Increased Serum Klotho With Age-Related Aortic Stiffness and Peripheral Vascular Resistance in Young and Middle-Aged Swine

Abstract

The anti-aging function of Klotho gene has been implicated in age-related diseases. The physiological importance of Klotho in the progression of arterial stiffness with aging, however, remains unclear. The goal of this study is to determine the correlation of circulating Klotho with early age-related aortic stiffening and peripheral hemodynamics. We measured serum Klotho levels in a group of pigs with age ranges of 1.5-9 years and investigated the relationship between Klotho levels and biomarkers of aortic stiffening with aging, including aortic pulse wave velocity (PWV), augmentation index (AIx), and pulse pressure (PP). The effects of aortic stiffening on peripheral vascular resistance, compliance, and function were also evaluated. We found that increased aortic stiffness occurred at middle age (>5 years old), as evidenced by an increase in PWV and AIx (p < 0.001), but with no changes in blood pressure and PP. With advancing age, increased femoral vascular resistance positively correlated with aortic PWV and AIx (p < 0.01). No significant difference in endothelium function and arterial compliance for femoral and small peripheral arteries was observed between young and middle-aged groups. The serum Klotho levels were lower in young and higher in middle-aged pigs (p < 0.001), and a positive correlation was found between Klotho and aortic PWV, AIx, and femoral vascular resistance (p < 0.01). Our findings suggest that early-aged aortic stiffening has adverse effect on peripheral hemodynamics, independent of blood pressure levels. Elevated Klotho secretion was associated with increased aortic stiffness and peripheral vascular resistance with aging.

No significant association of serum klotho concentration with blood pressure and pulse wave velocity in a Chinese population

“…Therefore, evaluation of circulating klotho concentrations or klotho genotypes could help identify patients at higher risk of developing age-related cardiovascular morbidities. However, previous studies on the relationship between circulating klotho and blood pressure and arterial stiffness had small sample sizes 13 , used a case–control design 14 , performed analyses only in select patients 13 , 15 , 16 , measured peripheral blood pressure only 8 , or reported conflicting results 15 , 17 . In a recent study in young and middle-aged swine, elevated klotho secretion was associated with increased aortic stiffness and peripheral vascular resistance with aging 17 .…”

“…However, previous studies on the relationship between circulating klotho and blood pressure and arterial stiffness had small sample sizes 13 , used a case–control design 14 , performed analyses only in select patients 13 , 15 , 16 , measured peripheral blood pressure only 8 , or reported conflicting results 15 , 17 . In a recent study in young and middle-aged swine, elevated klotho secretion was associated with increased aortic stiffness and peripheral vascular resistance with aging 17 . In the present population-based study, we investigated the associations between the serum klotho (i.e., secreted α-klotho) concentrations and the peripheral/central blood pressure and arterial stiffness based on the carotid–femoral pulse wave velocity (cfPWV).…”

Recovery of limb perfusion and function after hindlimb ischemia is impaired by arterial calcification

“…It remains unclear how such vascular changes could affect limb perfusion. Aortic stiffening has been associated with increased peripheral vascular resistance, and such changes can lead to decreased limb perfusion (Guo & Kassab, 2020). Moreover, human studies have demonstrated a decreased vasodilatory response in patients with significant coronary calcification (Wang et al, 2006).…”

Medial artery calcification in peripheral artery disease

“…However, arterial stiffness was increased in animals with calcified arteries and was associated with medial elastin degradation, suggesting that MAC may lead to worse outcomes in part due to its effects on arterial compliance. Other studies have also demonstrated that decreased arterial compliance is associated with increased peripheral vascular resistance and a decreased vasodilatory response, which may contribute to decreased perfusion ( 53 , 54 ). However, it is likely that other factors also contribute to the complex mechanisms behind MAC and decreased perfusion, warranting further investigation.…”