The Renin-Angiotensin System and Cardiovascular Autonomic Control in Aging

Abstract

Aging is the greatest independent risk factor for developing hypertension and cardiovascular-related diseases including systolic hypertension, vascular disease, ischemic events, arrhythmias, and heart failure. Age-related cardiovascular risk is associated with dysfunction of peripheral organ systems, such as the heart and vasculature, as well as an imbalance in the autonomic nervous system characterized by increased sympathetic and decreased parasympathetic neurotransmission. Given the increasing prevalence of aged individuals worldwide, it is critical to better understand mechanisms contributing to impaired cardiovascular autonomic control in this population. In this regard, the renin-angiotensin system has emerged as an important hormonal modulator of cardiovascular function in aging, in part through modulation of autonomic pathways controlling sympathetic and parasympathetic outflow to cardiovascular end organs. This review will summarize the role of the RAS in cardiovascular autonomic control during aging, with a focus on current knowledge of angiotensin II versus angiotensin-(1–7) pathways in both rodent models and humans, pharmacological treatment strategies targeting the renin-angiotensin system, and unanswered questions for future research.

Introduction

Aging is the greatest independent risk factor for the development of hypertension and cardiovascular disease (CVD).¹ Importantly, CVD is the leading cause of death in people over age 65, which is the fastest growing age group worldwide.² Several changes to the cardiovascular system occur in healthy aging that predispose this population to developing CVD (Figure 1). For example, aging leads to structural changes to the heart including cardiac fibrosis, left ventricular hypertrophy, and valve stenosis.¹ Additionally, arterial plaques develop throughout the lifespan causing endothelial dysfunction, arterial stiffening, and atherosclerosis with aging. Collectively, these age-related changes in cardiovascular physiology lead to the development and progression of CVD including systolic hypertension, vascular disease, acute ischemic events, arrhythmias, and heart failure.¹

Figure 1. Overview of Cardiovascular and Autonomic Changes in Aging.

Healthy aging is associated with several changes to the cardiovascular system that predispose this population to developing cardiovascular disease. This review will focus on autonomic nervous system mechanisms (bolded), such as reduced baroreceptor sensitivity and increased sympathetic activity, that occur with aging. While not a focus, additional non-autonomic mechanisms occur during aging that impact cardiovascular control such as structural changes to the heart and blood vessels including cardiac fibrosis, left ventricular hypertrophy, endothelial damage, and atherosclerosis. All these changes can manifest clinically as isolated systolic hypertension and arrhythmias in aged individuals.

Changes in autonomic control of the cardiovascular system are also well recognized to contribute to age-related CVD.³ In terms of blood pressure regulation, aging is associated with isolated systolic hypertension, which is largely attributed to increases in arterial stiffness as well as increased sympathetic nervous system activity.^4,5 Diastolic blood pressure and heart rate decrease after age 50 in humans due to large artery stiffening, reduced sinoatrial node firing, and decreased β-adrenergic receptor sensitivity.^5,6 In rodent models, while systolic and mean blood pressure increase with age similar to humans, diastolic blood pressure and heart rate remain stable throughout the lifespan.⁷ Sympathetic traffic to the heart and vasculature also increases progressively with age,³ prior to hypertension and CVD onset.⁸ This chronically elevated sympathetic tone increases catecholamine release to desensitize and downregulate adrenergic receptors. Desensitization of α-adrenergic receptors impairs acute vasoconstriction in response to physical stimuli (e.g., postural changes), and increases the risk for orthostatic hypotension and syncope in elderly adults.⁹ High sympathetic tone also desensitizes β-adrenergic receptors in the heart and vessels to impair heart rate, cardiac contractility, and vasodilation thus increasing risk for hypertension and heart failure. This desensitization is evidenced clinically by decreased cardiac and vascular responses to infusion of adrenergic receptor agonists in small mechanistic studies in older men.^10–12 In addition to increased sympathetic tone, aging is accompanied by reduced measures of cardiovascular parasympathetic tone including heart rate variability and the baroreflex sensitivity for control of heart rate.¹³ Overall, aging is associated with an imbalance in the sympathetic and parasympathetic arms of the autonomic nervous system, which predisposes to cardiovascular morbidity and mortality. As the aging population continues to increase, it is important to better understand mechanisms underlying age-related cardiovascular autonomic impairment to develop new therapies to reduce cardiovascular risk.

