Sedentary aging leads to left ventricular (LV) and vascular stiffening due in part to advanced glycation end-products (AGEs) cross-linking of extracellular matrix proteins. Vigorous lifelong exercise ameliorates age-related cardiovascular (CV) stiffening and enhances exercise LV function, although this effect is limited when exercise is initiated later in life. We hypothesized that exercise training might be more effective at improving the impact of age-related CV stiffening during exercise when combined with an AGE cross-link breaker (Alagebrium). Sixty-two seniors (≥60 yr) were randomized into four groups: sedentary + placebo, sedentary + Alagebrium, exercise + placebo, and exercise + Alagebrium for 1 yr. Moderate-intensity aerobic exercise was performed 3-4 sessions/wk; controls underwent similar frequency of yoga/balance training. Twenty-four similarly-aged, lifelong exercisers (4-5 sessions/wk) served as a comparator for the effect of lifelong exercise on exercising LV function. Oxygen uptake (Douglas bags), stroke index (SI; acetylene rebreathing), and effective arterial elastance (Ea) were collected at rest and submaximal and maximal exercise. Maximum O2 uptake (23 ± 5 to 25 ± 6 ml·kg(-1)·min(-1)) increased, while SI (35 ± 11 to 39 ± 12 ml/m(2)) and Ea (4.0 ± 1.1 to 3.7 ± 1.2 mmHg·ml(-1)·m(-2)) were improved across all conditions with exercise, but remained unchanged in controls (exercise × time, P ≤ 0.018). SI or Ea were not affected by Alagebrium (medication × time, P ≥ 0.468) or its combination with exercise (interaction P ≥ 0.252). After 1 yr of exercise plus Alagebrium, exercise SI and Ea remained substantially below that of lifelong exercisers (15-24 and 9-22%, respectively, P ≤ 0.415). In conclusion, Alagebrium plus exercise had no synergistic effect on exercise LV function and failed to achieve levels associated with lifelong exercise, despite a similar exercise frequency.