Age is the dominant risk factor for cardiovascular diseases. However, until recently, convincing mechanistic or molecular explanations for the increased cardiovascular risks conferred by aging have been elusive. Aging is associated with alterations in a number of structural and functional properties of large arteries, including diameter, wall thickness, wall stiffness, and endothelial function. Emerging evidence indicates that these age-associated changes are also accelerated in the presence of cardiovascular diseases, and that these changes are themselves risk factors for the appearance or progression of these diseases. In this review, the evidence demonstrating that arterial aging is accelerated in cardiovascular diseases and that accelerated arterial aging is a risk factor for adverse cardiovascular outcomes is briefly reviewed, and selected advances in vascular biology that provide insights into the mechanisms that may underlie the increased risks conferred by arterial aging are summarized. Remarkably, a host of biochemical, enzymatic, and cellular alterations that are operative in accelerated arterial aging have also been implicated in the pathogenesis and progression of arterial diseases. These vascular alterations are thus putative candidates that could be targeted by interventions aimed at attenuating arterial aging, similar to the lifestyle and pharmacological interventions that have already been proven effective. Therefore, the notion that aging is a chronological process and that its risky components cannot be modulated is no longer tenable. It is our hope that a greater appreciation of the links between arterial aging and cardiovascular diseases will stimulate further investigation into strategies aimed at preventing or retarding arterial aging.
Cardiovascular diseases are the leading causes of morbidity, mortality, and disability in industrialized countries, and according to World Health Organization estimates, they are poised to also become, within the next decade, the major causes of mortality in developing nations. This cardiovascular disease epidemic is occurring despite unprecedented advances in the diagnosis and treatment of these conditions. This situation is only expected to worsen because the world population is aging.
Epidemiological studies have unequivocally shown that age is the dominant risk factor for cardiovascular diseases. Indeed, the incidence and prevalence of hypertension, coronary heart disease, congestive heart failure, and stroke all steeply increase with advancing age. However, most of the research efforts have focused on developing interventions that target “traditional” risk factors for coronary heart disease (eg, hypertension, hypercholesterolemia, etc.) or identifying newer ones, whereas little attention has been devoted to aging. This is because age has usually been viewed as a chronological and unmodifiable, hence unpreventable or untreatable, risk factor. Instead, the risky components of aging have been attributed, in part, to an increased time of exposure to other established cardiovascular risk factors, which, in turn, may vary in number and severity with increasing age.
These arguments expose our major shortcoming in understanding why age is such a potent risk factor for cardiovascular diseases, namely our poor insight into the specific elements that constitute the risky components of aging vis a vis the cardiovascular system. In other words, although we have always intuitively accepted age as being a risk factor and have taken this to be a “truism,” we did not have, until recently, good mechanistic or molecular explanations as to why this would be the case.1
In this article, we briefly review the evidence implicating arterial aging as a cardiovascular risk factor, summarize selected recent advances in vascular biology that provide insights into the mechanisms that may underlie the increased risks conferred by arterial aging, and discuss existing interventions to prevent or retard accelerated arterial aging, as well as potential new ones worthy of investigation.
Arterial Aging in Apparently Healthy Humans
The age-associated changes in arterial structure and function in apparently healthy humans are summarized in the Table and have been reviewed recently.1 Cross-sectional studies show that elastic arteries, such as the central aorta, on average, dilate with age (Figure 1A), leading to an increase in lumen size.2 The thickness of the arterial wall, as indexed by the thickness of the intimal and medial layers, increases in a linear fashion nearly 3-fold between the ages of 20 and 90 years even in the absence of atherosclerotic plaques3 (Figure 1B). Postmortem studies show that this age-associated increase in arterial wall thickening is caused mainly by an increase in intimal thickening,4 even in populations with low incidence of atherosclerosis. Note in Figure 1B that not only the average intimal medial thickness (IMT) increases with advancing age, but that the range of values for IMT is greater at higher ages, suggesting significant heterogeneity in the magnitude of the age-associated thickening process among older individuals: some exhibit low values of IMT for their age and are termed “successful,” whereas others have “accelerated” alterations.
