It has been reported that calorie restriction (CR) improves ischemic tolerance in aged myocardium, though mechanisms by which this occurs are not well understood. We sought to identify potential involvement of pro-survival kinases in this cardioprotective response. To this end, hearts from young and aged mice (standard diet or CR) were isolated and perfused. All hearts were subjected to 25 min global ischemia and 45 min reperfusion. Hearts were then frozen for Western analysis. Young hearts showed a moderate degree of ischemic tolerance with > 50% recovery of contractile function (EDP, 21 ᠲ mm Hg; LVDP, 57 ᠴ%). Standard diet aged hearts displayed a significantly greater degree of post-ischemic contractile dysfunction (EDP, 43 ᠲ mm Hg; LVDP, 25 ᠳ%). In stark contrast, CR aged hearts recovered similarly to young hearts (EDP, 7 ᠱ mm Hg; LVDP, 60 ᠳ%). Moreover, both LDH and cardiac troponin release was significantly elevated in the standard diet aged mouse, but equivalent to the young hearts in the aged CR group. Examination of pro-survival kinases (Akt, p70S6K, GSK3߬ ERK1/2 and p38 MAPK) primarily reveals an increase in both phosphorylated and total Akt and GSK3ߠwith CR in aged hearts. In addition, ratios of phosphorylated:total ERK1/2 and p38 MAPK were identical between young and aged CR. While significantly different from young hearts, there was no distinction in p70S6K observed in the two aged diets. In summary, we show that caloric restriction effectively restores ischemic tolerance in aged hearts, possibly via alterations in Akt, GSK3߬ ERK1/2 and p38 MAPK.