Keynote lecture: strategies for optimal cardiovascular aging

Abstract

This review summarizes the opening keynote presentation overview of the American Physiological Society Conference on Cardiovascular Aging: New Frontiers and Old Friends held in Westminster, CO, in August 2017. Age is the primary risk factor for cardiovascular diseases (CVDs). Without effective intervention, future increases in the number of older adults will translate to a greater prevalence of CVDs and related disorders. Advancing age increases the risk of CVDs partly via direct effects on the heart and through increases in blood pressure; however, much of the risk is mediated by vascular dysfunction, including large elastic artery stiffening and both macro- and microvascular endothelial dysfunction. Although excessive superoxide-related oxidative stress and chronic low-grade inflammation are the major processes driving cardiovascular aging, the upstream mechanisms involved represent new frontiers of investigation and potential therapeutic targets. Lifestyle practices, including aerobic exercise, energy intake (caloric) restriction, and healthy diet composition, are the most evidence-based strategies (old friends) for optimal cardiovascular aging, but adherence is poor in some groups. Healthy lifestyle “mimicking” approaches, including novel forms of physical training, intermittent fasting paradigms, exercise/healthy diet-inspired nutraceuticals (functional foods and natural supplements), as well as controlled environmental stress exposure (e.g., heat therapy), may hold promise but are unproven. Mitigating the adverse effects of aging on cardiovascular function and health is a high biomedical priority.

INTRODUCTION

The combination of increasing life expectancy and low birth rates is remodeling the age demographics of both developed and developing nations, resulting in unprecedented numbers of older adults. Meanwhile, cardiovascular diseases (CVDs) remain the leading cause of morbidity (illness) and mortality in most societies, and aging is by far the strongest independent risk factor for CVDs (3). This intersection of age-associated CVD risk and an increasing pipeline of older adults is the key factor driving predictions of a significant rise in future CVD prevalence (17).

In this summary of the opening keynote presentation of the 2017 American Physiological Society Conference on Cardiovascular Aging: New Frontiers and Old Friends, we provide a brief overview of several key issues in the field of cardiovascular aging based largely on our three-plus decades of work in the area. We attempt to emphasize both what has been and continues to be investigated (old friends) as well as emerging areas of investigative interest (new frontiers).

WHY AGING INCREASES THE RISK OF CVDs

The projected increases in age-associated CVDs and the need to establish effective interventions lead to the question of why aging is associated with such a marked increase in CVD risk. The answer is multifactorial. Some of the increase in risk is mediated by the direct effects of aging on the heart, which include left ventricular fibrosis, myocyte apoptosis (and hypertrophy of the remaining myocytes), impaired calcium homeostasis, dysregulation of cardiac stem cells, and blunted β-adrenergic signaling/responsiveness (23). Age-related increases in systolic blood pressure (SBP) are another major factor in the increase in CVD risk observed with aging (3). However, much of the striking effect of age on CVD risk is transduced through the development of vascular dysfunction (22). Several changes to arteries contribute to this “vascular aging” phenotype, but stiffening of the large elastic arteries (aorta and carotid arteries) and diffuse impairments in macro- and microvascular endothelial function, assessed as reduced dilation to endothelium-derived nitric oxide (NO), are among the most important clinically (22). These changes in arterial function also contribute to the progressive rise in SBP with aging (and widening of arterial pulse pressure) as well cardiac dysfunction, including left ventricular hypertrophy and diastolic dysfunction (22, 23).

MECHANISMS OF CARDIOVASCULAR AGING

A complex array of dynamically interacting cellular and molecular mechanisms underlie the effects of aging on cardiovascular function and health. The major established processes involved (old friends) are excessive superoxide-driven oxidative stress and chronic low-grade inflammation featuring increased expression of proinflammatory cytokines (21, 39). These are mutually reinforcing processes, each sustaining and amplifying the other.