|Humans >65 Years||Monkeys 15–20 Years||Rats 24–30 Months||Rabbits 3–6 Years|
|? indicates unknown.|
|Table adapted from Wang and Lakatta.62|
|Diffuse intimal thickening||+||+||+||+||+||+|
|↑ VSMC number||+||+||+||+||+||+|
|↑ Local Ang II-ACE||+||+||+||+||+||+|
|↑ NADPH oxidase||?||?||+||?||+||+|
|↓ NO bioavailability||?||?||+||+||+||+|
|↓ Telomere length||+||+||+||?||?||+|
The age-associated increase in thickness of the central arterial wall is accompanied by an increase in stiffness (Figure 1C).5 This has been attributed to the repeated cycles of distensions and elastic recoils of the arterial wall, which are thought to accelerate the fragmentation and depletion of elastin, as well as the deposition of collagen.6 Stiffness can be further amplified in the presence of specific gene polymorphisms.7 The age-associated increase in central arterial stiffness, in turn, contributes to shifting the return of reflected waves to an earlier time during systole, which leads to an increase in central pressure augmentation (Figure 1D).8 Thus, although peripheral systolic blood pressure and pulse pressure increase with age,9 for a given brachial blood pressure, central blood pressure is higher in older persons.10
Endothelial cells play a pivotal role in regulating several arterial properties, including vascular tone, vascular permeability, angiogenesis, and the response to inflammation. Endothelial-derived substances (eg, NO, endothelin-1) are determinants of large arterial compliance,11 suggesting that endothelial cells may also modulate central arterial stiffness. However, endothelial function in central arteries has not been directly assessed in humans. In the brachial artery, endothelial function, as assessed by agonist- or flow-mediated vasoreactivity, has been shown to decline with advancing age.12,13 However, in contrast to central arteries, the stiffness of muscular arteries does not increase with advancing age.14 Thus, the manifestations of arterial aging may vary among the different vascular beds, reflecting differences in the structural compositions of the arteries and, perhaps, differences in the age-associated signaling cascades that modulate the arterial properties (see below), or differences in the response to these signals across the arterial tree.
There is growing recognition that telomere length may be construed as a tissue-specific marker of biological, as opposed to chronological, age. Telomeres are specialized structures located at the end of chromosomes, which shorten with each replication, unless they are rescued by the enzyme telomerase reverse transcriptase. When telomere length reaches a critical size, reflecting numerous cycles of attrition, no further cellular replication is possible and the cell becomes senescent. Telomere length has been shown to be inversely associated with chronological age in endothelial cells from human abdominal aorta, iliac arteries, and iliac veins.15,16 The impact of telomere-induced vascular senescence may be accentuated in older individuals, in whom recent studies indicate that the number17 and activity18 of endothelial progenitor cells is reduced, suggesting an age-associated diminution in regenerative capacity, which may contribute to the age-associated impairment in angiogenesis.19
Arterial Aging in Cardiovascular Diseases
Although the aforementioned changes in arterial structure and function with aging were thought previously to be part of normative aging, this concept was challenged when data emerged showing that these changes are accelerated in the presence of cardiovascular diseases.
