What Is The Mechanism That Causes The Drop Of The Maximal Heart Rate During Normal Aging?

Gahlul S, Hofmann P, Morris G and Hoffmeister M

Published on: 2021-05-29



Aging reduces exercise capacity because of a general decline of body functions including the functions of the cardiovascular system. A major change is an age-dependent near linear decrease of maximal heart rate (HRmax).


In this narrative review, we highlight putative mechanisms causing the age-related decline in the HRmax.


The exact molecular mechanisms causing HRmax to decline with normal aging are unknown. Possible mechanisms responsible for the functional changes in the aging heart are:

  • Anatomical and structural changes,
  • Electrophysiological changes such as a decline in intrinsic heart rate and beta-adrenergic responsiveness and
  • Changes in the rate of gene expression in human cardiac tissue. All these contribute to the age-dependent reduction of HRmax and consequently the decrease of the aerobic power (VO2max). Regular exercise is suggested to affect at least some of the prescribed influences on the age-related HRmax


Cardio-respiratory fitness, an important predictor of morbidity and mortality declines with normal aging partly due to the decline of the HRmax. However, the molecular mechanisms are unknown and to date there is no intervention with the potential to reverse this age-related decline in HRmax. Possible effects of exercise training are suggested but need to be proven.


Aging; Cardiac physiology; Molecular mechanisms; Maximal heart rate; Exercise training

Introduction and Aims

Aging is a continuous decline of physiological functions increasing morbidity and mortality [1]. One major component is the reduction of cardiorespiratory fitness (CRF) which was shown to be highly related to health [2,3]. Aging induces, beside other function declines, a progressive impairment of heart functions, including stroke volume, ejection fraction and cardiac output. Such impairment of cardiac functions with aging was prescribed to be a result of structural remodeling and changed Ca+2 handling. The rate of programmed cell death in the left ventricle increases with advancing age, and contributes to a 30% reduction in myocytes [4]. These contribute at least in part to the age-dependent decline in HRmax. Additionally, the decline of HRmax with aging was shown to be related to a reduced beta-adrenergic responsiveness but was mainly explained by a reduction in intrinsic heart rate [5]. Furthermore, the decline in HRmax with age is the main cause of the reduction of cardiac output and subsequently VO2max [6,7]. which declines by about 0.24 l/min per year (about ≈1%) [7,8]. However, despite their importance, the mechanisms responsible for the decrease in HRmax with aging remain incompletely illustrated [5].

Several authors prescribed the age-related changes in HRmax. A calculated trend line equation based on measured HRmax data has been presented by Tanaka [9]. which is shown in Figure 1. The decline in HRmax was shown not to be substantially influenced by gender, lifestyle, or physical activity in most studies [10-12]. or BMI and smoking status (Nes et al. 2013) although earlier studies showed an influence of cardiorespiratory fitness also [13]. A recent study by Birnbaumer [14]. supported such a fitness effect in a large age-heterogenous group of both male and female healthy subjects who presented higher HRmax values with higher CRF independent of age.

Figure 1: Decline in maximal heart rate with aging in male (m) and female (f) groups with different levels of cardio-respiratory fitness (adapted from Ozemek C, Whaley MH, Finch WH, Kaminsky LA.: Maximal heart rate declines linearly with age independent of cardiorespiratory fitness levels.

In order to prescribe the decrease of HRmax a trend line-based formula “HRmax = 208 - 0.7 x age” [9,11] has been presented. These data are supported by actual results showing a linear but somehow stronger decrease of HRmax with age in male (HRmax = 212–0,93∗ age, r = 0.82) and female (HRmax = 205–0.85∗ age, r = 0.80) healthy untrained subjects. HRmax declined from 191 ± 9 bpm (male) and 185 ± 7 bpm (female) in the youngest age group down to 133 ± 8 bpm (male) and 128 ± 9 bpm (female) in the oldest age group [14]. According to the Tanaka estimate, 20-year-old individuals show a comparable mean HRmax of 194 beats/ min, but the decrease was smaller down to 151 at 80 years of age.

Older healthy individuals present a reduction in sub-maximal and maximal work capacity which starts at about 50 years of age. However, the assessment of the lower 25%-quartile of Pmax still revealed 102 ± 6% (male) and 103 ± 12 (female) of age-related normal Pmax [14]. This age-related decline of maximal performance in male and female subjects is caused by reduced chronotropic and inotropic characteristics of the heart [15]. Additionally, Hossack and Bruce [16] reported that in younger men the normal range of heart rate was higher compared to women, but due to a stronger reduction in men, higher heart rates were present in older women compared to age-matched men. On the other hand, some investigations showed that females had an increased parasympathetic and a decreased sympathetic heart rate control as well as lower baroreflex sensitivity [17]. The recent study by Birnbaumer [14]. Showed sex dependent differences in the pattern of the heart rate curve which was suggested to be caused by differences in ß-adrenergic receptor sensitivity between male and female subjects.

Whilst this functionally important drop of the HRmax with aging is now well described, there has been little progress towards identifying the molecular mechanisms responsible for it. This is a clear gap with respect to one of the most important phenomena of the age-related decline in exercise capacity. It is clear evidence that exercise training has beneficial influences on cardiovascular risk, and directly affects cellular and molecular remodeling of the heart [18]. It additionally induces exercise intensity and duration dependent cardiovascular and metabolic changes (De Angelis et al. 2004). In addition, exercise training provides meaningful protection against cardiac cell death [4]. Additionally, Ozemek [13]. Evidenced, that high or moderate cardiorespiratory fitness maintenance slowed the age-related decline of HRmax in both male and female subjects, supported by recent data presented by Birnbaumer [14].

The aim of this narrative review is therefore to explore the molecular, cellular and physiological mechanisms explaining the decline of HRmax with normal aging. At first, we discuss the heart rate regulation during rest and exercise and secondly, we review putative mechanisms contributing to the decline in HRmax with advancing age. A third part addresses the possibilities of exercise training to slow the decline of the maximal heart rate during normal aging.