Oxidative stress and proinflammatory signaling stimulate collagen deposition in the walls of arteries (fibrosis), cause fragmentation and degradation of elastin filaments, and induce the formation of advanced glycation end products that cross-link structural proteins, all of which lead to stiffening of the heart and large elastic arteries (13, 21–23). Vascular oxidative stress with aging is largely related to elevated superoxide levels, created by excessive superoxide production from dysregulated cellular respiration (4, 44), increased expression and activity of the oxidant enzyme NADPH oxidase (10, 12), and uncoupling of the endothelial isoform of the (normally) NO-producing enzyme endothelial NO synthase (45) in combination with either the absence of an appropriate compensatory upregulation of antioxidant enzymes such as superoxide dismutase (12, 39) or an actual age-related decrease in the expression and/or activity of antioxidant enzymes (14, 16).

One of the new frontiers of cardiovascular aging research is to establish the upstream, interacting, and/or reinforcing molecular events driving cellular oxidative stress and inflammation. Presently, there is evidence for mitochondrial dysfunction, impaired autophagy/mitophagy, altered signaling of energy-sensing pathways (e.g., 5′-AMP-activated protein kinase and NAD⁺-dependent sirtuin activation), and sex hormone deficiency playing important roles (40). However, other fundamental mechanisms of biological aging, including cellular senescence, reduced stress resistance, genomic instability, telomere attrition, reduced proteostasis, stem cell dysfunction, and/or epigenetic modifications, along with dysbiosis of the gut and/or oral microbiomes (35, 40), also may contribute. Interestingly, all but one of these putative mechanisms (gut dysbiosis) are among those recently described as “hallmarks of aging,” i.e., fundamental biological processes implicated in the development of cellular aging phenotypes in multiple tissues (27). It is likely that in the future, many if not all of these mechanisms also will be viewed as hallmarks (molecular transducers) of cardiovascular aging (Fig. 1, top).

Fig. 1.

Top: established and putative cellular and molecular mechanisms driving cardiovascular dysfunction and common clinical disorders of aging. Bottom: lifestyle and pharmacological strategies may protect against the development of cardiovascular dysfunction with aging (primary prevention) and/or improve existing dysfunction to slow progression to clinical disorders (secondary prevention).

Presently, most of the work in this area is being conducted on wild-type and genetically modified mice, but new efforts are underway using high-throughput molecular analyses of accessible biological samples from humans that may add complementary translational insights (9). These analyses may also yield novel biomarkers that discriminate individual cardiovascular aging status in a more sensitive manner than chronological age or assessment of conventional CVD risk factors.

STRATEGIES FOR OPTIMAL CARDIOVASCULAR AGING

Strategies for achieving optimal cardiovascular aging may be viewed as lifestyle or pharmacological approaches aimed at primary or secondary prevention of CVDs and other clinical consequences of age-related cardiovascular dysfunction, including chronic kidney disease, cognitive impairment, Alzheimer’s disease, and exercise intolerance (Fig. 1, bottom) (40). Primary prevention efforts focus on slowing/delaying, minimizing, or completely preventing the adverse effects of aging on cardiovascular function, whereas secondary prevention strategies seek to exert the same effects on the progression of age-associated cardiovascular dysfunction to clinically relevant end points. Successful strategies often demonstrate benefits for both primary and secondary prevention.

Healthy Lifestyle Strategies

By far, healthy lifestyle strategies have the strongest established evidence for efficacy in the primary and secondary prevention of adverse cardiovascular aging (24, 28, 38, 40, 41) and thus can be considered “old friends” in this context (Fig. 2).

Fig. 2.

Healthy lifestyle- and pharmacological-based approaches for achieving healthy cardiovascular aging, from old friends (the most evidence-based strategies) to new frontiers (promising interventions that remain unproven).

Aerobic exercise.