Patients with hypertension exhibit greater carotid wall thickness,20 central arterial stiffness,21 and central pressure augmentation22 than normotensive subjects, even after adjusting for age. They are thought to have higher central arterial diameters,23 although this is presently debated.6,24 Hypertensive individuals exhibit endothelial dysfunction,25 and the mechanisms underlying their endothelial dysfunction are similar to the ones that occur with normotensive aging, albeit they appear at an earlier age.26 The normotensive offspring of hypertensives also exhibit endothelial dysfunction,27 suggesting that endothelial dysfunction may precede the development of clinical hypertension. Among hypertensive men, shorter telomere length of circulating white blood cells is associated with greater arterial stiffness.28
The metabolic syndrome, which is quite prevalent among older individuals,29 is associated with elevated carotid arterial thickness and stiffness.30 Diabetics also exhibit higher carotid IMT than nondiabetics,31 and they have accelerated progression of their IMT.32 Although their central arterial stiffness is increased,21 this is not accompanied by an increase in the central pressure augmentation.33 Diabetics also exhibit endothelial dysfunction,34 which can be found in their first-degree relatives who have insulin resistance.35 The circulating white blood cells of insulin-dependent diabetics have shorter telomere lengths than those from normoglycemic controls or noninsulin-dependent diabetics.36
Patients with atherosclerosis have increased thickness,3,37 and stiffness38 of their central arterial walls, greater central pressure augmentation,39 and shorter telomere lengths on their circulating white blood cells.40,41 They also exhibit endothelial dysfunction,42 which has been implicated in the pathogenesis of atherosclerosis43 and is one of its earliest pathologic manifestations.44
Accelerated Arterial Aging Is Risky
Increased IMT is associated with silent ischemia among asymptomatic older individuals3 and is an independent predictor of stroke and future myocardial infarction45 (Figure 2A). The strength of IMT as a risk factor for cardiovascular diseases equals or exceeds that of most other traditional risk factors. Over and above IMT, arterial geometry, which is derived from the interplay between IMT and lumen diameter,46 is also an independent predictor of coronary or cerebrovascular events.47 Furthermore, increased central arterial stiffness is an independent predictor of future cardiovascular outcomes, even after adjusting for blood pressure, in subjects with hypertension,48 patients with end-stage renal disease,49 and community-dwelling older individuals50 (Figure 2B). Increased central arterial pressure augmentation is an independent predictor of all-cause and cardiovascular mortality in patients with end-stage renal disease51 (Figure 2C). Several studies have now demonstrated that impaired endothelial vasoreactivity, in both the coronary and peripheral arterial beds, is an independent predictor of future cardiovascular events43 (Figure 2D).
Age-Associated Arterial Remodeling Under the Microscope
Further insights into the mechanisms that may underlie the increased cardiovascular risks associated with accelerated arterial aging can be gleaned from animal studies because they allow us to probe the cellular and molecular determinants of the macroscopic changes observed in humans, and because in many species, arterial diseases do not accompany vascular aging, thus allowing us to distinguish between effects attributable to aging and those attributable to superimposed disease. As shown in the Table, the patterns of age-associated changes in arterial structure and function in rodents, rabbits, and nonhuman primates are quite similar to those in humans.
Aging of the Arterial Intima
In rodent52 and nonhuman primate53 models of aging, diffuse intimal thickening is observed with advancing age, even though these animals do not develop atherosclerosis. The diffusely thickened aging intima (Figure 3A) contains matrix proteins, collagen, glycosaminoglycans, vascular smooth muscle cells (VSMCs) that are thought to have migrated from the media, increased expression of aortic intimal adhesion molecules52 (Figure 3B), and increased adherence of monocytes to the endothelial surface.54 Within the thickened intima, the levels of the inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) and its receptor, which have been implicated in the pathogenesis of atherosclerosis,55 are also elevated.56 Of note, in aged rats and monkeys, there is no evidence that “traditional” inflammatory cells (ie, leukocytes) infiltrate the aortic wall; instead, inflammatory molecules, including MCP-1,56 are produced and secreted by endothelial cells and VSMCs.
The expression and activity of transforming growth factor-β1 (TGF-β1), a multifunctional growth factor that regulates cell replication, synthesis of extracellular matrix components, and the response to injury,57 are also increased in the aged intima.58 Furthermore, the bioavailability of NO is decreased with aging, whereas the activity of NAD(P)H oxidase and the production of reactive oxygen species are increased,59,60 which can lead to peroxidation of lipids and oxidative modifications of proteins.
Thus, increased intimal thickening should not be construed as “subclinical atherosclerosis” but as a marker of arterial aging. However, the 2 are linked because the biochemical, enzymatic, metabolic, inflammatory, and cellular changes within the diffusely thickened intima that accompanies advancing age are the very same ones that are implicated in the pathogenesis and pathophysiology of arterial diseases such as atherosclerosis. Indeed, in mice, rabbits, and nonhuman primates, experimental atherogenesis is more severe in older versus younger animals, even when the intensity or duration of the exposure to risk factors (eg, elevated plasma lipids) is equivalent54,61 (Figure 3C).