In this regard, the renin-angiotensin system (RAS) has emerged as an important hormonal mechanism contributing to aberrant cardiovascular autonomic control in aging. This review will summarize current understanding of the role of the RAS in cardiovascular autonomic control in aging, with a focus on angiotensin II versus angiotensin-(1–7) pathways in both rodent models and humans. Additionally, pharmacological strategies to target the RAS during aging will be discussed, as these therapies are commonly used to treat hypertension and CVD in elderly individuals. Importantly, this focus on aging builds on our recent review describing sites of interaction between the RAS and autonomic nervous system for cardiovascular control in younger models of CVD.¹⁴ While not a focus of this review, the RAS has been implicated in the regulation of numerous other physiological and pathophysiological processes during aging including glucose homeostasis, energy balance, neuroinflammation, cognition, mitochondrial redox balance, physical performance, renal disease, and osteoporosis.^15–18

Angiotensin II Pathways in Cardiovascular Autonomic Control

Angiotensin II is an important hormonal contributor to homeostatic regulation of blood pressure, fluid and electrolyte balance, and control of the cardiovascular system via the brain and peripheral organs. Inappropriately elevated levels of angiotensin II, however, are implicated in the pathophysiology of numerous CVD-related states (e.g., hypertension, heart failure, atherosclerosis, stroke, obesity, diabetes). Angiotensin II has primary actions at type 1 receptors (AT1R), which are g-protein coupled receptors that facilitate increased blood pressure via neural, renal, vascular, and cardiac mechanisms.^19,20 Specifically, AT1R activation promotes vasoconstriction, endothelial and cardiac dysfunction, release of aldosterone and vasopressin, oxidative stress, inflammation, sympathetic tone, and baroreflex dysfunction.²¹

As recently reviewed,¹⁴ chronic stimulation of AT1R by angiotensin II can also lead to hypertension in younger animal models via interactions with the autonomic nervous system. AT1R are abundant at each synaptic relay of the autonomic nervous system (e.g., preganglionic neurons, ganglia, nerve terminals, regulatory brain regions), with activation by angiotensin II increasing sympathetic and decreasing parasympathetic neurotransmission.²² Angiotensin II signaling can also affect adrenergic receptors through the sympathetic nervous system, to alter cardiovascular autonomic control. Angiotensin II desensitizes and downregulates adrenergic receptors, specifically β-adrenergic receptors in the heart, kidney, and blood vessels. For example, one study showed that exogenous angiotensin II downregulates β2-adrenergic receptor protein expression in human endothelial progenitor cells.²³ Additionally, AT1R activation by angiotensin II affects β-arrestin binding to β2-adrenergic receptors to desensitize and downregulate these receptors in cultured kidney cell lines.²⁴ Finally, angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), therapies which decrease both angiotensin II and sympathetic activity, can restore β-adrenergic receptor expression and sensitivity in cardiac tissue from rat models of hypertension independent of effects on blood pressure or cardiac hypertrophy.²⁵ Overall, a handful of studies in cultured cells or isolated tissues provide evidence for crosstalk between Ang II AT1R and β-adrenergic receptor signaling. The functional importance of these interactions for cardiovascular autonomic regulation in vivo, however, remains unclear.

