Healthy lifestyle-based approaches for successful vascular aging

Abstract

This review summarizes a presentation given at the 2016 Gerontological Society of America Annual Meeting as part of the Vascular Aging Workshop. The development of age-related vascular dysfunction increases the risk of cardiovascular disease as well as other chronic age-associated disorders, including chronic kidney disease and Alzheimer’s disease. Healthy lifestyle behaviors, most notably regular aerobic exercise and certain dietary patterns, are considered “first-line” strategies for the prevention and/or treatment of vascular dysfunction with aging. Despite the well-established benefits of these strategies, however, many older adults do not meet the recommended guidelines for exercise or consume a healthy diet. Therefore, it is important to establish alternative and/or complementary evidence-based approaches to prevent or reverse age-related vascular dysfunction. Time-efficient forms of exercise training, hormetic exposure to mild environmental stress, fasting “mimicking” dietary paradigms, and nutraceutical/pharmaceutical approaches to favorably modulate cellular and molecular pathways activated by exercise and healthy dietary patterns may hold promise as such alternative approaches. Determining the efficacy of these novel strategies is important to provide alternatives for adults with low adherence to conventional healthy lifestyle practices for healthy vascular aging.

CARDIOVASCULAR DISEASES AND VASCULAR AGING

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the US and most modern societies (5, 34a). Advancing age is the primary risk factor for CVD, and as such, >90% of CVDs occur in middle-aged and older adults (5). Importantly, a new epidemic of CVD is projected in the near future as a consequence of a demographic shift toward older populations in developed nations (132a, 43). In the US alone, the number of older adults is expected to double by 2050 (132a); without effective intervention, it is predicted that 40% of adults in the US will have one or more forms of CVD by 2030 (43).

The key intermediate event linking aging with increased risk of CVD is the development vascular dysfunction (56, 88, 117). Although numerous adverse changes in vascular function occur with advancing age, two primary expressions of vascular aging that increase CVD risk are endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries) (56, 117). Importantly, healthy lifestyle behaviors such as regular aerobic exercise and certain dietary approaches favorably modulate these processes and reduce CVD risk with aging (62, 70, 86, 114, 116, 117).

Despite the well-documented benefits of these behaviors, however, many older adults do not meet the recommended guidelines for exercise and diet (104, 143). Thus, as we move toward the age of precision (personalized) medicine, alternative and complementary strategies must be established to provide options to those individuals for whom adherence to current guidelines may be unrealistic. Circumventing established barriers to healthy lifestyle behaviors with novel, time-efficient forms of aerobic exercise and/or via mild, controlled exposure to environmental stress to promote physiological adaptation, and more adherable dietary practices may hold promise in this context. Targeting specific cellular and molecular mechanisms of action by which healthy lifestyle behaviors exert their favorable effects with nutraceutical and/or pharmacological approaches represents another promising strategy for improving vascular health with aging.

In this summary of our presentation, which focused on strategies for enhancing vascular function with aging for the Vascular Aging Workshop at the 2016 Gerontological Society of America’s annual meeting, we will provide an overview of the physiology underlying the development of age-related vascular dysfunction, discuss how healthy lifestyle behaviors favorably modulate this process, and provide examples of novel lifestyle and nutraceutical-based interventions to recapitulate, at least in part, the benefits of these healthy lifestyle behaviors.

VASCULAR AGING

Vascular Endothelial Dysfunction

The vascular endothelium plays a critical role in the regulation of vascular tone and systemic blood flow, immune function, metabolism, thrombosis, and numerous other processes (115), in part through the release of the vasodilatory and vasoprotective molecule nitric oxide (NO). Mechanical (i.e., blood flow) and chemical (e.g., acetylcholine) stimuli elicit NO production in endothelial cells by activation of endothelial NO synthase (eNOS), which catalyzes the conversion of l-arginine and oxygen to NO. Endothelium-derived NO subsequently diffuses to vascular smooth muscle cells, where it activates an intracellular signaling cascade, leading to vasodilation [endothelium-dependent dilation (EDD)]. The degree of NO-mediated EDD can be assessed experimentally in humans by the vasodilatory response of the brachial artery to an increase in blood flow produced by temporary forearm ischemia (i.e., brachial artery flow-mediated dilation), which is considered the gold standard noninvasive assessment of macrovascular (conduit artery) function (115). In addition, microvascular (resistance vessel) EDD can be assessed by the forearm blood flow response to brachial artery-infused acetylcholine (ACh) (115). In rodents, flow-mediated dilation and the change in diameter of isolated arterial segments in response to pharmacological stimuli such as ACh can also be used to assess EDD (110, 112). Both macrovascular and microvascular EDD are key indices of endothelial health and independent predictors of CVD risk in older adults (22, 66, 115, 126, 127, 150, 151).

