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

Jochen Steppan, Huang Tran, Alexandre M. Benjo, Laxsmi Pellakuru, Viachaslau Barodka, Sungwoo Ryoo, Sineád M. Nyhan, Craig Lussman, Gaurav Gupta, Anthony R. White, Joao P. Daher, Artin A. Shoukas, Benjamin D. Levine, Dan E. Berkowitz

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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±0.4mmHg/μL, P<0.05), dP/dt max was attenuated (6054±685 vs 9540±939mmHg/s, P<0.05), ventricular compliance (end-diastolic pressure-volume relationship (EDPVR)) was impaired (1.4±0.2 vs 0.5±0.4mmHg/μL, P<0.05) and diastolic relaxation time (tau) was prolonged (21±3 vs 14±2ms, P<0.05). In old rats, combined ALT+Ex (4weeks) increased dP/dt max and Ees (8945±665 vs 6054±685mmHg/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±3ms, 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±0.3ms, 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±0.3ms, 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.

Original languageEnglish (US)
Pages (from-to)565-572
Number of pages8
JournalExperimental Gerontology
Volume47
Issue number8
DOIs
StatePublished - Aug 2012

Keywords

  • AGE
  • Advanced glycation end-products
  • Alagebrium
  • Exercise
  • Ventricular-vascular coupling

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Cell Biology

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  • Cite this

    Steppan, J., Tran, H., Benjo, A. M., Pellakuru, L., Barodka, V., Ryoo, S., Nyhan, S. M., Lussman, C., Gupta, G., White, A. R., Daher, J. P., Shoukas, A. A., Levine, B. D., & Berkowitz, D. E. (2012). Alagebrium in combination with exercise ameliorates age-associated ventricular and vascular stiffness. Experimental Gerontology, 47(8), 565-572. https://doi.org/10.1016/j.exger.2012.04.006