Angiotensin II also binds to type 2 receptors (AT2R) to oppose actions mediated by activation of AT1R; although these receptors have limited expression and affinity, particularly in adulthood.²⁶ Activation of AT2R induces several cardioprotective effects including vasodilation and natriuresis through nitric oxide (NO) and prostaglandin pathways.²⁷ Pharmacological blockade of AT1R with ARBs can increase angiotensin II binding to AT2R, which partially contributes to the antihypertensive effects of these drugs.²⁸ AT2R are also expressed in cardiovascular autonomic pathways and promote sympathoinhibition. For example, overexpression of AT2R in the rostral ventrolateral medulla decreases blood pressure and norepinephrine release in normal rats.²⁹ Furthermore, AT2R activation or overexpression in brain reduces sympathetic outflow in rat models of heart failure.^29,30 In rat models of heart failure, hypertension and obesity, chronic AT2R stimulation or overexpression also improves the baroreflex sensitivity for control of both heart rate and renal sympathetic nerve activity,^30–32 an important mechanism to restrain cardiovascular sympathetic outflow. Thus, accumulating data support that AT2R may provide a novel target to counteract Ang II actions at AT1R in animal models of CVD, at least in part by decreasing sympathetic and increasing parasympathetic neurotransmission. The translatability of these findings to humans remains unknown, although a few controlled clinical studies are registered on clinicaltrials.gov using AT2R agonists, such as compound 21, in diseases such as Covid-19 and idiopathic pulmonary fibrosis.

The sympathetic nervous system also regulates angiotensin II activity in a bidirectional manner, with high sympathetic tone increasing angiotensin II levels. Sympathetic innervation of β1-adrenergic receptors in the kidney stimulates renin release, which increases angiotensin II formation.¹⁴ As clinical evidence of the importance of this relationship, patients with pure autonomic failure and chronic sympathetic denervation have low and often undetectable levels of plasma renin activity.³³ Furthermore, methods to suppress efferent sympathetic outflow, such as renal denervation or electrical activation of the carotid baroreflex, reduce circulating renin activity, angiotensin II and aldosterone levels in experimental animal models and in patients with resistant hypertension.³⁴

Angiotensin II Pathways and Cardiovascular Autonomic Actions in Aging

During aging, there are several changes in the activity and responsiveness of the RAS that affect cardiovascular autonomic control (Figure 2; Table 1). In normotensive and hypertensive individuals, there is an age-related suppression of the systemic RAS. Specifically, renin formation and release decline in aging resulting in decreased plasma renin concentrations.³⁵ Additionally, older individuals exhibit impaired renin responsiveness to physiological stimuli such as upright posture and sodium depletion as well as have increased prevalence of low renin hypertension.^36,37 While not fully understood, mechanisms that have been proposed to reduce systemic RAS activity in the elderly include: reduced baroceptor-mediated renal renin release due to elevated arterial pressure;³⁸ decreased renin production via reduced renal beta1-adrenergic receptor sensitivity;³⁹ and more rarely reduced sympathetic innervation to attenuate renin release from renal juxtaglomerular cells in patients with autonomic impairment.³³ Studies examining for circulating levels of prorenin, the renin precursor, and the prorenin receptor during aging are limited, with one report showing decreased plasma prorenin in hypertensive but not normotensive subjects, one showing increased soluble prorenin receptor in hypertensive subjects, and a few reporting no change in prorenin or soluble prorenin receptor levels, with age.^40–44

Figure 2. Renin-Angiotensin and Autonomic Interactions in Aging for Cardiovascular Control.

During aging, angiotensin II, angiotensin converting enzyme (ACE), and angiotensin type 1 receptor (AT1R) pathways are increased while angiotensin-(1–7), angiotensin converting enzyme 2 (ACE2), and mas receptor (MasR) are decreased. This imbalance in the renin-angiotensin system contributes to impaired measures of parasympathetic tone, such as baroreflex sensitivity (BRS) and heart rate variability (HRV). This reduced parasympathetic tone allows for unrestrained sympathetic activation, which can desensitize adrenergic receptors in the kidney, heart, and vasculature; these end organs are less responsive to sympathetic stimulation in aging.

Table 1.