Mechanisms of Endothelial Dysfunction

Multiple molecular and cellular mechanisms underlie the adverse effects of aging on endothelial function. Of these, superoxide-related oxidative stress, characterized by an excess of reactive oxygen species (ROS) production relative to endogenous antioxidant defenses, is a primary mechanism contributing to reduced NO bioavailability and vascular dysfunction with age (Fig. 1) (21, 22, 28, 82). Excessive ROS within endothelial cells react directly with NO, leading to its deactivation and formation of another ROS, peroxynitrite. Moreover, ROS can oxidize tetrahydrobiopterin, an essential cofactor for NO synthesis by eNOS, which further compromises NO bioavailability and results in eNOS uncoupling, whereby eNOS itself becomes a ROS generator, producing superoxide instead of NO (13, 58). Additional important sources of vascular ROS include increased NADPH oxidase activity (21, 25) and excess ROS produced as a consequence of age-related declines in mitochondrial health/function (7, 38, 144). Unchanged or decreased endogenous antioxidant enzyme defenses with aging, including superoxide dismutases (115), contribute to this state of vascular oxidative stress.

Fig. 1.

Primary mechanisms of age-related vascular dysfunction. Vascular dysfunction is a key intermediary event linking aging to increased cardiovascular disease risk. Endothelial dysfunction (bottom left) is characterized by reduced bioavailability of nitric oxide (NO) as a result of excess reactive oxygen (ROS) production by dysfunctional mitochondria, increased NADPH oxidase activity, and uncoupling of endothelial NO synthase (eNOS). Increased proinflammatory cytokine production and an upregulation of the proinflammatory mediator NF-κB also contribute. Arterial stiffening (bottom right) occurs with age as a consequence of increased collagen deposition, loss/fragmentation of elastin, and formation of advanced glycation end products (AGEs). These processes are driven, at least in part, by age-associated increases in oxidative stress and inflammation.

Increases in chronic, low-grade inflammation with age also play a prominent role in promoting endothelial dysfunction (Fig. 1) (55, 115). Central inflammatory mediators such as the master transcription factor nuclear factor-κB (NF-κB) increase with aging in endothelial cells and contribute to impaired endothelial function, at least in part, by promoting increased oxidative stress (20, 100, 141).

Large Elastic Artery Stiffness

The large elastic arteries (i.e., the aorta and carotid arteries) expand and recoil with each bolus of blood that is ejected by the left ventricle during systole. This action dampens the oscillatory pulse of blood ejected into the arterial system, aids in the propulsion of blood to the periphery, and helps to maintain perfusion of the heart during diastole (110). The pulsatility-dampening effect of large elastic arteries is critical for reducing the transmission of high pulsatile pressures to low-impedance, high-flow-sensitive organs such as the kidneys and the brain (78). However, the large elastic arteries stiffen with age, and blood must be ejected into a stiffer aorta, which increases central and peripheral systolic blood pressure as well as the work of the heart to overcome the consequent increase in afterload (114). Moreover, the forward-moving pressure wave generated by the ejection of blood into the aorta travels at a higher velocity along the stiffer arteries, which alters the timing of the pressure wave reflected by points of impedance in the arterial tree, such that the returning pressure wave reaches the heart during systole; the early return of the reflected pressure wave further augments central systolic blood pressure and afterload and negates the ability of the reflected wave to support perfusion of the heart during diastole (77, 114). The change in timing of the reflected wave also results in a greater transmission of the forward-moving pressure wave to the microcirculation, which may damage small arterioles and capillaries leading to reduced blood flow and oxygen delivery to distal organs, such as the kidneys and brain (78). The pathophysiology and broad clinical implications of arterial stiffening for age-associated CVD, brain aging, and chronic kidney disease are the focus of another review from this series.

Arterial stiffness can be assessed regionally by measuring the velocity of the arterial pressure pulse wave [pulse wave velocity (PWV)] traveling through a defined arterial segment. The gold standard measure of PWV in humans is carotid-femoral (aortic) PWV (132), and aortic PWV can also be assessed in mice (110). Similar to EDD, carotid-femoral PWV independently predicts CVD risk with aging (79). Growing evidence also implicates aortic stiffening in the pathogenesis of Alzheimer’s disease (46) and declines in cognition (113, 139), as well as decreases in renal function (71, 142), consistent with the notion of greater pulsatility transmission-related damage to these high-flow organs (78). Arterial stiffness can also be evaluated locally by measuring arterial distensibility, which is most commonly assessed in the carotid artery as carotid artery compliance (inverse of stiffness). Carotid artery compliance decreases with advancing age (81, 130) and is associated with an increased risk of cardiovascular events, particularly incident stroke (134).

