Based on the role of tumor necrosis factor alpha (TNF) in ischemic preconditioning (IPC) and the age-associated loss of both TNF-induced platelet-derived growth factor (PDGF)-AB-mediated cardioprotection and IPC-mediated cardioprotection, we hypothesized that targeting of PDGF-AB-based pathways would restore cardioprotection by IPC in the aging heart. To study this, IPC was induced in 4- and 24-month-old F344 rats. Sections of young hearts isolated 1d post-IPC revealed increased TNF compared with controls. In old rats, TNF was higher at baseline than IPC-young rats and was not significantly altered after IPC. Treatment of old rats with PDGF-AB with vascular endothelial growth factor, and angiopoietin-2 (a combination termed PVA), but not PDGF-AB alone, at the time of IPC decreased TNF. In addition, compared with young hearts, IPC induced greater apoptosis in the old hearts, which was decreased with PVA treatment but was markedly increased with PDGF-AB. To test the significance of these findings, additional rats underwent permanent coronary ligation 1d post-IPC. IPC was cardioprotective in young rats (14d post-myocardial infarction (MI) fractional shortening 29±6% vs. Control-MI-17±4%, P<0.05; Masson's trichrome stain MI size: 13±2% vs. Control-MI-17±4% left ventricular area (LVA); P<0.05). In old rats, however, IPC reduced post-MI 14d survival (33% vs. controls-67%; P<0.05). Treatment of IPC-aging rats with PVA, but not PDGF-AB-alone, reversed IPC-induced mortality (PVA-IPC-MI survival-88%; PDGF-AB-IPC-MI-14%) and reduced myocardial injury (fractional shortening: PVA-IPC-31±1% vs. Control-MI-21±6%, P<0.05; MI size: PVA-IPC-12±2% vs. Control-MI-18±3% LVA, P<0.05), and thus demonstrated that PDGF-AB-based strategies can reverse the senescent impairment in IPC-mediated cardioprotection.