Changes in Renin-Angiotensin System Components with Aging

	Age-Related Change	References	Model
Plasma Expression
Aldosterone	↓	35,45	rat, human
Angiotensin converting enzyme (ACE)	↓	47	human
Angiotensin converting enzyme (ACE2)	↑	47	human
Angiotensin-(1–7)	↓	72	human
Angiotensin II	↓	47	human
Prorenin	↓, -	40–44	human
Renin	↓	35, 36,37	human
Cardiovascular Tissue Expression
ACE	↑	52,53	mouse, rat
ACE2	↓	52,72	mouse
Angiotensin-(1–7)	↑	45	rat
Angiotensin-(1–7) mas receptor (MasR)	↓	52,72	mouse
Angiotensin II	↑	45,50–52	rat, mouse, non-human primate
Angiotensin II type 1 receptor (AT1R)	↑	45,50–53	rat, mouse, non-human primate
Angiotensin II type 2 receptor (AT2R)	↓	50	rat, mouse
Angiotensinogen	↑	53	rat
Prorenin receptor	↑	52	mouse
Renin	↑	35	rat, human

Plasma aldosterone levels also decline during healthy aging in rodents and humans.^35,45 As described in our prior review,¹⁴ aldosterone can activate either mineralocorticoid receptors or angiotensinergic signaling pathways within the brain to elevate sympathetic outflow and blood pressure in younger animal models of CVD. To our knowledge, there is no information on direct interactions of aldosterone with the autonomic nervous system during aging. Of potential relevance, a small controlled study showed that the mineralocorticoid receptor antagonist spironolactone effectively lowers blood pressure in elderly patients with stage I hypertension, in part by reducing sympathetic activity.⁴⁶ This effect may not be specific to aldosterone, however, as spironolactone also blocks the actions of other hormones including angiotensin II and cortisol.

Similar to renin and aldosterone, circulating angiotensin II levels and angiotensin converting enzyme (ACE) activity decrease in healthy aged humans.⁴⁷ Interestingly, acute intravenous angiotensin II infusion elicits exaggerated pressor responses and peripheral vasoconstriction in small trials in older healthy humans, perhaps reflecting increased AT1R sensitivity.^48,49 Indeed, despite declines in systemic RAS activity, production of angiotensin II and AT1R expression and sensitivity increase in local RAS tissue systems during aging in animal models.^45,50–52 In the heart of aged rats, angiotensinogen, ACE and AT1R are increased, independent of changes in the circulating RAS,⁵³ which may contribute to age-related changes in cardiac structure and function. Similarly, renal expression of renin and ACE are increased during aging in rodents with enhanced renal responsiveness to angiotensin II, which may predispose to renal damage and fluid-electrolyte imbalances.³⁵ Vascular changes are also evident with increased protein expression of the prorenin receptor, ACE, angiotensin II, and AT1R observed in the thoracic aorta of aged mice.⁵² Additionally, endothelial and renal AT2R expression decreases with age, thus potentially limiting the protective cardiovascular effects of angiotensin II.⁵⁰ While AT2R is cardioprotective in young animals, one study showed AT2R agonism induced paradoxical vasoconstriction via oxidative stress in aging rats.⁵⁰

In addition to peripheral tissues, a local RAS exists within the brain, which appears regulated independent from the circulating system. Altered brain RAS activity has been implicated in the autonomic imbalance observed during aging, to precipitate elevations in blood pressure. In particular, a chronic imbalance in which brain angiotensin II is increased and angiotensin-(1–7) is decreased has been observed in aging.⁵⁴ In terms of autonomic effects, it is well established that angiotensin II, both endogenous to the brain and when given exogenously, increases cardiovascular sympathetic outflow and impairs the baroreceptor reflex control of heart rate in aged animal models. The precise mechanisms underlying the deleterious cardiovascular autonomic effects elicited by brain angiotensin II signaling, however, remain poorly understood.

These overall findings suggest that tissue angiotensin II production, ACE activity, and AT1R expression and sensitivity are increased in animal models during aging and contribute to age-related cardiovascular pathophysiology. In particular, activation of angiotensinergic signaling within brain may contribute to excess sympathetic outflow to cardiovascular end organs to elevate blood pressure and lead to the development and progression of hypertension. Additional research is needed to better understand the neural pathways and cellular mechanisms engaged by brain angiotensin II to elicit age-related changes in cardiovascular autonomic control (Table 2). The status of tissue angiotensin II pathways and their functionality during aging in humans is also largely unexplored, likely reflecting limitations in obtaining these samples.

Table 2.