How Is Heart Rate Regulated At Rest And During Exercise?

The cardiac conduction system is comprised of the pacemaker sinoatrial node (SAN), the atrio-ventricular nodes (AV) and the His-Purkinje system [19]. A healthy heart conducts the SAN action potential to the periphery in 3 steps. First, action potential starts from the center of the leading pacemaker SAN [20,21] and spreads to the periphery [22,23]. Then the electrical impulse (action potential) propagates via the atrial muscle to the atrio-ventricular Node (AV node) and then by the HIS Bundle to the Purkinje fibers [24,25] activating the ventricles in a rapid and coordinated fashion, assisted by the presence of specialized cellular electrical gap junctions [22]. All these action through several physiological and molecular mechanisms. For instance, action potentials in contractile cardiomyocytes initiate by opening of sodium channels [26]. The sodium ion influx through voltage?gated cardiac sodium channels was prescribed to be responsible for an initial fast increase of the cardiac action potential, triggering the myocardial initiation and propagation of action potentials. Cardiac sodium channels play therefore a key role for the excitability of the myocardium and adequate conduction of electrical impulses within the heart [27].

The autonomic nervous system regulates heart rate primarily by actions via sympathetic and parasympathetic branches on sinus node autorhythmic control. At rest, parasympathetic activity is dominant and is progressively inhibited with the start of exercise up to a first threshold of intensity where sympathetic activity starts to increase when exercise intensity further increases [28].

For basic anatomy and physiology of the sinoatrial node as the primary pacemaker of the heart the readers are referred to a review by Monfredi [29]. These also authors discussed dysfunctions of SAN with aging or endurance training as well as pathological changes such as heart failure or atrial fibrillation presenting a variety of clinical syndromes.

Beta-adrenergic receptors also contribute to activity of the SAN pacemaker [22,30]. However, it was suggested that the age-dependent declines in HRmax and left ventricular contractility during vigorous exercise are manifestations of a decrease of beta-adrenergic responsivity with aging which is partly compensated by exercise-generated ventricular dilation [31]. In the SAN, increasing heart rate engages hyperpolarization-activated cyclic nucleotide-gated ion channel (HCN4) by stimulation of beta-adrenergic receptor agonist (fight or flight). The action potential conduction time through cardiac tissues depends on number and type of gap junctions present between adjacent cells, which are controlled by the Connexin protein synthesis rate versus the degradation rate [32].

By What Mechanism Does Normal Aging Reduce Hrmax?

Several causes for the decrease in the maximal heart rate have been discussed. These are typically anatomical and physiological changes for which the molecular causes are unknown. Table 1a shows selected articles on age-related changes in the anatomy and structure, electrophysiology, and the decline of the intrinsic heart rate and the responsiveness to beta-adrenergic stimuli. Table 1b shows selected articles on age-related changes in the rate of the gene expression and the decline of the intrinsic heart rate, and Pacemaker activity.

Table 1: Age-related changes in gene expression, pacemaker activity, anatomy and structure, electrophysiology, and the decline of the intrinsic heart rate as well as the responsiveness to beta-adrenergic stimuli.


Change with aging

Effect of the aging change on Heart rate




41% and 51% decrease in nodal cells in 12- and 18-month-old rats. The mean volume of the nodal cell was decreased by 17% from 3- to 12-month old rats. changes in the cell and fiber content of the Sinoatrial Node (SAN)

Slowing of the heart rate

Twenty-one rat hearts, in 3 different groups:3-, 12- and 18-month old



Regional conduction slowing, sinus node dysfunction, increase in the atrial effective refractory period (ERP), anatomical and structural changes

Slowing of the heart rate, increase of the propensity to atrial fibrillation (AF)

Group A= 13 patients (66.4 ± 1.7 years) group B= 13 patients (50 ± 2.1 years) and group C= 15 patients (24.7 ± 1.0 years).



Decrease in chronotropic -adrenergic responsiveness and intrinsic heart rate

Reduction in intrinsic and maximum heart rate and VO2max

Healthy humans



Structural remodeling of the SAN, enlargement of the SAN, hypertrophy of the SAN cells, remodeling of the extracellular matrix, change in the position of the leading pacemaker site, lacking the expression of Nav1.5

Decline in SAN function, Slowing in the pacemaker action potential, drop in the intrinsic heart rate

Right atrial preparations from male Wistar-Hanover rats aged 3 and 24 months (equivalent to young adult and ∼69-year-old humans



Abolished ICa,T-Type in nodal cells

Bradycardia in vivo, slowed intrinsic heart rate in vivo, prolonged sinus node recovery time, and slowed pacemaking in vitro

Wild-type and Cav3.1/ mice.



Reduced beta-adrenergic responsivity

Decline in maximal HR and left ventricular contractility during vigorous exercise

Human, healthy men 28 to 72 years



Cycle length increases with age in both the rabbit and cat SA node enlargement of the area with low phase 0 upstroke velocities

Sinoatrial conduction time increases in both rabbit and cat, nodal action potential duration increases

Rabbits (2 days–5.6 years) and cats (6 weeks–1.8 years)



Slowing in the inward current, carried by Ca2+, decrease in action potential amplitude, maximum upstroke velocity of phase 0

Slowing of the conduction system

Normal beagle dogs of five age groups



Diminished spontaneous excitability of SA myocytes, decrease the set of action potential parameters, changes in the membrane currents, ICa L-type and ICa T-type decreased

Changes in the AP wave form, and decreased SAN cell firing rate and heart rate.

