Changes in the injury and protection thresholds in aging heart. (A) Aging diminishes the hearts threshold to sustain injury (e.g., from ischemia/reperfusion, etc.). Lifestyle modifications, including exercise and possibly caloric restriction, may partially diminish the aging effect. Comorbidities (such as diabetes) have negative influence. (B) Aging increases the hearts threshold to activate protection-signaling mechanisms. Various pharmacologic agents (e.g., sulfonylureas, antioxidants, partial fatty acid oxidation (PFAO) inhibitors, and COX-2 inhibitors) that can interfere with cardioprotective signaling-pathways can exacerbate this trend and further increase the protection threshold. Exercise and caloric restriction might attenuate the age-dependent trends (Modified from Juhaszova M, Rabuel C, Zorov DB, et al: 2005. Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res 66: 233–244).