Questions for Future Research on Renin-Angiotensin System: Autonomic Interactions for Cardiovascular Control in Aging

What is the status of local tissue RAS in humans during aging, and do these local systems interact with the autonomic nervous system to influence age-related cardiovascular risk?

What are the precise autonomic pathways and cellular mechanisms engaged by the RAS to influence cardiovascular control during aging?

How do aldosterone, and more recently discovered angiotensin-(1–7) pathways, interact with the autonomic nervous system to impact cardiovascular regulation during aging?

Are there sex differences in RAS cardiovascular autonomic actions during aging? What is the impact sex hormones, menopause, and hormone replacement therapy?

Are there racial or ethnic differences in RAS cardiovascular autonomic actions during aging?

Do the autonomic mechanisms involved in RAS actions or therapies differ in healthy aging versus in aged individuals with cardiovascular or metabolic diseases?

Ang-(1–7) Pathways in Cardiovascular Autonomic Control

Angiotensin-(1–7) is a more recently discovered RAS hormone that is formed from angiotensin II cleavage by angiotensin converting enzyme 2 (ACE2) or from angiotensin I cleavage by endopeptidases, such as neprilysin.^14,55 Angiotensin-(1–7) binds to g-protein coupled mas receptors (MasR) to induce cardioprotective effects including vasodilation, endothelial NO release, enhanced baroreflex function, and reductions in sympathetic tone, cardiac hypertrophy, inflammation, oxidative stress, and fibrosis in animal models.⁵⁶ In vivo studies support MasR as the primary receptor-mediated mechanism for angiotensin-(1–7) actions; however, MasR can heterodimerize with AT1R, AT2R, bradykinin B2 receptors, and dopamine D2 receptors in cellular models.^56,57 While having minimal effects on cardiovascular function under normal conditions, angiotensin-(1–7) lowers blood pressure in younger rodent models of hypertension and CVD, in which circulating levels of the peptide appear deficient.^58,59 The most studied acute mechanism for angiotensin-(1–7) depressor effects is peripheral vasodilation by activating endothelial nitric oxide synthase (eNOS) and stimulating endothelial NO release.⁶⁰ Angiotensin-(1–7) also improves cardiac function, reduces cardiac fibrosis, and prevents cardiac remodeling following ischemia in younger rodent models of hypertension, obesity and metabolic syndrome.^61–64

In addition, there is growing evidence that angiotensin-(1–7) interacts with autonomic nervous system pathways to regulate blood pressure.^14,56 The mechanisms by which angiotensin-(1–7) interacts with the autonomic nervous system both centrally and peripherally, however, are less well understood. Studies support that depressor effects of angiotensin-(1–7) are associated with reduced peripheral and central measures of sympathetic tone in younger hypertensive rodents.^65–69 Specifically, angiotensin-(1–7) has been shown to decrease norepinephrine release from the hypothalamus, kidney, and heart in rats.^67,70 There is also evidence that angiotensin-(1–7) reduces norepinephrine synthesis and release from sympathetic nerve terminals innervating resistance arteries in hypertensive rats.^67,69 Angiotensin-(1–7) also increases measures of parasympathetic tone, such as the baroreflex sensitivity for control of heart rate, in hypertensive rats.^22,68 These autonomic effects of angiotensin-(1–7) are largely mediated by MasR, which are highly expressed in autonomic pathways similar to the distribution of angiotensin II receptors. For example, MasR antagonism in the midbrain prevents angiotensin-(1–7)-induced improvements in baroreflex control of sympathetic nerve activity and blood pressure.^22,71 The sympathoinhibitory effects of angiotensin-(1–7) may also, however, be mediated in part through AT2R activation.⁶⁷ Overall, these data suggest that angiotensin-(1–7) levels and MasR and ACE2 expression are reduced in younger rodent models of CVD, and that restoration of this hormone provides a novel target to restore the balance of the RAS to improve cardiovascular control.