Mechanisms of Arterial Stiffening

Age-related stiffening of the large elastic arteries is mediated by structural changes in the arterial wall as well as functional changes, leading to increases in vascular smooth muscle tone (Fig. 1) (90). Structural changes include extracellular matrix remodeling (increased collagen deposition and elastin degradation) and formation of advanced glycation end products, which increase stiffening by cross-linking structural proteins (29, 56, 57). These stiffness-promoting processes are driven by mechanical events (i.e., repeated mechanical loads associated with cyclical changes in arterial pressure). In addition, preclinical findings indicate that oxidative stress may also contribute, as age-related collagen deposition is reversed with short-term treatment with the superoxide dismutase mimetic TEMPOL (29, 31). Oxidative stress and proinflammatory signaling also likely play a role in arterial stiffening with aging by increasing vascular smooth muscle tone, at least in part, by reducing NO bioavailability (132, 145). Greater sympathetic nervous system activity, renin-angiotensin-aldosterone system signaling, and endothelin-1 system activation also contribute to increased vascular smooth muscle tone and arterial stiffening with aging (67, 93, 123), and augmented intrinsic vascular smooth muscle cell stiffness also plays a role (102).

HEALTHY LIFESTYLE STRATEGIES FOR VASCULAR AGING

Aerobic Exercise

Regular aerobic exercise is considered a first-line strategy for preventing or reversing age-related arterial endothelial dysfunction and large elastic artery stiffening and reducing CVD risk with aging (Fig. 2) (26, 114). Regular aerobic exercise is advanced as the most effective overall approach, at least in part, because it acts to preserve vascular function with aging and improves function in previously sedentary late middle-aged and older adults. For example, macro- and microvascular EDD assessed in regularly exercising older men is higher than in their sedentary peers and, in some cases, similar to young, healthy control subjects (17, 80, 99). Moreover, exercise training in previously sedentary older men nearly restores EDD back to levels observed in young adults (17, 99).

Fig. 2.

Aerobic exercise and “exercise-inspired” approaches for preventing and reversing vascular aging. Continuous moderate-intensity aerobic exercise is one of the most evidence-based strategies for ameliorating vascular aging. The beneficial effects of aerobic exercise are mediated by reduced inflammation and oxidative stress and increased nitric oxide (NO) bioavailability. Aerobic exercise also exerts favorable effects on the composition of the arterial wall (i.e., reduces collagen deposition and advanced glycation end product formation). The efficacy of novel, potentially more adherable forms of exercise and/or “exercise-inspired” approaches such as high-intensity interval training, high-intensity inspiratory muscle strength training, and passive heat therapy for healthy vascular aging remains to be established.

Evidence for a beneficial effect of regular aerobic exercise on endothelial function in postmenopausal women, however, is less clear and consistent. In estrogen-deficient postmenopausal women, a large cross-sectional comparison of aerobic exercise-trained and untrained subjects (99) as well as selective exercise intervention studies (11, 99) fail to show exercise-related differences. In contrast, some studies in estrogen-deficient postmenopausal women suggest improved brachial artery macrovascular EDD (6, 125) or leg microvascular EDD (91) following aerobic exercise interventions, although the latter is in recently postmenopausal women. Results of a clinical trial assessing the interactive effects of training and sex hormones suggest that “premenopausal” circulating concentrations of estrogen may be necessary for transducing the beneficial effects of aerobic exercise on endothelial function in postmenopausal women, as a 12-wk aerobic exercise intervention improves brachial artery FMD in estrogen-supplemented but not estrogen-deficient individuals (84).

Lifelong aerobic exercise also favorably modulates arterial stiffness with aging in both men and postmenopausal women. Carotid-femoral PWV is lower and arterial compliance higher in older habitually exercising adults versus their sedentary peers (63, 81, 118, 129, 130, 133), and greater physical activity levels are associated with lower carotid-femoral PWV (35). Even lifelong causal exercisers (i.e., older adults exercising 2–3 days/wk for ≥20 yr) exhibit greater arterial compliance than sedentary older adults; however, a higher lifelong exercise dose of ≥4–5 days/wk appears to be necessary for preventing age-related aortic stiffening (118). Moreover, aerobic exercise interventions in previously sedentary adults have favorable effects on large elastic artery stiffness, although these effects are more clearly established for carotid artery compliance (81, 96, 130). Importantly, in contrast with endothelial function, aerobic exercise interventions appear to improve carotid artery compliance in both estrogen-deficient postmenopausal women (3, 128) and postmenopausal women on hormone replacement therapy (81). In terms of aortic stiffness, although some studies suggest beneficial effects of aerobic exercise interventions on carotid-femoral PWV in middle-aged and older men and women (42, 137, 152), this is not a universal observation (94, 96).

