Alagebrium in combination with exercise ameliorates age-associated ventricular and vascular stiffness

Advanced glycation end-products (AGEs) initiate cellular inflammation and contribute to cardiovascular disease in the elderly. AGE can be inhibited by Alagebrium (ALT), an AGE cross-link breaker. Moreover, the beneficial effects of exercise on aging are well recognized. Thus, we investigated the effects of ALT and exercise (Ex) on cardiovascular function in a rat aging model. Compared to young (Y) rats, in sedentary old (O) rats, end-systolic elastance (Ees) decreased (0.9 ± 0.2 vs 1.7 ± 0.4 mm Hg/μL, P < 0.05), dP/dtmax was attenuated (6054 ± 685 vs 9540 ± 939 mm Hg/s, P < 0.05), ventricular compliance (end-diastolic pressure–volume relationship (EDPVR)) was impaired (1.4 ± 0.2 vs 0.5 ± 0.4 mm Hg/μL, P < 0.05) and diastolic relaxation time (tau) was prolonged (21 ± 3 vs 14 ± 2 ms, P < 0.05). In old rats, combined ALT + Ex (4 weeks) increased dP/dtmax and Ees (8945 ± 665 vs 6054 ± 685 mm Hg/s, and 1.5 ± 0.2 vs 0.9 ± 0.2 respectively, O with ALT + Ex vs O, P < 0.05 for both). Diastolic function (exponential power of EDPVR and tau) was also substantially improved by treatment with Alt + Ex in old rats (0.4 ± 0.1 vs 0.9 ± 0.2 and 16 ± 2 vs 21 ± 3 ms, respectively, O with ALT + EX vs O, P < 0.05 for both). Pulse wave velocity (PWV) was increased in old rats (7.0 ± 0.7 vs 3.8 ± 0.3 ms, O vs Y, P < 0.01). Both ALT and Ex alone decreased PWV in old rats but the combination decreased PWV to levels observed in young (4.6 ± 0.5 vs 3.8 ± 0.3 ms, O with ALT + Ex vs Y, NS). These results suggest that prevention of the formation of new AGEs (with exercise) and breakdown of already formed AGEs (with ALT) may represent a therapeutic strategy for age-related ventricular and vascular stiffness.

► Aging decreases PWV, Ees, dP/dt, ventricular compliance and diastolic relaxation time.
► Exercise or an AGE-breaker alone ameliorate those effects.
► Combining exercise and an AGE-breaker improves those indices comparable to young animals.