Ang-(1–7) Pathways and Cardiovascular Autonomic Actions in Aging

While cardioprotective in younger animal models of CVD, there is limited research on levels and actions of angiotensin-(1–7) pathways during aging (Table 1). There is sparse and conflicting data on angiotensin-(1–7) levels in aging. For example, a small cross-sectional study showed lower circulating angiotensin-(1–7) in aged overweight and obese human subjects,⁷² while another study showed higher levels with aging in a rat model of metabolic syndrome.⁴⁵ In another small cross-sectional study in healthy individuals, serum ACE2 activity appears higher in older women when compared with younger women, with no differences in other RAS enzyme activities.⁴⁷ In contrast, MasR and ACE2 expression is decreased in the aorta of aged mice, which may diminish the vascular protective effects of Ang-(1–7) in aging.^52,72 These disparate findings may reflect differences in species as well as in the analytical methods to measure RAS peptides and enzyme activities. Furthermore, while animal studies often focus on RAS levels in tissues, clinical studies typically assess circulating peptides and enzyme activities due to sampling limitations.

In terms of functional actions, one study found that angiotensin-(1–7) vasodilatory effects are impaired in aortic rings obtained from older versus younger female mice and restored by estrogen replacement, but with no male comparator.⁷³ Chronic angiotensin-(1–7) treatment also decreases mean blood pressure to a greater extent in aged compared to young healthy rodents.^74,75 This decrease in mean blood pressure was driven by changes in systolic blood pressure, as diastolic pressure and heart rate were unaffected.⁷⁵ These depressor effects appear dependent on MasR in aging, with a greater contribution of AT2R-mediated effects in younger rodents.⁷⁴ Additionally, the cardiovascular phenotype produced by genetic deletion of ACE2 in mice (e.g. systolic hypertension, cardiac autonomic imbalance, oxidative stress, vascular inflammation) appears associated with age, but may depend on the genetic background.⁵⁴

Importantly, the depressor effects of angiotensin-(1–7) in aging are associated with decreased cardiovascular sympathetic tone. Our group recently published that chronic systemic angiotensin-(1–7) treatment decreases cardiac sympathetic tone in healthy aging mice.⁷⁵ More specifically, we found that aged mice treated with angiotensin-(1–7) have reductions in the sympathetic component of heart rate variability as well as gene expression of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis, in cardiac tissue.⁷⁵ Additionally, low endogenous brain angiotensin-(1–7) levels contribute to reductions in the baroreflex sensitivity during aging in rodents. More specifically, low levels of angiotensin-(1–7) in the solitary tract nucleus of the dorsomedial medulla contribute to baroreflex impairment in aged rodents.⁵³

Overall, these limited findings in rodent models suggest that circulating angiotensin-(1–7) levels and tissue ACE2 and MasR expression are reduced during healthy aging and associated with decreased parasympathetic and increased sympathetic tone (Figure 2; Table 1). Restoration of angiotensin-(1–7) may provide a novel target to maintain proper baroreceptor reflex function and decrease cardiovascular sympathetic tone, systolic hypertension, and age-related risk for CVD. Additional studies are needed to:confirm these findings in aged animal models of CVD, identify precise cellular and neural mechanisms involved, and determine the status of angiotensin-(1–7) pathways during aging and the potential impact of its restoration on cardiovascular regulation during aging in humans (Table 2).

RAS Therapies in Aging

ACE Inhibitors and Angiotensin Receptor Blockers

Pharmacological therapies blocking angiotensin II activity are widely used for the treatment of hypertension and CVD due to their antihypertensive and cardioprotective effects. The two main classes of drugs clinically used are ARBs and ACEi.⁷⁶ ACEi prevent the conversion of angiotensin I to angiotensin II, whereas ARBs prevent angiotensin II from binding AT1R to limit downstream signaling effects. The beneficial effects of these therapies on blood pressure are partially attributed to autonomic mechanisms. ACEi and ARBs reduce central sympathetic neural discharge and norepinephrine spillover while improving norepinephrine tissue clearance at peripheral nerve terminals in essential hypertension.⁷⁷ These therapies also improve the gain and set point of the arterial baroreflex for control of heart rate and sympathetic activity to preserve autonomic reflex control.^78,79 A few initial studies have also shown that ACEi and ARBs increase β2-adrenergic receptor expression and sensitivity and eNOS expression in human endothelial progenitor cells and isolated cardiac tissue from hypertensive rats, which could contribute to the vasodilatory effects of these drugs.^23,25 In addition to blocking angiotensin II activity, ACEi and ARBs are established to increase circulating angiotensin-(1–7) levels, which contributes to the beneficial cardiometabolic effects of these therapies in rodent models of CVD and obesity.^80–83

