Arterial aging is a major risk factor for cardiovascular morbidity and mortality [1]. The main age-related changes that occur within the vascular system are arterial stiffening and endothelial dysfunction ^[1][2][3][4][1,2,3,4]. Arterial stiffness is typically assessed from measurements of pulse wave velocity (PWV) in different arterial segments ^[4][5][4,5]. Epidemiological studies have highlighted the role of carotid–femoral (cf) (aortic) PWV measurements in determining the risk of all-cause and cardiovascular mortality ^{[6][7][8][9][10]}[6,7,8,9,10]. The morphometry and biostructure of the different arterial segments are heterogeneous with different age-related consequences ^[4][11][4,11]. In younger populations, arterial stiffening increases progressively from the ascending aorta to the muscular peripheral conduit arteries. There is, therefore, an arterial stiffness gradient ^{[12][13][14][15][16]}[12,13,14,15,16] that exerts a marked effect on blood flow, pressure wave propagation and reflection along the arterial tree, and ultimately, the degree of pulsatile pressure reaching the microcirculation ^[17][18][19][17,18,19]. Arterial aging is characterized by a steeper increase in aortic stiffness—the main factor influencing the stiffness gradient—with a subsequent reduction in or reversal of the stiffness gradient ^{[12][14][15][16][20][21][22][23][24][25][26]}[12,14,15,16,20,21,22,23,24,25,26]. One study showed that the arterial stiffness gradient is a more reliable predictor of cardiovascular mortality than cfPWV alone in dialysis patients [25], although these findings were not replicated in a community-based sample [23]. However, another study comparing diabetic and nondiabetic individuals reported that the age-related decline in the stiffness gradient was observed with no significant age-related increases in cfPWV [26]. These observations suggest a potential direct pathophysiological role for peripheral arteries in reducing or reversing the physiological stiffness gradient in certain clinical conditions. In the study by Fortier et al., 43% of the study population of dialysis patients were diabetic [25]. Their findings led the researchers to hypothesize that uremia and diabetes may each play specific roles in the process of arterial aging in end-stage renal disease (ESRD) populations.

2. Aging and Arterial Stiffness

The characteristic physiologic, histologic, and molecular changes to aging arteries have been widely described and reviewed elsewhere ^{[2][3][4][14][18][27][28][29][30][31][32][33][34][35]}[2,3,4,14,18,32,34,35,36,37,38,39,40,41]. The vessel wall is subjected to lifelong exposure to biomechanical and biochemical stressors. Biomechanical stress is, therefore, the consequence of a lifetime of continuous cycles of stretching and recoiling, during which shear stress and changes in wall tension lead to biomaterial fatigue, arterial remodeling, and deterioration of the vascular extracellular matrix (fragmentation and loss of elastin, accumulation and crosslinking of collagen, and an increased collagen/elastin ratio) ^{[4][5][14][18][28][30]}[4,5,14,18,34,36]. VSMCs exhibit a high degree of plasticity, are prone to phenotype switching, and play a key role in arterial remodeling ^{[4][5][18][29][31]}[4,5,18,35,37]. In physiologic conditions, VSMCs have a contractile phenotype that, with time, shifts toward a senescence-associated secretory phenotype. This activates microinflammation and oxidative stress, renews collagen synthesis, and triggers production of metalloproteinases, collagenases, and elastases, which in turn instigates an osteogenic program resulting in arterial wall calcification, as well as a decrease in VSMC division and numbers ^{[28][29][30][31][32][33][34][35]}[34,35,36,37,38,39,40,41]. The age-related changes that come about in both elastic aortic segments and in muscular peripheral arteries are contingent on the specific properties of the arterial wall. Aortic stiffness increases steadily with age ^{[12][13][14][15][16][20][21][22][25]}[12,13,14,15,16,20,21,22,25]. In younger individuals, stiffening of the aorta is significantly lower than that of peripheral arteries, thus explaining the significant ‘stiffness gradient’. However, with aging, stiffness of the aorta increases, while stiffening in the peripheral arteries remains unchanged or diminishes. This reduces the normal gradient—increasing stiffness as the distance from the heart increases—and leads to a progressively reduced or inversed stiffness gradient and, consequently, potential damage to the microcirculation (decline in kidney function, cognitive dysfunction, and vascular dementia) ^{[15][16][17][18][19][22][23][24][25]}[15,16,17,18,19,22,23,24,25]. The progression of age-related stiffness is not uniform and varies with different clinical conditions, as well as environmental and genetic factors ^{[4][11][23][25][26]}[4,11,23,25,26]. Certain individuals exhibit ‘accelerated arterial aging’ or ‘early vascular aging’, defined as arterial stiffness that is abnormally high for a given chronological age ^[36][42]. This is calculated from the intercept and slope of the age/arterial stiffness (typically