Mechanisms of Aerobic Exercise

The mechanisms by which exercise prevents or reverses vascular dysfunction with aging are multifactorial. In humans and animal models, the contribution of specific pathways to vascular dysfunction can be quantified by acutely inhibiting the pathway and evaluating the improvement in function; the greater the improvement, the greater the contribution of the pathway to the dysfunction observed without pathway inhibition (i.e., under basal conditions). This experimental paradigm has been employed to elucidate the mechanisms by which aerobic exercise preserves/restores vascular function with aging. For example, a primary mechanism of age-related vascular dysfunction affected by exercise is oxidative stress (114). Incubation with the general, superoxide-scavenging antioxidant TEMPOL to inhibit oxidative stress restores age-related declines in EDD in arteries from old sedentary mice, with no effect in old mice that underwent voluntary wheel running (25). Similar effects are observed following incubation with the NADPH oxidase inhibitor apocynin in arteries from sedentary but not voluntary wheel-running old mice (25). In sedentary but not endurance-trained older adult humans, infusion of supraphysiological doses of the superoxide scavenging antioxidant vitamin C acutely improves macro- and microvascular EDD (28, 126), and endothelial cells biopsied from the brachial artery exhibit increased abundance of nitrotyrosine, a marker of oxidant stress (98). Moreover, in estrogen-supplemented postmenopausal women, the aerobic exercise training-associated improvement in macrovascular endothelial function is mediated by reduced oxidative stress (84). Collectively, these findings suggest that oxidative stress contributes to the tonic suppression of endothelial function with sedentary and preserved endothelial function in exercising older adults is due to an absence of oxidative stress.

Aerobic exercise training also reverses age-related increases in inflammation. In old mice, voluntary wheel running normalizes NF-κB and proinflammatory cytokine expression in arteries, which is associated with improved EDD (64). In humans, NF-κB expression is lower in biopsied endothelial cells from older aerobic exercise-trained men versus their sedentary peers (98). Moreover, inhibition of NF-κB signaling with 4 days of administration of the anti-inflammatory drug salsalate restores macrovascular EDD in older sedentary men to levels observed in older endurance-trained men; this effect is mediated in part by a suppression of oxidative stress (141). Collectively, these findings implicate an overall suppression of ROS and reduced inflammation as primary mechanisms by which aerobic exercise improves endothelial function (Fig. 2).

Increased vascular stress resistance, i.e., the ability to maintain function in the presence of external stressors, is another mechanism by which regular aerobic exercise preserves/restores vascular function with aging. In support of this concept, macrovascular EDD in older adults who perform regular aerobic exercise is similar to EDD in healthy young subjects even in the presence of traditional CVD risk factors, such as elevated low-density lipoprotein cholesterol and impaired fasting glucose (18, 140). Moreover, voluntary wheel running mitigates the adverse effects of a high-fat/high-sugar “Western”-style diet on EDD in old mice (65). Similarly, acute exposure to a simulated Western-style diet stress (i.e., high-fat, high-sugar media) reduces EDD in arteries isolated from old sedentary mice, but not in those from young mice or old mice engaged in voluntary wheel running (37). This enhanced stress resistance appears to be related to improved mitochondrial health/reduced mitochondrial reactive oxygens species (ROS) in old arteries (37).

Reduced oxidative stress and inflammation are also mechanisms by which aerobic exercise reduces age-associated increases in arterial stiffness. Exercise-induced improvements in arterial stiffness in old mice are associated with reduced abundance of the oxidant stress marker nitrotyrosine in the aorta (30). Moreover, in sedentary, but not endurance-trained, postmenopausal women, an acute vitamin C infusion increases carotid artery compliance (83); similar effects, however, have not been observed in older men (27), suggesting that other factors apart from reductions in oxidative stress-related increases in vascular smooth muscle tone may contribute. Observations in old mice suggest that wheel running-associated reductions in oxidative stress may decrease arterial stiffness by modifying the composition of the arterial wall, namely by reducing collagen and advanced glycation end products (30, 89). With regard to inflammation, 4 days of treatment with the anti-inflammatory agent salsalate to inhibit NF-κB signaling reduces (improves) carotid-femoral PWV in older sedentary men, with no effect in older endurance exercise-trained men (47).