In aged rodent models, ACEi and ARBs appear less effective at lowering blood pressure;^35,84 however, data in preclinical models may not translate to clinical use. Given the well-recognized age-related decline in systemic RAS activity, some guidelines for hypertension pharmacotherapy, such as those provided by the National Institute for Health and Care Excellence in the United Kingdom, have recommended ACEi and ARBs as first line therapy in individuals less than 55 years of age, and calcium channel blockers for non-diabetic individuals aged 55 years and older. Clinically, however, several large trials support that ACEi and ARBs effectively lower blood pressure and decrease cardiovascular morbidity and mortality in older adults with CVD.^74,85–87 This finding suggests that beneficial effects of these therapies are at least in part due to suppression of the local tissue RAS. In addition to cardioprotection, long-term RAS blockade extends lifespan and protects against age-related declines in physical performance and metabolic, cognitive, renal, and mitochondrial functions.⁵³

Despite these protective effects, large population-based studies have shown that ACEi and ARBs may be less well tolerated in aging clinical populations. For example, the risk of angioedema and renal failure is greater with these treatments in older populations.^88,89 In general, ACEi are reported to be limited in ~11% of patients by cough due to off-target production of kinins.^89,90 In patients over 60, however, the incidence of dry cough with ACEi treatment is 32%; this may be a greater concern due to decreased lung function with aging.⁸⁹ Elderly hypertensive patients also often have comorbid conditions including chronic kidney disease and autonomic disorders such as orthostatic hypotension, which may make use of angiotensin II blocking therapies more hazardous in aging.⁸⁸ Therefore, there is need to develop alternative treatments targeting the RAS with a better risk profile for blood pressure lowering and cardioprotection in aging populations.

Direct Renin Inhibitors

Direct renin inhibitors offer a therapeutic approach to potentially achieve more complete RAS inhibition, by blocking the rate-limiting step for downstream RAS peptide formation. Aliskiren is a first-in-class nonpeptide orally active renin inhibitor that binds renin and non-proteolytically activated prorenin to prevent cleavage of angiotensinogen to angiotensin I, to ultimately reduce angiotensin II formation. The effects of aliskiren appear partially mediated by the autonomic nervous system as centrally administered aliskiren lowers blood pressure, in part by reducing renal sympathetic nerve activity and restoring arterial baroreflex function, in hypertensive rats.⁹¹ Aliskiren monotherapy has been shown to elicit sustained antihypertensive effects in large double-blind randomized controlled clinical trials;⁹² however, this drug has increased side effects compared with ACEi and ARBs as well as contraindications in patients with diabetes or renal impairment. In geriatric populations, aliskiren significantly reduces systolic blood pressure and is better tolerated than ACEi and other common antihypertensive drugs such as diuretics and calcium channel blockers.^92–94 Despite promise in controlled clinical trials, aliskiren is not yet recommended as first line treatment for the elderly as data for safety and effectiveness in older patients in the real-world settings of clinical practice are still lacking;⁹² however, observational studies are currently ongoing to address this.

Angiotensin-(1–7)

Targeting angiotensin-(1–7) directly may provide an ideal approach to mitigate hypertension and CVD in aging, while bypassing the known side effects of ACEi and ARBs. Despite evidence for cardioprotective effects in animal models, however, there are few clinical trials with angiotensin-(1–7). Angiotensin-(1–7) has been shown to improve NO-mediated vasodilation in the cutaneous microcirculation and isolated human coronary microvessels.^95,96 Two studies have established safety, tolerability, and dosing for acute intravenous angiotensin-(1–7) infusion in younger healthy humans.^97,98 A few small mechanistic studies have also shown that intra-arterial angiotensin-(1–7) infusion dilates forearm and renal vessels in patients with obesity or hypertension, but with inconsistent effects in younger healthy humans.^99–101 In terms of aging, despite implications for angiotensin-(1–7) deficiency in CVD pathogenesis in aged animal models, there are no clinical trials to date investigating angiotensin-(1–7) effects in older clinical populations. A major challenge to conducting clinical research with angiotensin-(1–7) in humans is the short half-life of this peptide in the circulation. While approaches to chronically elevate angiotensin-(1–7) levels are in development and early phase clinical trials (e.g., oral formulations, stable analoges, ACE2 activators, MasR agonists), these are not yet widely available, thus currently limiting more long-term studies in humans.