Aging of Endothelial Cells
Important alterations in the structure and function of endothelial cells accompany advancing age,62 including a higher prevalence of cells with polyploid nuclei, increased endothelial permeability, alterations in the arrangement and integrity of the cytoskeleton, the appearance of senescence-associated β-galactosidase staining, and the expression of several inhibitors of the cell cycle. Endothelial cells of aged arteries secrete more plasminogen activator inhibitor-1, favoring thrombosis formation. Furthermore, with aging endothelial cell production of vasoconstricting growth factors such as angiotensin II (Ang II) and endothelin increases, and that of vasodilatory factors (eg, NO, prostacyclin, and endothelium-derived hyperpolarizing factor) is reduced. These age-associated alterations in the arterial wall create a metabolically and enzymatically active milieu that is conducive for the initiation or progression of superimposed vascular diseases (eg, atherosclerosis).
Endothelial cells exhibit shorter telomere lengths with aging15 and suppressed activity of telomerase reverse transcriptase.63 Senescence-like phenotypic changes in endothelial cells can also be induced in the absence of telomere length changes through glycation of collagen 1.64 Advanced glycation end products, which accumulate with aging, increase the production of superoxide anion through the activation of NAD(P)H/oxidase. The coupling of advanced glycation end products to their receptors on endothelial cells also triggers inflammatory cell recruitment and activation and enhances thrombogenesis by stimulating platelet aggregation.65
Aging of the Arterial Media
Salient features of the age-associated changes in the media include the deposition of extracellular matrix proteins such as fibronectin and type-2 matrix metalloprotease (MMP-2),52,58,66 which promotes matrix protein degradation and facilitates VSMC migration.67
Aortic medial VSMCs from older rats are larger in size and fewer in number than those in the aorta from young adult rats.68 Some of these cells appear to have undergone an age-associated phenotypic modulation toward a dedifferentiated and synthetic state. VSMC migration from the medial to the intimal compartment is a plausible mechanism for the increased number of VSMC within the diffusely thickened intima of central arteries as they age. Furthermore, after arterial injury, they underlie, in part, the muscle cell growth that accompanies the exaggerated neointimal formation in older versus younger rats69 and the accelerated remodeling response in older versus adult rats.70 This exaggerated response is attributable to factors intrinsic to the vessel wall because the excessive intimal hyperplasia is still observed when aortae from old animals are transplanted into younger ones.69
The aged media are also characterized by alterations in the content and integrity of the structural matrix proteins that are implicated in arterial stiffening, namely elastin and collagen, as well as their linkages to other matrix constituents or each other. Elastin content decreases with advancing age because of a deficiency in the synthesis of elastin, which is attributed, in part, to repression of elastin gene expression by B-Myb, a process that could be experimentally rescued by expression of cyclin A,71 and to degradation of elastin fibers, a process that is accelerated by age-associated enzymatic processes, such as MMP-2, the levels and activity of which in the aortic wall are increased with advancing age.66 The elastin fragments that are generated, far from being inert, interact with the elastin–laminin receptor that is present on the surface of a variety of cells, including endothelial cells and VSMCs, and induce their motility and proliferation, as well as the release of proteolytic enzymes.72 In contrast to the reduction in elastin content, there is excessive synthesis and deposition of collagen types I and III in the media from old animals.58 With advancing age, adjacent collagen fibrils undergo nonenzymatic glycation and oxidation of free amino groups to form advanced glycation end products,73 which further increase the stiffness of the collagen network. The stiffness of the arterial wall is also modulated by interactions between VSMCs and extracellular matrix constituents, which are themselves altered with aging.7
Ang II Signaling
Arterial components of the Ang II–signaling cascade increase with aging in rats, nonhuman primates, and humans. The highest expression of Ang II is observed in the thickened intima.66 Several factors such as sympathetic activity and hemodynamic factors (eg, shear and circumferential stress) likely contribute to the age-associated increase in Ang II within the arterial wall. Ang II signaling increases collagen production within the arterial wall, promotes NADPH oxidase activity, and enhances the migration of VSMCs. Infusion of Ang II to young rats in concentrations that elicit a modest increase in arterial pressure imparts to their central arteries some of the structural and molecular characteristics of arterial aging.