Alternative “Exercise-Inspired” Approaches

Despite the large evidence base supporting conventional aerobic exercise training (i.e., 150 min/wk of moderate-intensity exercise; see Ref. 105) for improving vascular function with aging, adherence remains low; it is estimated that only 20–50% of older adults meet current recommendations for physical activity (1). The reasons for low adherence are not completely understood and vary by sex, race, geography, and socioeconomic status; however, commonly cited barriers include limited time, motivation, access to facilities, and safety (85, 108). To circumvent these barriers, increasing attention is being paid to novel, time-efficient and/or easier-to-adopt strategies involving physical training or controlled exposure to environmental stress. In this section, we will highlight three such strategies that may be relevant for older adults and hold promise for healthy vascular aging (Fig. 2).

Perhaps the most well characterized of these interventions to date in younger adults and patients with clinical disorders is high-intensity interval training (HIIT), which consists of short exercise intervals performed at higher intensities (e.g., 85–95% of maximal heart rate) interspersed with periods of rest. HIIT has been reported to induce physiological adaptations similar to or even greater than conventional (continuous) moderate-intensity exercise (44, 68, 146). A growing body of evidence supports benefits of HIIT on vascular function in clinical populations, including patients with type 2 diabetes, hypertension, and established CVD (103). The efficacy of HIIT to improve endothelial function and/or arterial stiffness in older adults, however, remains to be fully elucidated and is currently under investigation (clinicaltrials.gov no. NCT01883271).

Another novel, potentially time-efficient form of exercise is high-intensity inspiratory muscle strength training (IMST). IMST involves inhaling against a resistance while exhaling unimpeded (15, 138). Using a modified version of IMST involving only 30 breaths against higher resistance (∼5 min/day) performed on most days of the week, clinically significant reductions in blood pressure (e.g., 10–12 mmHg) have been observed in normotensive young adults and patients with obstructive sleep apnea following 6 wk of training (15, 138). Interestingly, these reductions in blood pressure with IMST appear to be greater than those achieved with traditional aerobic exercise (typically ≤5 mmHg). Whether the benefits of IMST on blood pressure extend to older adults and include improvements in vascular function is unknown and currently being evaluated (Clinicaltrials.gov no. NCT03266510).

Lastly, passive heat therapy, characterized by repeated hot water immersion to raise core body temperature ∼1.0–1.5°C, improves macro- and microvascular (cutaneous) EDD and reduces arterial stiffness in young healthy subjects (8, 9). The cardiovascular benefits of passive heat therapy are thought to be mediated by some of the same physiological mechanisms that induce adaptations to aerobic exercise, including increases in core temperature, heart rate, and cardiac output, blood flow-related shear stress in the peripheral circulation, and activation of protective stress response mediators, such as heat shock proteins (9). The efficacy of heat therapy for improving vascular function in older adults is not known and is currently being investigated (Clinicaltrials.gov no. NCT03264508).

Additional investigation is needed to establish the safety, short- and long-term adherence, and efficacy of these novel exercise and/or exercise-like interventions for improving vascular function with aging.

Energy Intake

Caloric restriction, or energy intake restriction without malnutrition, is the most powerful lifestyle-based strategy for extending maximal lifespan and healthspan (period of healthy living) in rodents (7, 24). In regard to vascular aging, long-term (i.e., life-long) caloric restriction in mice prevents age-related declines in endothelial function and increases in large elastic artery stiffness (23); these effects are related to reduced oxidative stress (23). Short-term (i.e., 3–8 wk) caloric restriction also reverses age-related vascular dysfunction in old mice (106, 153). In humans, 3 mo of caloric restriction-based weight loss in overweight and obese middle-aged and older adults improves macrovascular and microvascular endothelial function (97) and large elastic artery stiffness (16) and is associated with reduced oxidative stress (97).

Mechanisms of Caloric Restriction

The beneficial effects of caloric restriction on vascular function most likely result from activation of multiple energy-sensing cellular signaling networks, including sirtuin-1 (SIRT-1) and AMP-activated protein kinase (AMPK), and inhibition of pro-growth mediators such as mammalian target of rapamycin (mTOR) (Fig. 3) (70, 73). These networks respond to the energy state of the cell; under low-energy conditions (e.g., high NAD/NADH ratio, low ATP levels, low glucose and amino acid availability), they activate cell stress resistance pathways such as autophagy and mitochondrial homeostasis networks, which ultimately increase NO bioavailability and reduce oxidative stress and inflammation in arteries (22, 70). SIRT-1 and AMPK may also directly increase NO bioavailability by posttranslationally modifying eNOS (70). As such, these intracellular mediators of the beneficial effects of caloric restriction can be considered as therapeutic targets for diet-based and/or pharmacological strategies for improving vascular function with aging (62, 70).

Fig. 3.