Three different age groups 2-3, 21-24 and 32+ months Mice corresponding to 17-20, 65-69 and 87+ years in humans



Loss of Cx43 protein in the SA node

Altering the conduction properties of the SA node and contribute towards the reduced function of the aged SA node

Guinea-pigs between birth to 38 months of age



Decline in the Cav1.2 channel protein and reduced spontaneous activity of the SA node

Age-related deterioration of the cardiac pacemaker

Guinea pigs between birth and 38 months of age



Reduction in Co

50% reduction in Cx43 protein expression, leading to a significant reduction of ventricular conduction velocity and reduction in electrical coupling

Heterozygous Cx43+/− mice,


nnexin 43 (CX43) protein expression

in comparison to wild-type mice


Structural remodeling of the SAN (SAN), enlargement of the SAN, hypertrophy of the SAN cells, remodeling of the extracellular matrix, change in the position of the leading pacemaker site, reduced expression of Nav1.5

Decline in SAN function, Slowing in the pacemaker action potential, drop in the intrinsic heart rate

Right atrial preparations from male Wistar-Hanover rats aged 3 and 24 months (equivalent to young adult and ∼69-year-old humans



Decline in the cardiac sodium channel Nav1.5 expression

Impaired action potential propagation, conduction block, re-entrant arrhythmias, prolonging the duration of the RR interval, P-wave, PR interval, QT interval

Adult Scn5a ± mice and Wild-Type mice


in homozygous Scn5a ± mice,


Decrease in ryanodine receptor RYR2 mRNA and K+ channels, increase in SERCA2a protein in the SAN, increase in Na+–K+ pump isoforms (α2 and α3) in the SAN. Changes in the Genes expression (Nav1.5, Navβ1, Cav1.2, Cavα2δ3, Kv1.5), Cx30.2, Kir3.4, RYR2, HCN1 and TASK1

Prolonging of the Action potential of SAN, slowing of the intrinsic heart rate, increase in SAN conduction time and decrease in parasympathetic regulation.

Three- and 25-month-old Wistar-Hannover rats



Decrease in D307H CASQ2 protein expression and changes in the SERCA gene activity

abnormal Ca2+ release, arrhythmia in the whole heart

mutation (D307H) or CASQ2 (KO) and wild type (WT) Mice


Anatomical and Structural Changes

Aging changes the SAN but the molecular mechanisms are unknown. The older heart hypertrophies slightly [43] and responds less to sympathetic stimuli, so that the increases in heart rate and myocardial contractility induced by exercise are blunted in aged hearts [44]. Furthermore, the number of SAN myocytes of rats decreased [33,35], but each SAN myocyte became larger [35]. These changes are suggested to cause a decline of SAN function [34] and slows the action potential in humans [37]. In addition, aging decreases atrial voltage with particular low voltage areas, prolongs conduction time, and causes a sinus node dysfunction [34]. The cell and fiber content of the SAN is modified resulting in slowing heart rate [6,33], (Table.1). However, aging did not cause cardiac myocytes loss or myocytes cellular hypertrophy in women, which indicates a minor role of sex differences for harmful effects of aging on the heart (Olivetti et al. 1995). The average relative collagen amount in the human SAN was shown to increase from 38% in young to 70% in old subjects [45]. Furthermore the age-dependent increase of the surface area of pacemaker tissue is associated with the slowing of the action potential in rabbit and cat [37] which was shown to be responsible for the drop in SAN function [46]. Finally, an age-related transition in the location of the pacemaker leading site from near the superior vena cava in young animals to the inferior vena cava in old animals was presented (Figure 3). These changes result in an action potential duration increase and a decline of the SAN function caused by the loss of nodal cells [35] from cell death by apoptosis [47,48].

Figure 2: Right atrial activation is altered in sinoatrial node (SAN disease. The importance of electrical remodeling is illustrated by the similarities between human idiopathic SND and SND in mice with abnormalities of the Ca2+ clock [55] reproduced with permission from the Japanese circulation society.

(A) In a patient with SND earliest activity (red) occurred at an inferior location and over a greater extent of the CT and there was conduction velocity slowing across the atrium and SAN pacemaker complex. Bipolar voltage mapping.

(B) Demonstrates large areas of low voltage (red), multiple double potentials (blue dots) and fractionated signals (red dots), indicating slowed conduction across the pacemaker complex and adjacent RA [34].

(C) CSQ2−/− mice have an abnormal Ca2+ clock (see Figure 3) and this results in remodeling of the SAN pacemaker complex with wide distribution and inferior shift of the leading pacemaker (black dots, basal conditions; red dots, isoprenaline; white dots, acetylcholine).

(D) Conduction slowing is also observed in the CSQ2−/− mice (D, white asterisk denotes pacing site). AVJ, atrioventricular junction; CS, coronary sinus; CSQ2−/−, homozygous calsequestrin 2 deletion; LAA, left atrial appendage; LV/RV, left/ right ventricle; WT, wild type [55] reproduced with permission from the Japanese circulation society.

Electrophysiological Changes with Aging

As mentioned above, in the human SAN there is a relative increase in the amount of collagen with aging [45] and the age-related increase of the surface area of pacemaker tissue causes a slowing of action potential in rabbit and cat [37]. This was shown to be responsible for the drop in SAN function [46]. Furthermore, the spontaneous activity of SAN myocytes is depressed with aging in mice due to age-related changes of membrane properties within the SAN cell. Therefore the main reason for the drop of HRmax additionally to the decline of intrinsic heart rate (HRI) and the responsivity to beta-adrenergic stimuli is the change in the activity of ion-channels within SAN [6]. As the main source of Ca2+ influx to initiate cardiac excitation-contraction coupling voltage-gated L-type Ca2+ channels have been prescribed [49]. A down-regulation of Ca2+ channels was suggested to contribute aged SAN myocyte hypertrophy by a reduced Ca2+ flux through L-type channels known to regulate cardiac gene expression [6,49], see Table. 1).

