Aging is associated with shifts in autocrine and paracrine pathways in the cardiac vasculature that may contribute to the risk of cardiovascular disease in older persons. To elucidate the molecular basis of these changes in vivo phage-display biopanning of 3- and 18-month-old mouse hearts was performed which identified peptide epitopes with homology to brain-derived neurotrophic factor (BDNF) in old but not young phage pools. Quantification of cardiac phage binding by titration and immunostaining after injection with BDNF-like phage identified a 2-fold increased density of the BDNF receptor, truncated Trk B, in the aging hearts. Studies focused on the receptor ligand employing a rat model of transient myocardial ischemia, revealed increases in cardiac BDNF associated with local mononuclear infiltrates in 24- but not 4-month-old rats. To investigate these changes, both 4- and 24-month-old rat hearts were treated with intramyocardial injections of BDNF (or PBS control), demonstrating significant inflammatory increases with activated macrophage (ED1+) in BDNF-treated aging hearts compared with aging controls and similarly treated young hearts. Additional studies with permanent coronary occlusion following intramyocardial growth factor pretreatment revealed that BDNF significantly increased in the extent of myocardial injury in the old rat hearts (BDNF-35+/-10% left ventricular injury vs. PBS-16.2+/-7.9%; P<0.05) without affecting younger hearts (BDNF-15+/-5.1% left ventricular injury vs. PBS-14.5+/-6.0%). Overall, these studies suggest that age-associated changes in BDNF-Trk B pathways may predispose the aging heart to increased injury after acute myocardial infarction and potentially contribute to the enhanced severity of cardiovascular disease in older individuals.