Ca2+-handling and contractility [15]. Although, in this study, a short-term antioxidant treatment attenuated age-dependent alterations in cardiomyocyte mechanical function, the efficacy of antioxidants in older humans to correct cardiac dysfunction is questionable as clinical trials have failed to show consistent beneficial effects of vitamin E on age-induced myocardial changes [55]. In addition to characteristic changes in Ca2+-handling proteins, the increased vulnerability of the senescent heart to stress (ischemic events) may also be linked to a concomitant attenuation of endogenous cytoprotective mechanisms [56, 57].

Potential Interventions Leading to Prevention and Delay of Cardiac Dysfunction due to Age

Interventions that can partially reverse some of the reported changes of the aging heart are summarized in Table 26.1. For example, modification of lifestyle has been shown to improve cardiac function in the elderly. In fact, exercise training of sedentary old mammals produced an upregulation of the SERCA and a faster cardiac relaxation [58]. In addition, it has been suggested that the risk of Ca2+-overload in the senescent heart can be prevented by antioxidants to reduce oxidative stress and by dietary measures to reverse altered membrane composition through normalization of the n − 6 PUFA to n − 3 PUFA ratio [59, 60]. Likewise, caloric restriction (40 % energy reduction) has recently been reported to ameliorate age-associated deterioration in intracellular Ca2+ -handling and enhance autophagy [61]. It has been suggested that caloric restriction can upregulate sirtuins (SIRT). SIRT3, located in the mitochondria, has been found to abolish aging-induced oxidative stress due to activation of MnSOD [59]. In addition, SIRT3 is likely to inhibit cardiomyocyte death because of the modulation of cyclophilin D, a modulatory and structural protein of mitochondrial permeability transition pore (mPTP), the opening of which induces apoptosis. SIRT3 activity progressively declines with the aging process and leads to hyperacetylation of cyclophilin D, which increases mitochondrial permeability transition and thereby induces cardiomyocyte apoptosis [62]. Thus, it appears that activation of SIRT3 is necessary to prevent impairment of mitochondrial function as well as cardiac dysfunction due to aging. Maintenance of endogenous cardioprotective mechanisms, which are activated during preconditioning and postconditioning in a healthy heart but attenuated in the senescent heart [56, 57], may be additional targets to delay aging-induced defects in heart function. In addition, gene therapy, pertaining to normalization of SERCA expression may also be a promising intervention to restore Ca2+ regulatory proteins in the senescent heart. Figure 26.2 summarizes the major consequences of aging-induced Ca2+-overload and a cascade of events that leads to heart dysfunction.

Table 26.1 Interventions that can prevent or delay cardiac aging
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Fig. 26.2
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Mechanisms of Ca 2+-overload induced defects leading to impaired function of the aging heart. The development of cardiac dysfunction in the aging heart is proposed to be occurring due to the development of intracellular Ca2+-overload as a consequence of defects in Ca2+-handling proteins in cardiomyocytes. A wide variety of mechanisms such as apoptosis, necrosis, energy depletion, proteolysis, and arrhythmias are associated with cardiac dysfunction due to intracellular Ca2+-overload

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Conclusion

Understanding the effects of aging on cardiovascular system assumes greater clinical relevance as the global population ages. Although considerable effort has been made to identify the mechanisms of cardiac remodeling and dysfunction in the senescent heart, the molecular basis for such age-related changes is not fully understood. The interpretation of some of the reported changes in the senescent heart is contentious because of limited knowledge on the interaction between age, comorbidities, lifestyle-related risk factors, and diminished intrinsic endogenous cytoprotective mechanisms. Although a number of different mechanisms have been suggested to play a role in the pathogenesis of the aging heart, changes in Ca2+-homeostasis appear to be crucial in the increased sensitivity to the development of myocardial abnormalities. Alterations in Ca2+-handling proteins (Ca2+ channels and Ca2+-pumps located at both SL and SR membranes as well as NCX in the SL membrane) at the molecular level as well as protein density and activity can underlie cardiac systolic and diastolic dysfunction and prolongation of the action potential duration and induce hypertrophic and apoptotic processes. It is assumed that altered Ca2+ homeostasis due to aging is closely related to mitochondrial dysfunction, sensitivity to oxidative stress, and altered membrane composition, and thus detailed insights into these processes might advance our understanding of the biology of senescence. Particularly, alterations in both SR and SL membranes due to oxidative stress may be of critical importance in determining their Ca2+-handling characteristics of aging cardiomyocytes. Such information will be of value for the development of pharmacological interventions to prevent or reduce the higher sensitivity of the aging heart to ischemic injury and failure.