The ion channel and Ca2+ clock genes expression changes in the aged SAN and these changes partially clarify the decline in pacemaker function with aging [41]. Furthermore, the SAN tissue conductivity presents a sensitive balance and depends on the level of coupling between the pacemaker cells [32]. In an earlier study, Kucera [50] reported, that the slowing of cardiac tissue conduction with aging is controlled by one or a combination of the following three mechanisms, explaining slow conduction under physiological and pathological conditions: (I) decrease of excitability and inward calcium current (ICa)–dependent propagation, (II) decrease of intercellular coupling, and (III) mismatch of impedance and wave front curvature which was suggested to be caused by specific tissue structures or appearing in continued excitable media.

Additionally, gap junction (connexin) plays a central role in the electrical coupling between myocytes [51]. Aging changes the conduction velocity of action potentials in guinea-pigs and this is probably partially caused by a loss of Connexin43 (Cx43) protein [32]. A 50% decline of Cx43 caused a significant slowing in the ventricular conduction in aged mice. This reduction had no effect on the atrial conduction. Connexin40 (Cx40), expressed on the atrium is suggested a major electrical coupling protein in atrial muscle [39]. Investigations of Cx43-deficient mice showed that declined Cx43 protein expression reduced electrical coupling, slowed conduction and accelerated the onset, the duration and the number of arrhythmias [32]. In addition, Jones and Lancaster [52] examined the relationship between elevated levels of c-jun N-terminal kinase (JNK) and the loss of the Cx43 protein with aging, utilizing the right atria from aged guinea pigs between 1 day and 38 months of age. The authors demonstrated that increased levels of activated JNK are responsible for the loss of Cx43 with aging, which results an impaired conduction and contributes to an increased risk for atrial arrhythmias with increasing age [52]. The inactivation of JNK expression within the SAN however, was suggested to upregulate Cx43 expression and as an alternative, viral gene transfer therapy may be used to upregulate Cx43 expression to restore SAN function of older patients [32,53].

Figure 3: Molecular basis of sinoatrial node (SAN) pacemaking and disease [55] reproduced with permission from the Japanese circulation society.

(A) Representative action potentials for the atrial myocardium (green) and central SAN (red). The temporal contributions of the main membrane and calcium currents to the diastolic depolarization are shown by the black bars [54].

(B) Schematic representation of a SAN cell with central pacemaker currents, cyclic adenosine monophosphate (cAMP) and regulatory mechanisms. Pacemaking by the SAN cell depends on the membrane clock (black symbols) and the Ca2+ clock (green symbols) shown on the left. Points of entrainment (ie, processes that contribute to both the membrane and Ca2+ clocks) are shown in both black and green. The funny current (If) and decay of the inward rectifier current (Ik) are primarily responsible for the membrane clock and early phase 4 depolarization. Influx of Ca2+ through the T-type Ca2+ channel (Ica,T) and release of Ca2+ via ryanodine receptor 2 (RYR2) from the sarcoplasmic reticulum (SR) activates INCX. Calsequestrin (CSQ) regulates Ca2+ release from the SR by binding Ca2+ and also by inhibiting RYR2. The Ca2+ clock is reset by pumping of Ca2+ into the SR by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2). Normal pacemaker function is dependent on high levels of protein phosphorylation (blue symbols in center). Constitutively active adenylate cyclase produces cAMP, which binds directly to HCN channels to enhance If Protein kinase A (PKA) is activated by cAMP binding, which acts in parallel with Ca2+/calmodulin-dependent protein kinase II (CaMKII) to phosphorylate and modulate the function of the target ion channels (blue stars). Under normal conditions this process is regulated by high phosphodiesterase activity that acts to reduce and control phosphorylation levels (not shown). These opposing pathways facilitate rapid heart rate variation. Regulatory pathways are shown on the right (afferent limb in red, efferent limb in purple). Angiotensin II elevates reactive oxygen species (ROS) within SAN cells via activation of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase). ROS directly and permanently activates CamKII (double red arrow) independent of calmodulin and cellular Ca2+ by oxidation and this causes cellular apoptosis, fibrosis and down regulation of HCN4.35 Popeye domain proteins (Popdc 1/2) bind cAMP and are protective against pathological bradycardia.96 The transcription factors Tbx3, Tbx18, Med2c, and Sp1 and the micro-RNA miR1 are known to control HCN4 expression, but the interaction between these and the afferent pathways is not known.” [55] reproduced with permission from the Japanese circulation society.


Gene Expression

It is well known, that aging decreases SAN function in humans and other mammals. This is evidenced by a decline in the intrinsic heart rate and slowing of sinus node conduction velocity [46,41]. The slower upstroke action potential of the SAN is caused by SAN tissue lacks in the inward sodium current INa and cardiac sodium Channel Nav1.5, which appears with aging or mutation [35]. The age-dependent changes in the SAN were suggested to be the result of ion channels and gap junction changes [46]. Remodeling of the expression of gap junctions, which occurs during aging can change the conduction properties of the SAN and affects towards a declined function of the aged SAN [32]. The changes in gene levels in old animal could be responsible for the decline in the intrinsic HR (RYR2), the decrease in parasympathetic regulation (Kir3.4), as well as an increase in SAN conduction time (Cx30.2) and SAN action potential duration (Nav1.5 and Cav1.2) [41].

Table 2: Overview of Genes and Electrical Remodeling suggested for some causes of Sinus Node Dysfunction (SND) (adapted from Choudhury et al. [56]).

Causes for SND

Involved Ion Channels and genes


↓Navv1.5, ↓Cx43, ↓Cav1.2, ↓RYR2, ↓HCN1, ↓HCN4

Atrial tachyarrhythmia

↓HCN2, ↓HCN4


HCN4, SCN5A (Nav1.5), RYR2, CASQ2, ANKB

Exercise training

↓HCN4, ↓Tbx3

Heart failure


The inherited genes are mutations seen in human families with sinus node dysfunction (SND), whereas in other types of SND electrical remodeling was seen in animal models. Downward arrows mean downregulation.