Calorie restriction and “calorie restriction-inspired” approaches for preventing and reversing vascular aging. Caloric restriction (i.e., energy intake restriction without malnutrition) prevents or reverses vascular aging, primarily by inducing a low-cellular energy state and modulating key energy-sensing pathways such as AMP-activated protein kinase (AMPK), the deacetylase sirtuin-1 (SIRT-1), mammalian target of rapamycin (mTOR), and autophagy. However, chronic caloric restriction is not practical in older adults. As a result, there is considerable interest in determining the safety, efficacy, and adherence of alternative, caloric restriction-inspired approaches for healthy vascular aging. One such caloric restriction-inspired approach presently under investigation is time-restricted feeding, which entails consuming all daily calories within a shorter time period (e.g., 8 h) than normal and fasting for the remainder of the day.

Alternative Caloric Restriction-Inspired Approaches

Despite the strong evidence for efficacy of caloric restriction in both preclinical models and humans, adherence to chronic caloric restriction is poor due to several factors, including readily available calorie-rich foods in developed societies and the social and cultural importance of food (72). Moreover, caloric restriction reduces skeletal muscle and bone mass, which are significant concerns for normal-weight older adults (76, 136). An alternative, potentially safer and more adherable strategy is “intermittent fasting,” characterized by alternating periods of unrestricted feeding with periods of caloric restriction to activate energy-sensing networks (70, 72, 73). One novel form of intermittent fasting that may recapitulate the benefits of caloric restriction while minimizing its risks is time-restricted feeding (Fig. 3). Time-restricted feeding involves consuming all daily calories within a shorter time period (e.g., 8 h) than normal and fasting for the remainder of the day (74). Recent findings in young, prediabetic men support beneficial effects of time-restricted feeding on cardiovascular function (reduced blood pressure) and oxidative stress without any changes in body weight, although no effects on arterial stiffness were observed (124). The efficacy of time-restricted feeding for improving vascular function in older adults remains to be determined and is currently being investigated (Clinicaltrials.gov no. NCT02970188); however, the safety, feasibility, and effects on muscle and bone mass must first be established in this population (70).

Dietary Influences

Broad dietary patterns prioritizing fruit and vegetables, whole grains, low-fat dairy, and moderate consumption of lean meats (e.g., the Mediterranean and DASH diets), as well as dietary patterns associated with increased fiber and fish consumption, are supported by both observational data and clinical trials for improving endothelial function and reducing arterial stiffness, particularly in older adults with CVD risk factors (62). Conversely, suboptimal dietary patterns appear to accelerate vascular aging; preclinical evidence demonstrates that consumption of a high-fat, high-sugar, low-fiber Western-style diet reduces endothelial function and increases arterial stiffness with age (45, 65). The micronutrient composition of the diet appears to also modulate vascular function with aging; specific electrolytes, such as magnesium, potassium, and calcium improve vascular function, whereas excess dietary sodium consumption exerts adverse effects on vascular function (62). Accordingly, low sodium intake is associated with better endothelial function and lower arterial stiffness, and dietary sodium restriction lowers blood pressure and reduces large elastic artery stiffness and improves both macro- and microvascular function in middle-aged and older adults (34, 48, 49). Future research is needed to distinguish between the efficacy of broad, healthy dietary patterns versus specific foods or bioactive ingredients within those patterns for promoting healthy vascular aging.

HEALTHY LIFESTYLE-MIMICKING STRATEGIES

Despite the well-documented benefits and robust effects of conventional aerobic exercise and certain dietary approaches, issues with adherence may preclude their utility in some individuals. As such, there is significant interest in repurposed pharmaceutical drugs (e.g., statins, antihypertensive or anti-inflammatory agents) or nutraceuticals, natural food ingredients or components with bioactive properties that may benefit human health. One approach for identifying potentially efficacious pharmaceutical or nutraceutical compounds is to select those that target the same mechanisms of action as healthy lifestyle behaviors, such as aerobic exercise and select dietary approaches (Fig. 4). In the sections below, we will illustrate this concept with examples of nutraceutical-based, healthy lifestyle-mimicking strategies focusing on those supported by preclinical and clinical evidence and highlighting work performed in our laboratory.

Fig. 4.

Nutraceutical compounds selected to activate signaling pathways of aerobic exercise, caloric restriction, and a healthy diet. Certain nutraceuticals targeting the signaling pathways modulated by exercise, caloric restriction, and/or a healthy diet hold promise for preventing or treating vascular aging. Examples include nitric oxide (NO)-boosting strategies through increased intake of nitrates or nitrites, which are naturally found in high concentrations in beets, compounds to modulate energy-sensing pathways by increasing levels of the sirtuin-1 substrate NAD⁺ or activation of autophagy via trehalose (found in mushrooms) or spermidine (found in grapefruit) supplementation, anti-inflammatory therapies such as curcumin, and mitochondria-targeted antioxidants to reduce reactive oxygen species (ROS).