Among healthy lifestyle factors, regular aerobic exercise has the most extensive evidence base. Habitual aerobic exercise is associated with enhanced cardiac function, lower SBP and large elastic artery stiffness, and greater macro- and microvascular endothelial function during aging compared with less active states and exerts significant therapeutic effects in older animals and humans with existing cardiovascular dysfunction (2, 8, 12, 15, 25, 26, 34, 38). The mechanisms underlying these benefits of aerobic exercise include suppression of oxidative stress and inflammation as well as increased mitochondrial quality control (12, 15, 25, 38). Aerobic exercise also increases resistance to stressors in aging arteries (38), essentially shielding them from a variety of chronic adverse influences, including a Western diet (15, 26) and suboptimal CVD risk factors (8). Novel forms of aerobic exercise such as high-intensity interval training are presently understudied strategies in this area (new frontiers), although continuous, moderate-intensity aerobic exercise remains a highly effective and well-established option (7).

Energy intake (caloric) restriction.

Another highly effective lifestyle strategy for preserving cardiovascular function with aging is reduced energy intake (calorie restriction) without malnutrition (43). In rodents, lifelong caloric restriction prevents age-related cardiac changes, increases in SBP, arterial stiffening, and endothelial dysfunction (1, 11), whereas shorter-term calorie restriction initiated later in life reverses several features of cardiovascular aging (36). Consistent with the latter findings in mice, short-term (12-wk) caloric restriction-based weight loss lowers SBP and improves both large elastic artery stiffness and macro- and microvascular endothelial function in overweight and obese middle-aged and older humans (6, 33). However, sustained caloric restriction is not feasible from a public health perspective due to poor adherence, and the accompanying weight loss and reductions in muscle and bone mass would have negative implications for normal-weight older adults (24, 28, 40). As a result, currently there is great interest in alternatives to chronic caloric restriction involving intermittent fasting (fasting ≥2 days/wk or daily time-restricted feeding) or periodic fasting (fasting several days/month) paradigms (24, 28). However, the feasibility, efficacy, and safety of these approaches remain to be determined in humans and represent new investigative frontiers (24).

Diet composition.

Diet composition also exerts an important influence on cardiovascular aging. There is good evidence that broad healthy dietary patterns featuring unprocessed, plant-based foods, and sources of fat (e.g., olive oil), such as the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets, as well as general diets that are high in fruit, vegetable, fatty fish, and fiber intake, are associated with better preservation of cardiovascular function and health with aging (24, 32). In preclinical models (rodents and nonhuman primates), “Western” style diets (high in saturated fat and refined sugar, low in fiber) exacerbate the effects of aging on cardiovascular dysfunction (24, 26), but more research is needed in humans.

Individual micronutrients in the diet also appear to influence cardiovascular aging. Greater natural intake of potassium, magnesium, and calcium as well as lower sodium intake in the diet are positively related to cardiovascular health with aging (18, 24, 41); moreover, dietary sodium restriction markedly reduces SBP and improves vascular function in older adults (19). There also is evidence that whey protein, dairy, and cocoa products, dark chocolate, seeds, whole grains, nuts, legumes, and coffee are among the foods associated with favorable cardiovascular aging (24). A future research priority will be to determine if the cardiovascular benefits of established healthy dietary patterns (e.g., DASH diet) are mediated by specific foods within those diets or rely on the interactive (holistic) effects of multiple bioactive components.

Healthy Lifestyle-Mimicking Compounds

There are many well-established barriers to meeting current public health guidelines for physical activity and consuming a healthy diet, including time, motivation, access (to facilities and healthy foods), safety, and expense (31, 37); as a result, adherence to these recommendations is notoriously low, particularly in groups with lower income and education. This situation has driven recent interest in the development of pharmacological compounds intended to “mimic” or recapitulate at least some of the benefits of healthy lifestyle practices (Fig. 2, top). One investigative approach to identifying promising compounds has been to establish the molecular and cellular mechanisms underlying positive effects of exercise and/or healthy diet and then to view these pathways as putative targets for primary and secondary prevention of cardiovascular aging (24, 28). Mitochondria-specific antioxidants, anti-inflammatory agents, NO bioavailability-boosting molecules, autophagy-enhancing compounds, and activators of energy-sensing signaling pathways are among the many mechanisms identified using this approach (28, 40, 41).