It has been argued that the presence of SCN5A cardiac sodium gene encoding the sodium ion channel Nav1.5 and Na+ Inward current (Ina) in the node periphery is significant for the ability of the node to drive the circumjacent atrial muscle [46]. This influences the cardiac conduction and other cardiovascular and electrophysiological phenotypes [57]. However, this effect can be age dependent, and SCN5A gene defects were shown to be associated with age-related diseases of cardiac conduction [58]. SCN5A gene mutations lead to a dysfunction in the sodium channel, which are important for the initial fast upstroke of the cardiac action potential [27,59] demonstrated a slightly affected conduction related to a 50% decline of SCN5A expression or age-related interstitial fibrosis, and a reduced SCN5A expression. These changes were accompanied by reactive fibrosis and disarrangement of gap junctions (connexin) in aged heterozygous mice, which resulted severe conduction impairment. Additionally, sinus node dysfunction and age-dependent degeneration of sinus node tissue was shown in mice with a heterozygous SCN5A mutation [58], as well as age-related lengthening of the conduction time [59]. The slower conduction velocity in the rabbit SAN periphery was caused by a loss of INa from the periphery during aging [46].

The cardiac sodium gene SCN10A encoding the Nav1.8 sodium channel, which is expressed in mouse and human cardiac tissue [57], displays in both ventricular myocardium and conduction fibers. A selective SCN10A inhibitor, corresponding to the depolarization of the right and left ventricles, prolongs conduction time [51]. SCN10a affects cardiac conduction directly via cardiomyocytes and indirectly through neurons [60]. In this regard, SCN10a can also perform as an enhancer of SCN5a gene expression [61]. SCN10a-mice indicated shorter PR interval (atrial and atrio-ventricular nodal conduction) than the wild-type mice [57]. Complementary, Yang and colleagues (2012) argued, that, the gene expression in mouse and human heart indicated shorter PR interval and no effect on QRS duration in SCN10a-/- mice. Contrary, a QRS meta-analysis reported that the Nav1.8 blocker A-803467 prolonged both PR and QRS in wild-type mice and that the gene was expressed in heart and highly enriched in cells isolated from the conduction system [26].

Regarding calcium handling protein, there are candidate genes relevant for cardiac conduction system, which are exactly associated with QRS duration. The gene calsequestrin 2 (CASQ2) is responsible for the opening of the ryanodine receptor (RYR2) [51], which plays a major role in the intracellular sarcoplasmic reticulum (SR) Ca2+ release and in the Ca2+ clock [41,62]. Furthermore, it has been reported that adult D307H mice expressed only ~20% of the normal level of CASQ2 protein, and an age-related decrease in D307H CASQ2 protein expression was related to an abnormal Ca2+ release [42]. However, similar to the age- related decline in RYR2 elevation in SERCA2a could decrease the intracellular Ca2+ transient and, therefore, pace making [41].

On the other hand, phospholamban (PLN) regulates calcium uptake into the sarcoplasmic reticulum (SR) by SERCA2a and is related to both QT interval and heart rate [51]. The gene SERCA2a is the SR Ca2+ pump, and the abundance of SERCA2a mRNA was shown to be significantly reduced in the SAN compared to the atrial muscle, which resulted in a significant age-related increase in SERCA2a in the SAN [41]. Additionally, PRKCA protein kinase C alpha activity influences dephosphorylation of the sarcoplasmic reticulum SR Ca2+ ATPase-2 and Striatin, a Ca2+/calmodulin binding protein [51]. However, genes such as Calmodulin dependent protein kinase II (CaMKII), which activity declines with advancing age [63], are important for the regulation of the cardiac pacemaker activity largely by modulating L-type Ca2+ current inactivation and reactivation. Local Ca2+ critically contributes to these processes [64]. CaMKII prevents the effect of isoproterenol stimulation on SAN Ca2+ uptake, and it is related to the beta-adrenoceptor pathway in a “fight or flight” mechanism [65]. This gene affects the beta-adrenergic responsiveness, and alterations in the expression of this protein could be a putative explanation for the decline in maximal heart rate with aging [66]. To explore the effect of CaMKII on the heart rate, Santalla et al [67]. investigated the effect of the CaMKII in Drosophila melanogaster heart, utilizing 5 µmol/L of the specific CaMKII inhibitor (KN-93), which did not affect the different variables characterizing both contractility and relaxation. However, it induced a significant decline in spontaneous frequency with no effect on rhythmicity index. An age-dependent decrease in HCN1 in the SAN was prescribed, which could contribute to the age-related decrease in intrinsic HR, as HCN1 in combination with HCN4 was shown to be responsible for the inward funny current (If) [41]. It is possible that HCN isoform expression changes during age [6]. Directed deletion of HCN4 in adult mice resulted in heart rate–dependent sinus pauses but without impact on resting or maximal heart rate as well as the regulation of heart rate [68], and Mice with cardiomyocyte-specific HCN2 deletion presented sinus dysrhythmia, without altered heart rate [69].

Finally, Arash identified a crucial function for γ2 AMPK gene where AMPK conserves serine/threonine kinase maintaining cellular energy homeostasis. γ2 AMPK plays a role in the regulation of sinoatrial automaticity and resting heart rate. However, y2 AMPK gene activation was suggested to downregulate primary SAN myocytes pacemaker mechanisms, lowering heart rate including inward funny current (If). Contrary, loss of y2 AMPK was prescribed to cause a supplemental phenotype of elevated heart rate preventing the adaptation of the intrinsic bradycardia from endurance training.