cfPWV) correlation. Accelerated arterial aging is observed in several disease states (arterial hypertension, chronic kidney disease/ESRD, diabetes mellitus, and inflammatory diseases), and it is a reliable predictor of cardiovascular complications. ESRD is probably the most characteristic clinical hallmark of accelerated vascular aging ^{[6][19][20][21][22][25][37]}[6,19,20,21,22,25,30]. This is illustrated by the significantly steeper slope (β coefficient) of the non-adjusted age–cfPWV correlation (Figure 1A) and confirmed by multiple stepwise regression (Table 1). , right panel). In the control group, the factors documented as significant (after univariate analyses) accounted for 62% of cfPVW variance, compared to only 43% in ESRD patients. The burden of atherosclerotic disease increases in the early stages of chronic kidney disease, and the burden of arteriosclerotic cardiovascular complications increases with progression to ESRD ^[38][43]. To date, the majority of the data on aortic stiffness are based on the thoracic aorta, the abdominal aorta, and the femoral artery. However, understanding the role of age-related stiffness along the full length of the arterial tree is a complex undertaking given the heterogeneity of the structure, dimensions, and biomechanical composition of the different segments of the aorta ^[4][11][28][4,11,34]. While the relationships between aging and cfPWV are well documented, those between age and peripheral muscular conduit arteries are inconsistent ^[20][26][39][20,26,31]. When researchers compared data from a control population (normal kidney function and no history of cardiovascular disease), the carotid–radial (cr)PWV and finger–toe PWV were seen to be higher in younger individuals, and to progress more slowly with age (Figure 1B). In ESRD patients, age–stiffness correlations were inconsistent in muscular arteries, varying between moderate and absent, and were seen to increase ^[20][39][20,31] or decrease with age [25]. In ESRD, crPWV did not increase with age in non-adjusted analyses (Figure 1B). After adjustment in multiple regression analysis, crPWV increased moderately with age, although the rise was significantly less steep than in control subjects (p = 0.0389) (Table 1). The consequence of the different age-related changes to cfPWV and regional PWV is a reduction in or reversal of the stiffness gradient ^[39][31]. Certain characteristics are now recognized as having an influence on the age-stiffness relationships. Specifically, one recent study showed that the correlations between age and stiffness on one hand and pressure and stiffness on the other vary between diabetics and nondiabetics [26]. Given that the proportion of diabetics in dialysis populations is on the increase, researchers studied the same parameters (within the same age range) but while making the distinction between ESRD patients with and those without diabetes (Figure 2). In line with the observations made in the general population of diabetics [26], the non-adjusted correlations in ESRD diabetics and confirmed by multiple regression analysis (Table 2A) were characterized by higher cfPWV in younger individuals and a lower progression of age-related stiffness (Figure 2, left panel). The unadjusted age-related changes in crPWV showed that the main difference was a negative correlation between age and crPWV in diabetics (Figure 2 While the differences were only marginally significant in multiple regression analysis (Table 2B), the proportion of diabetics in the study population was relatively low (24%). Fortier et al. reported a negative correlation between age and crPWV in a study of ESRD patients of whom 43% were diabetic [25]. While age-related changes in the stiffness gradient are typically considered a consequence of aortic stiffening, a direct effect of the age-related decrease in the stiffening of muscular arteries cannot be excluded (crPWV). The notable differences in the age–stiffness relationships—and notably the rate of deterioration of vascular stiffness with advancing age—in diabetics and in the general population have led to the suggestion that vascular stiffening is more likely a characteristic of diabetes than of aging [26]. Although the assessment of arterial stiffness from PWV measurements has proven invaluable in improving the understanding of arterial pathophysiology, epidemiology, and clinical outcomes, this technique does have a number of limitations. Most clinical studies have looked at the arterial tree as a whole, from the carotid to the femoral arteries, with cfPWV measurements being used to estimate overall aortic stiffness. However, this approach can no longer be considered appropriate since the various segments are now known to have different properties, different embryologic origins, different sensitivity to risk factors, different progression of the stiffening process, and evolving morphometric properties (e.g., aortic tapering) ^{[4][11][13][14][27]}[4,11,13,14,32]. Given the changing biomechanical characteristics that are observed between the brachial and radial arteries, the same concerns can now be applied to assessments of crPWV ^[40][44].