Because strategies for healthy cardiovascular aging are aimed at preventing rather than treating clinical disease, much of the focus for testing compounds has centered on potential “nutraceuticals,” i.e., natural food ingredients with bioactive properties that may exert health benefits, including dietary supplements and functional foods, as opposed to prescription pharmaceuticals (24, 40, 41). As summarized in more detail in recent reviews (24, 28), several nutraceutical compounds have been assessed for possible beneficial effects on cardiovascular aging in mice and/or humans. Presently, the strongest translational evidence for beneficial effects on cardiovascular function with aging is associated with ω-3 fish oils and curcumin (antioxidant/endogenous antioxidant-inducing and anti-inflammatory), nitrite/dietary nitrate supplementation (NO-boosting), trehalose administration (autophagy activator/antioxidant), and resveratrol (sirtuin-1 activation); emerging support also exits for mitochondria-specific antioxidants (MitoQ) and NAD⁺-boosting compounds targeting activation of sirtuin energy-sensing cellular pathways (nicotinamide mononucleotide and nicotinamide riboside) (16, 24, 28, 40, 41). Establishing safety and efficacy in clinical trials, inconsistencies among formulations, and possible negative interactions with healthy lifestyle practices are among the challenges for future research in this area (24, 40, 41).

Other Strategies

Many other strategies for promoting healthy cardiovascular aging hold promise and are presently in the early stages of preclinical or clinical testing (new frontiers; Fig. 2). These include oral formulations targeting gut dysbiosis (prebiotics, probiotics) or gut-derived metabolites [e.g., trimethylamine lyase inhibitors (35, 42)], environmental stress-based interventions [e.g., heat therapy (5)], and repurposing of existing pharmaceuticals/development of new pharmaceuticals aimed at other fundamental mechanisms (hallmarks) of cardiovascular aging [e.g., anti-cell senescence therapies or “senolytics” (20)].

SEX DIFFERENCES IN CARDIOVASCULAR AGING

Sex differences in cardiovascular aging was the focus of another lecture in this American Physiological Society conference. However, it is important to emphasize in the present overview that cardiovascular changes driven by primary aging processes (i.e., hallmarks of cardiovascular aging) are strongly modulated by changes in the production and circulating concentrations of sex hormones as women progress through the premenopausal, perimenopausal, and postmenopausal stages of life (29). Moreover, it is crucial that putative strategies for enhancing cardiovascular health throughout the lifespan be rigorously investigated in both men and women because of potential sex differences in responsiveness to specific interventions (30).

CONCLUSIONS

Cardiovascular dysfunction not only plays a central role in the marked age-associated increase in CVD risk but also in the etiology of many other common disorders of aging. As such, identifying the key biological mechanisms driving cardiovascular aging (therapeutic targets) and establishing strong translational evidence for safe, feasible, and efficacious strategies for preventing/treating cardiovascular dysfunction with advancing age should be among our highest biomedical research priorities.

GRANTS

This research was supported by National Institutes of Health Grants AG-013038 (MERIT), HL-134887, AG-049451, AG-053009, HL-007822, AG-000279, HL-107120, HL-107105, AG-042795, AG-006537, and RR-000051/TR-001082.

DISCLOSURES

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

AUTHOR CONTRIBUTIONS

D.R.S., V.E.B., and M.J.R. prepared figures; D.R.S., V.E.B., and M.J.R. drafted manuscript; D.R.S., V.E.B., and M.J.R. edited and revised manuscript; D.R.S., V.E.B., and M.J.R. approved final version of manuscript.