Intrinsic Heart Rate (IHR)

The age-related decline in the maximal heart rate was suggested to be caused by an intrinsic heart rate decrease, measured without autonomic in?uences [5,32,70]. Jones reported that guinea-pig intrinsic heart rate dropped from 177 ± 5 beats min−1 in the young to 152 ± 5 beats min−1 in the aged animal. Comparable to these findings, changes in human intrinsic heart rate were prescribed to decline from 107 beats min−1 in young subjects (20 yrs) to 69 beats min−1 in old subjects (71 yrs) [32,71,72].

This age-related decline in intrinsic heart rate was suggested firstly to be due to an increasing collagen deposition (fibrosis) of the atrial tissue [73]. However, the spontaneous activity of the SAN myocyte will be depressed by aging as a result of changed membrane properties [6]. Additionally, sarcoplasmic reticulum function could be modified by substances during aging, and therefore cyclic changes in cytosolic calcium can affect heart rate [74]. Previously it was considered that Ca2+ release from the sarcoplasmic reticulum in SAN cells is influenced by aging, a process known to be critical for the activity of the pacemaker [6,75].

Secondly, it is noteworthy, that aging decreases the sinoatrial nodal function, due to a reduction in Na+ current (INa). Blockade of sodium current was shown to slow pace making [46]. Furthermore, the decline of pacemaker inward funny current (If) with aging, which is conducted by HCN4, can also reduce SAN function[46]. The age-dependent decrease in the intrinsic heart rate was proven to be either the result of an age-related decline in sodium current (INa) or pacemaker current (If), as blocking the corresponding ion channel was suggested to have a reduced effect on heart rate in aged animals [35]. In this regard, blockade of the pacemaker current (If) by 2 mM cesium (Cs+) is nearly selective and complete [76]. This result indicated the important role of the pacemaker current (If) to contribution to the pacemaker depolarization of all sinoatrial nodal cells [77]. With abundant or no sodium current, the action potential was shown to have an L-type calcium current generated slow upstroke [35]. The peak current densities for both L-type and T-type calcium current decreased with advancing age [6]. To investigate the role of L-type Ca2+ in diastolic depolarization, Verheijck [78]. utilized 5 µM nifedipine blocking L-type Ca2+ in rabbit SAN myocytes by 81%, without affecting T-type calcium current, potassium current, and funny current (If) as well as sodium current, when present.

Numerous molecular mechanisms have been prescribed to induce the age-dependent changes, and can contribute to the declined intrinsic heart rate with aging. We observed the following mechanisms: The voltage-gated Calcium channels such Cav3.1 and Cav3.2 are responsible for ICa, T-type in the heart [46]. An abolished T-type calcium current in nodal myocytes in Cav3.1 knockout mouse, was shown to slow intrinsic heart rate in vivo, prolongs recovery time of the SAN, and slows individual sinoatrial nodal cells pace making [36]. The age-dependent decrease in the expression of sodium ion channel Nav1.5, HCN1 and ryanodine receptor RYR2 was suggested to be responsible for the intrinsic heart rate decline (see gene expression, Tellez et al [41]). To investigate the effect of sodium ion channel Nav1.5, [35]. demonstrated that the application of 2 μM Tetrodotoxin (TTX) could slow pace making in both young and old preparations. Furthermore it was revealed that, HCN4, blocked by 2 mM cesium (Cs+) or 10 μM ivabradine in albino rabbit SAN cells, caused an 81% blockade of (If) and a slight decrease in L-type calcium and potassium current (IK) [79]. Ivabradine at concentrations of 2 mM Cs+ and 10 μM slowed pacemaking in both young and old preparations, but the effect was greater in old preparations [35].

Thirdly, inward funny currents (If), L- and T-type calcium currents, sodium current and sodium / calcium exchange current activated by sarcoplasmic reticulum (SR) Ca2+ release, the so-called ‘Ca2+ clock, play an vital role in the pacemaker activity [46,80]. The expression of ion channel and Ca2+ clock genes in the SAN changes greatly in the old animal in comparison to young animals [41]. The intracellular release of Ca2+ from the sarcoplasmic reticulum is dependent on the ryanodine receptor (RYR2), which plays a major role, in the Ca2+ clock [41,62]. The ryanodine receptor expression in the SAN decreases with advancing age, and may result in a decline in intrinsic HR in old animals [41]. In this issue, it was evidenced that the ryanodine receptor is substantial for calcium release channels in single guinea-pig SAN cells and plays a significant role in beta-adrenergic heart rate modulation [81]. A membrane clock (M-clock) and a Ca2+- clock, were prescribed and both were shown to be coupled dynamically by diverse Ca2+- and voltage-dependent molecular mechanisms e.g. Na+/Ca2+ exchanger and Ca2+ L-type channel [62]. The clock is robust as long as similar drivers regulating sarcoplasmic reticulum Ca2+ cycling (e.g. Ca2+ and PKA and CaMKII dependent protein phosphorylation) govern sarcolemmal ion channel function and couple SR Ca2+ cycling to the surface membrane [82]. Finally, the SR Ca2+ pump is SERCA2a and the amount of SERCA2a mRNA was significantly less in the SAN compared to atrial muscle. The activity of SERCA2a was shown to increase significantly in the SAN with aging [41].