Thus, Ang II signaling appears to play a critical role in modulating many of the stimuli and signals that govern arterial aging and regulate its structural and functional response and adaptation (Figure 4). Importantly, many of the same metabolic, enzymatic and cellular factors that are activated or suppressed by Ang II signaling and by other signaling cascades (eg, NO, bradykinin, endothelin, norepinephrine, prostaglandins, etc.) are increasingly recognized as critical factors in the pathogenesis and promotion of arterial diseases such as hypertension and atherosclerosis. Thus, it is likely that the imbalance among the various growth factor signaling cascades in the aged arterial wall not only accounts for age-associated arterial remodeling but also provides a mechanistic link between arterial aging and arterial diseases and provides insight into why accelerated vascular aging is a risk factor for these diseases.
Interventions to Retard or Prevent Accelerated Arterial Aging
As with other cardiovascular risk factors, lifestyle modifications, including the prescription of aerobic exercise, dietary modifications, caloric restriction, and weight loss, can prevent or retard the progression of intimal medial thickening74–76 and arterial stiffening77 and improve endothelial function.78–80
A detailed discussion of pharmacological interventions that can modulate the elements of arterial aging is beyond the scope of this article. It is worth noting that inhibiting angiotensin receptor signaling beginning at an early age markedly delays the age-associated increase in collagen content and intimal medial thickening in rodents,81,82 and that breaking nonenzymatic collagen cross-links with a novel thiazolium agent reduces arterial stiffness in nonhuman primates73 and in humans,83 although its blood pressure–lowering effects have been less impressive.84
The aforementioned insights from animal models and human studies indicate that the components of arterial aging are modifiable, so the traditional view of arterial aging, which attributes the age-associated changes solely to passive sequelae of wear and tear from repetitive cycles of distension and recoil of central arteries,6 is no longer tenable. These insights also provide us with a growing list of putative factors that could be targeted by specific interventions aimed at retarding or preventing accelerated arterial aging. For example, strategies to attenuate the effects of molecules or signaling cascades involved in accelerated intimal thickening (eg, TGF-β), stiffening (eg, NO bioavailability, deficits in elastin synthesis), protein degradation (eg, MMP-2), arterial wall inflammation (eg, MCP-1), fibrosis (eg, Ang II), or injury (eg, reactive oxygen species) are deserving of further investigation.
Summary and Perspectives
Age is the dominant risk factor for cardiovascular diseases, and the aforementioned age-associated changes in vascular structure and function are the likely culprits that underlie, in large part, the increased cardiovascular risks associated with aging. Insights from animal studies suggest that the links between vascular aging and vascular diseases stem from the fact that many of the biochemical, enzymatic, and cellular alterations that are operative in accelerated vascular aging, as well as the signals that modulate them, are also involved in the pathogenesis and progression of arterial diseases such as hypertension and atherosclerosis. This establishes the interaction between arterial aging and these diseases and provides a basis for the epidemiological observations that aging confers increased risks for the occurrence of these diseases, lowers the threshold for their appearance, and influences the severity of their manifestation.
An important corollary of this is that age should no longer be viewed as an immutable cardiovascular risk factor. It is our hope that a greater appreciation of the link between arterial aging and cardiovascular diseases will stimulate further investigation into strategies aimed at preventing or retarding arterial aging, with the hopes that this would attenuate the appearance or the severity of cardiovascular diseases. As a first step, there is a critical need to improve and standardize the methodologies used in the noninvasive measurement of the elements of arterial aging in humans, to develop age- and sex-specific normative values, and to devise guidelines for the appropriate timing and interpretation of these tests. This, in turn, will require the recruitment of, and intercollaboration among, a consortium of vascular biologists, translational researchers, and clinicians to catalyze a significant maturation in the field of arterial aging and bring it to the bedside.
The authors thank Christina R. Link for her editorial assistance in preparing this document.
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