The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial

Abstract

Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals. Forty-eight non-exercising individuals (mean age 70 ± 4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training & Alagebrium (200 mg/day); exercise training & placebo; no exercise training & Alagebrium (200 mg/day); and no exercise training & placebo. We performed a maximal exercise test (VO2max) and measured endothelial function using venous occlusion plethysmography and intra-arterial infusion of acetylcholine, sodium nitroprusside and NG-monomethyl-l-arginine. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS). In the exercise training groups, LRS and VO2max improved significantly (23.9 ± 4.5 to 27.2 ± 4.6mLO2/min/kg, p < 0.001). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging.

Trial registration: ClinicalTrials.gov NCT01417663.

Figures

Figure 1

Consort-style flowchart regarding inclusion, allocation and drop-out of participants.

Figure 2. Significant increase in physical fitness after one year of exercise training

Exercise training groups (solid lines: with Alagebrium ●; with placebo ○) significantly improved their physical fitness, while the control groups (dashed lines: with Alagebrium ■; with placebo □) showed a small, non-significant, decline in VO2max.

Figure 3. Improvement in Lifetime Risk Score with one year intervention of exercise training

Lifetime Risk Score improved significantly in the exercise training groups (solid lines: with Alagebrium ●; with placebo ○) while the control groups (dashed lines: with Alagebrium ■; with placebo □) did not change significantly. Alagebrium had no influence on the Lifetime Risk Score.

Figure 4. Mean blood flow response to intra-arterial infusion of vasoactive substances

No changes were observed in mean blood flow response to increasing dosage of vasoactive substances between any of the four groups during the year intervention: exercise training & Alagebrium (solid line + ●), exercise training & placebo (solid line + ○), control & Alagebrium (dashed line + ■), and control & placebo (dashed line + □). Pre = baseline measurements, post = after 1-year interventions.

Figure 5. Blood flow ratio response to intra-arterial infusion of vasoactive substances

No changes were observed in blood flow ratio (infusion/control leg) response to increasing dosage of vasoactive substances between any of the four groups during the year intervention: exercise training & Alagebrium (solid line + ●), exercise training & placebo (solid line + ○), control & Alagebrium (dashed line + ■), and control & placebo (dashed line + □). Pre = baseline measurements, post = after 1-year interventions.