Beta-Adrenergic Responsiveness

The age-dependent reduction in maximum heart rate was also shown to be related to a decline of beta-adrenergic responsiveness beside the prescribed changes in intrinsic heart rate [5,6]. With aging the chronotropic and the inotropic responsiveness to beta-adrenergic stimulation, as well as the catecholamine release decrease [83,44]. The beta-adrenergic receptor elevates the pacemaker current [84], which is important as a modulatory current in the control of pacemaker rate [77]. A reduction of chronotropic beta-adrenoceptor responsiveness was shown to be linked to the age-related decline in HRmax [5,85], found that SAN of the newborn rabbit heart had a higher intrinsic beating rate and a greater sensitivity to beta-adrenergic agonists than the adult SAN, which was explained by differences in phosphorylation. These data supported the idea, that beta-adrenergic responsiveness declines with aging. To test if the reduction of the beta-adrenergic responsiveness causes the decrease in maximum heart rate, Port and colleagues (1980) examined the effects of Propranolol on resting and exercise measurements of left ventricular function in healthy younger and older men [87]. The authors indicated that the effects of propranolol on resting and exercise hemodynamics in healthy adults are mainly due to alterations in heart rate, and demonstrated that the acute beta-adrenergic antagonist differentially affected the hemodynamic reaction to exhaustive upright cycle ergometer exercise in older against younger men. Additionally, the chronotropic response to the infusion of isoproterenol decreased with aging [88]. In a study of Kistler et al [34]. hearts of young (24.7 ±1.0 years), middle-aged (50 ± 2.1 years) and elderly (66 ± 2 years) patients were investigated. The authors utilized various electrophysiological methods and found an age-related decrease in the function of the SAN. These changes were interpreted by the prolonging of the conduction velocity and the SA node recovery time. The ability to increase heart rate is dependent on maximal beta-adrenergic receptor mediation, which requires involving CaMKII [65].

Can We Delay Or Reverse The Decline Of Maximal Heart Rate During Normal Aging?

As with every detrimental change, a key question is whether such changes can be prevented to potentially delay the loss in performance and morbidity and mortality.

One non-pharmacological option considered recently to reduce sympathetic activity was exercise training which is of considerable importance, given the other enhancements in risk factor reduction that regular training produces [88]. So far, there is only sparse information available on effects of endurance training on the decline in maximum heart rate [89]. Recently, Birnbaumer [14]. showed in a large group of age-heterogenous healthy male and female subjects that HRmax was smaller in subjects in the 75%-quartile compared to the 25%-quartile of maximal power output in an incremental cycle ergometer test, despite the lower trained subjects were still within normal performance limits. This lower HRmax could be attributed to a reduced motivation of less trained subjects, however the pattern of the heart rate curve was also different, showing a greater number of atypical curves in the less trained [21]. This effect was sex dependent and male subjects presented stronger changes. Interestingly, the trained subjects presented a pattern typical for 20-years younger subjects, indicating that performance may at least delay the change in patter. Maximal HR was only slightly higher in the trained but the decline in HRmax was not affected by fitness. As some influence of exercise or fitness can be expected from this study, we will discuss the effects of endurance training on different mechanisms associated with the age-dependent decline of HRmax.

Long-term endurance training significantly influences autonomic control of the heart. Endurance training enhances Heart rate variability (HRV), increases parasympathetic activity and decreases sympathetic activity in the human heart at rest [17]. In middle-aged men, a 10-months aerobic training program (three 60 min / sessions / week at 70-85% HRmax) produced significant physiological adaptations, a decrease in the sympathetic effects on heart rate as the main effect which was associated with an increased oxygen uptake during exercise [90]. The increase in heart rate during exercise is blunted with aging due to reduced withdrawal of cardiac vagal tone and declined beta-adrenergic responsiveness [30,91]. Former Athletes reveal a resting sinus bradycardia in training and competitions. Elite cyclists resting heart rate has been reported to be as low as 30beats/min. Although this is usually prescribed by a markedly increased vagal tone, a decrease of the intrinsic heart rate with autonomic blockade was present, thus making a decrease in the intrinsic pacemaker activity of the SAN plausible [55,92]. However, track athletes indicate maintained aerobic capacity when training was continued over a 10 year’s period whereas those who reduced their training exhibited a significant decline in VO2max over the same period [93]. In addition, Pollock and colleagues [94] reported in their 20 years follow-up study, that older athletes presented reduced physiological capacities by approximately 8 to 15% per decade despite continued vigorous endurance training over 20 years period. Whereas, HRmax showed a consistent and significant reduction after 10 and 20 years of high- and moderate-Intensity exercise training, but was maintained by the low-Intensity exercise training at the same period. Recent results from Birnbaumer [14]. support these results but additionally showed that fitness had an impact on the pattern of the HR curve, which was related to ß1-recepter sensitivity [21].

Although some investigations showed that trained animals resting bradycardia was attributed to an intrinsic heart rate decline, although several other studies also prescribed a potential role for high vagal tone or decreased sympathetic tone [41]. This deterioration of the functional capacity of the cardiovascular system is reflected by the decrease in maximal oxygen consumption (VO2max) [95], which is at least in part caused by the drop of maximal heart rate [7].

An earlier study by Rogers [89]. showed that endurance training reduced the rate of decline in VO2max to only 5% per decade in men. These Authors also reported that HRmax did not decrease during a 7.5 years follow-up in master athletes. It was therefore suggested by these authors, that endurance exercise training may dampen the age-related decline of maximal heart rate [89].

It is well known, that active and athletic individuals present a greater VO2max compared to sedentary individuals of similar age indicating that the cardiovascular system is adaptable to training even at older age [7]. Exercise training provoked favorable adaptations in functional capacity in individuals well into their 70th and 80th years of life [95]. Long term high-intensity training delayed the loss in VO2max by as much as 50% in young and middle-aged men, but not in middle-aged and older females [7]. In this regard, Wang [96] reported, that high intensity aerobic interval training improved VO2max by 13% in younger and 6% in older subjects, respectively. Intense aerobic training appears to increase VO2max, decreases resting heart rate, increases heart rate variability (HRV), and enhances parasympathetic tone in both older and younger men, contributing to the decline in mortality associated with regular exercise training [97,98] also reported, that after a one-year fitness training program (2-3 sessions / week, moderate intensity) heart rate at rest and at the same metabolic demand as well as the HRV remained unchanged in the training group, in spite of an increase of the VO2max by 6, 4%. A similar effect was presented by Birnbaumer et al [14]. showing that performance did not change significantly until 50 yrs of age although HRmax already declined, indicating that the HRmax decline effect on performance could be compensated by other mechanisms.