NO Signaling

Because reductions in NO bioavailability play a central role in vascular aging, and restoration of NO signaling is a primary mechanism by which aerobic exercise and a healthy diet improve vascular function, NO-boosting strategies are ideal candidates for improving vascular function in older adults. There is now considerable preclinical and clinical evidence for the potential benefits of supplementation with nitrates and/or nitrites, which are found in high concentrations in beets and green leafy vegetables. In the blood and tissues, nitrate, nitrites, and related molecules serve as precursors for NO. Increasing nitrate primarily through diet-based approaches such as consumption of concentrated beetroot juice has been well studied for its blood pressure lowering effects, largely in groups with hypertension and/or other CVD risk factors (2). In these populations, nitrate also improves macrovascular endothelial function and reduces arterial stiffness (52, 135). Direct supplementation with inorganic nitrite is another, more direct approach for increasing nitrite levels (119). Nitrite supplementation improves endothelial function and reduces arterial stiffness in old mice, which is associated with reduced oxidative stress and inflammation in arteries (120). Nitrite also has favorable effects on macrovascular endothelial function in healthy middle-aged and older adults and may reduce large elastic artery stiffness (i.e., reduce carotid artery stiffness) in this population (19).

Inflammation and Oxidative Stress

Targeting inflammation and oxidative stress is another logical approach given the centrality of these processes in mediating age-related vascular dysfunction. Curcumin, considered to be the major bioactive component of the Indian spice turmeric, is a naturally occurring phenolic compound with antioxidant and anti-inflammatory properties. Curcumin supplementation in old mice completely restores age-related endothelial dysfunction and large elastic artery stiffening back to young adult levels, which is mediated by increased NO bioavailability and reduced oxidative stress and inflammation (32). Three months of curcumin supplementation also improves both macro- and microvascular endothelial function, the latter by increasing NO bioavailability and reducing oxidative stress, in middle-aged and older adults (111). Evidence suggests that curcumin may also reduce arterial stiffness (increase carotid artery compliance) in healthy postmenopausal women (3), although a lack of such effects also has been reported (111).

Given the prominent role of age-related increases in oxidative stress as a mechanism of vascular dysfunction, substantial research has focused on various antioxidant strategies for improving vascular function. However, the general consensus is that oral antioxidants such as vitamin C and E are ineffective for vascular aging and reducing CVD risk and may actually be harmful (28, 41, 50, 54). The short half-lives and inability of these traditional exogenous antioxidants to accumulate at key cellular sources of ROS are likely key contributors to their lack of efficacy. To circumvent these issues, considerable effort has been directed toward the development of more targeted antioxidant strategies (24, 87). Among these, mitochondria-targeted therapies are emerging as a promising option for age-related vascular dysfunction (95, 121). The mitochondria-specific antioxidant MitoQ is a compound consisting of the natural antioxidant coenzyme Q10 conjugated to a lipophilic compound; these properties enable MitoQ to accumulate in the mitochondrial matrix, where it is optimally positioned to reduce ROS produced by mitochondria (122). In old mice, MitoQ supplementation completely ameliorates age-related endothelial dysfunction by increasing NO bioavailability and reducing mitochondrial ROS and reverses age-associated arterial stiffening (36, 38). Recent evidence indicates that MitoQ also improves macrovascular endothelial function in late middle-aged and older adults and may reduce aortic stiffness in individuals exhibiting age-related arterial stiffening (107).

Energy Sensing Pathways

As mentioned above, interventions targeting the energy sensing networks activated by caloric restriction are another promising approach for preventing/reversing vascular dysfunction in older adults. This general approach is the subject of a recent review from our laboratory (70) and a focus of another review in this series (40).