Conclusions and Future Research Directions

The RAS has emerged as an important hormonal modulator of blood pressure in aging, in part through modulation of autonomic nervous system pathways controlling sympathetic and parasympathetic outflow to cardiovascular end organs. While the circulating RAS appears largely suppressed with aging, emerging evidence supports a role for increased angiotensin II and decreased angiotensin-(1–7) pathways in age-related sympathoexcitation and baroreflex dysfunction. Blockade of angiotensin II activity with ACEi or ARBs lowers blood pressure and provides cardioprotection in aged individuals, with effects of these therapies partially mediated via suppression of tissue angiotensin II signaling, autonomic mechanisms, and increased endogenous angiotensin-(1–7) levels. Additional therapies targeting the RAS, to restore the balance of angiotensin II versus angiotensin-(1–7), but with a more favorable side effect profile, would advance our ability to reduce cardiovascular risk in aging.

There are several unanswered questions remaining regarding the role of the RAS in cardiovascular autonomic regulation in aging that warrant additional research (Table 2). First, the precise neural pathways and cellular mechanisms engaged for RAS: autonomic interactions in aging are unknown, particularly related to aldosterone as well as more recently discovered angiotensin-(1–7)-ACE2-MasR pathways. Second, there is limited data on sex differences in RAS autonomic actions in aging. In this regard, future research should investigate if the cardiovascular autonomic pathways engaged by angiotensin II versus angiotensin-(1–7) differ in aged males versus females, as well as the impact of sex hormones, menopause, and hormone replacement therapy on these pathways. Emerging data in rodent models suggest that angiotensin-(1–7) provides added protection in females, although these studies are predominately in younger models.^102,103 Postmenopausal women have higher sympathetic activity and blood pressure than males,^104,105 as well as attenuated β2-adrenergic receptor-mediated vasodilation.¹⁰⁶ Thus, it is possible that older females will be more responsive to the sympathoinhibitory and depressor effects of RAS therapies, including angiotensin-(1–7) treatment. Third, despite well-established differences in hypertension development and therapeutic approaches,¹⁰⁷ there is limited information the impact of racial or ethnic influences on RAS: autonomic interactions or age-related changes in the RAS. African Americans are established to have lower plasma renin activity and aldosterone compared with Caucasians, which appear independent of blood pressure and age.^107,108 While RAS blockers are less likely to be used as first line therapy in African Americans, emerging data suggests no evidence for reduced efficacy of these therapies perhaps due to a paradoxical increase in tissue RAS activation. Initial evidence also suggests increased sympathetic neurotransmission contributes to enhanced cardiovascular risk in African Americans,¹⁰⁹ but the role of the RAS in this phenomenon is unknown. Finally, studies investigating age-related changes in RAS components and treatments have largely focused on healthy aging. Since healthy aging is atypical, additional studies are needed to investigate RAS actions and therapies, including potential autonomic mechanisms, in healthy versus diseased aging populations in both preclinical models and clinical trials.

Abbreviations

ACE

angiotensin converting enzyme

ACE2

angiotensin converting enzyme 2

ACEi

angiotensin converting enzyme inhibitors

ARBs

angiotensin receptor blockers

AT1R

angiotensin II type 1 receptors

AT2R

angiotensin II type 2 receptors

CVD

cardiovascular disease

eNOS

endothelial nitric oxide synthase

MasR

angiotensin-(1–7) mas receptors

NO

nitric oxide

RAS

renin-angiotensin system