Regarding training effects on cardiovascular responses to beta-adrenergic stimulation in young and older humans, Stratton [97]. Demonstrated, that intense exercise training did not increase isoproterenol stimulated beta-adrenergic cardiac responses in both young and older men.

Jones suggested that exercise training could affect the electrical connections between the cardiac myocytes declining with aging, offering a possibility to preserve the stability of the heart’s electrical activity into old age without pharmacological treatment [99]. In this regard, Bellafiore [100]. Investigated the role of Cx43 in exercise training induced cardiac ventricular walls mechanical stretch in mice for 30 and 45 days. The authors reported that, the left ventricle from the trained mice presented a significant increase of Cx43 expression compared to untrained controls. Exercise training upregulated Cx43 expression in a training duration-dependent manner. This reveals benefits of the exercise training on cardiac myocytes to reverse the electric coupling, which declines with aging.

Exercise training exerts beneficial influences on cardiovascular function in both humans and animals. In a previous study Zhang et al [101]. presented, that high-intensity sprint training (HIST) enhanced intracellular Ca2+ dynamics, increased sarcoplasmic reticulum Ca2+ uptake and Ca2+ content, and restored Na+/Ca2+ exchange current toward normal. In this issue, exercise training was shown to facilitate Ca2+ transport mechanisms and improves extracellular Ca2+ availability for cardiac contractile cycles, which are affected by catecholamine levels [102]. Concomitantly, Moore and coworkers [103] argued that chronic exercise influenced cardiac contractile function at the single myocyte level and provided evidence that exercise training affects myocyte Ca2+ influx and efflux pathways. Furthermore, these authors showed that cardiac adaptation to aerobic exercise training improved both cardiomyocyte contractility and calcium handling.

Exercise training can also impact molecular mechanisms contributing to the age-dependent decline in HRmax. In this regard, apoptosis is one putative mechanism contributing to the age-related decline in the HRmax. The activation of apoptosis was shown to be related to increased oxidative stress, whereas heat shock proteins (HSP70) were suggested to be capable of inhibiting apoptosis [104]. Because exercise training has been consistently shown to increase the antioxidant defense capacity and enhance the expression of HSP in skeletal and cardiac muscles in rats, it appears plausible to postulate that exercise training is capable to decline the level of apoptosis [104]. It has been convincingly demonstrated, that eight weeks (5 days a week) of moderate intensity treadmill exercise training in adult Sprague Dawley rats reduced the extent of cell death in cardiac and skeletal muscles when measurements were taken at 48 h after the last exercise bout [104]. Furthermore, treadmill-trained rats presented improved cardiac function in combination with a cardiac gene expression profile clearly different from pathological cardiac adaptation [105]. Age-induced connective tissue content decreases in the left ventricle can be retarded by exercise training. In this regard, after 12 weeks (5 days/week for 60 min/day) of exercise training at an intensity of 75% of VO2max increased the myocardial collagen in an age-dependent manner in 24-mo-old Fischer-344 rat and human hearts [106].

It has been reported, that aerobic interval training increased SERCA-2a protein expression within SR by about 25%, increased Ca2+ sensitivity and the enzyme activity of SERCA-2a in hearts from exercise trained mice. Additionally, improvements in cardiomyocyte contractility induced by training were related to changes in Ca2+ handling, specifically in the CaMKII-mediated regulation of SERCA-2a activity [107]. Moreover, Lu and coworkers investigated the effects of long-term exercise training on gene and protein expression (SERCA2a, NCX1, and RyR2) during the development of heart failure with 15 mongrel dogs from the same breed (age= 1–3 years) . These authors found that exercise training partially prevented hemodynamic abnormalities and normalized downregulated SERCA2a and upregulated NCX1 on both mRNA and protein levels during development of heart failure. Finally, the age-related changes in gene expression and protein may prolong the action potential of SAN, slow the intrinsic heart rate, increase SAN conduction time and decrease parasympathetic regulation in Wistar-Hannover rats [41]. However, no studies were found investigating the effects of exercise training on gene expression in the sinoatrial cells [108-121].

Independent of the intensity, the duration and the type of exercise intervention, not any substantial effects on the decline of HRmax could be found indicating a strong genetically fixed program reducing HRmax and subsequently performance with aging [122-146].


The well described age-dependent almost linear decline of maximum heart rate in humans is a major contributor of the decrease in aerobic capacity which can just be partially compensated by exercise training. This age-dependent decline in maximal heart rate is related to changes in several putative mechanisms such as the responsiveness to beta-adrenergic stimulation. Additionally, increases in SAN collagens which slow action potential, as well as a decrease of the structural remodeling of individual sinoatrial myocytes, resulting in a decline in SAN activity and a slower action potential of aged SAN cell contributes to the age-related decline in intrinsic and maximal heart rate. Furthermore, a loss of Connexin43 (Cx43) expression protein with aging decreases the connection between SAN myocytes and affects towards a declined function of the aged SAN. Interestingly, all these age-related influences do not explain the linear decline of HRmax in humans suggesting a much stronger and genetically fixed program with yet unknown mechanisms.

For numerous elderly people, low maximal oxygen consumption VO2max is a major factor limiting functional independence, and restricting the ability to perform daily activities. Although endurance training improves maximal exercise capacity at all ages, direct effects on the heart such as improved sarcoplasmic reticulum Ca2+ uptake paralleled by a normalized Na-Ca2+ exchanger current and increases of the expression of SERCA2, are not able to inhibit the decline in functional capacity with aging which is strongly dependent on the decrease in HRmax.

Just therefore it is even more important to recommend exercise training for the whole population but even more in the elderly to keep functional performance on an adequate level. It would however, be attractive to discover the specific details of this age-dependent decline of HRmax and nay interventions reversing this phenomenon.


We thanks the University of Graz for funding the publication.


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