Work from our laboratory has demonstrated favorable effects on cardiovascular function with aging through pharmacological activation of the SIRT-1 network using both pharmaceutical-based sirtuin-activating compounds (33) and by increasing levels of the SIRT-1 activation-dependent substrate NAD⁺ (14, 69). Treatment with the sirtuin-activating compound SRT1720 restores age-related decreases in aortic SIRT-1 expression and activity in mice and reverses the age-associated impairment in EDD by enhancing cyclooxygenase-2 dilation and normalizing arterial superoxide production, oxidative stress, and inflammation in old mice (33). Supplementation with nicotinamide mononucleotide, a natural (nutraceutical) precursor molecule for NAD⁺ biosynthesis, increases arterial NAD⁺ and SIRT-1 activity and restores endothelial function in old mice by reversing excessive aortic superoxide production, oxidative stress, and inflammation while also ameliorating age-associated increases arterial stiffness (aortic PWV and intrinsic stiffness) and aortic fibrosis (14). More recently, supplementation with nicotinamide riboside, another NAD⁺ precursor, was shown to increase NAD⁺ levels in healthy middle-aged and older adults and reduce arterial stiffness and systolic blood pressure in subjects with elevated blood pressure without influencing endothelial function (69). However, resveratrol, a polyphenol and strong SIRT-1 activator, improves macrovascular endothelial function in older obese adults and older adults with impaired glucose tolerance (101, 148).

Finally, activation of autophagy, the intracellular degradation and recycling of damaged macromolecules and organelles, holds promise as a therapeutic target, given its central role as an effector of the beneficial impact of caloric restriction (4). Nutraceutical approaches for enhancing autophagy include spermidine (a polyamine found in grapefruit and fermented soy products) and trehalose (a disaccharide found in mushrooms). Both of these compounds reverse age-related endothelial dysfunction and arterial stiffening in mice (59–61), and trehalose improves microvascular endothelial function by increasing NO bioavailability in late middle-aged and older healthy men and women (53).

Considerations

An important consideration for the strategies described above is the possibility of their interaction with other healthy lifestyle practices, such as aerobic exercise. For example, although not well-studied in the context of vascular function per se, evidence exists for adverse interactions between aerobic exercise training and concurrent administration of some supplements, such as nonspecific antioxidants (75) and resveratrol (39, 109). In contrast to adverse interactions, consumption of nitrate-rich beetroot juice before each exercise bout of a supervised exercise training program enhances the training-associated benefits of the program (e.g., augments the increase in 6-min walk distance after training) in individuals with peripheral artery disease (147); a similar enhancement of exercise training-associated improvements in physiological function is observed in young subjects with concurrent nitrate-rich beetroot juice supplementation during a training program (131). Clearly, more research is needed to determine the nature of the interaction (if any) between nutraceutical strategies and other healthy lifestyle practices in the context of vascular aging.

Another important consideration is whether adherence to the alternative strategies described in this review will actually be better than more established strategies. Although it is tempting to speculate that alternatives to exercise and eating a healthy diet may have broader appeal and be associated with greater adherence, recent data indicate that many older adults may not even adhere to such practices. For example, only 60% of older adults are classified as “highly adherent” to antihypertensive medication, defined as meeting their recommended dose >80% of the time (149). Similar low rates (<50%) are observed for long-term adherence to statins prescribed for primary prevention of CVD in older adults (92). Considerably less is known about the use of nutraceuticals or dietary supplements and adherence to recommended dosage for specific indications (51), and it is important to consider that adherence to the nutraceuticals described above may be less than assumed.

Regardless, it is likely that certain individuals are more or less motivated to adhere to specific types of strategies, and therefore, it is necessary to establish diverse, evidence-based options that may be utilized by these individuals to preserve vascular health with aging. Indeed, personalized medicine is based on the concept of tailoring medical decisions, practices, and interventions to the individual based on their predicted response or risk of disease. Thus, it is biomedically compelling to continue to identify and assess novel interventions that may be the best fit for a given person. In contrast to advancing pharmaceutical or nutraceutical strategies as panaceas for the adherence issues commonly associated with following healthy lifestyle guidelines, the goal of this research should be to establish evidence for alternative interventions to ultimately provide options to individuals for whom current practices are ineffective.

SUMMARY AND CONCLUSIONS

The development of age-related vascular dysfunction is a key intermediary event linking aging with increased CVD risk and other common age-associated disorders. Healthy lifestyle behaviors, including regular aerobic exercise and select dietary practices, are the most well-established strategies for enhancing vascular function with aging. Determining the safety, feasibility, and efficacy of novel interventions intended to recapitulate the effects of established healthy lifestyle behaviors on healthy vascular aging, to ultimately provide preventive and therapeutic options to individuals, should be viewed as a biomedical research priority.

GRANTS

Work from the authors’ research was supported by National Institutes of Health Awards AG-013038 (MERIT), HL-134887, AG0-49451, AG-053009, AG-000279, HL-107120, HL-107105, AG-042795, AG-006537, and RR-000051/TR001082.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.J.R., T.J.L., and C.R.M. prepared figures; M.J.R. and D.R.S. drafted manuscript; M.J.R., T.J.L., C.R.M., and D.R.S. edited and revised manuscript; M.J.R., T.J.L., C.R.M., and D.R.S. approved final version of manuscript.