A key feature of the heart in advanced age is a reduced threshold for tolerance to Ca2+ loading during events that stimulate increased Ca2+ entry, such as augmented cardiac work, oxidative stress or post-ischemic reflow. Age-associated modification of cardiac membrane composition is a major factor underlying the relative Ca2+ intolerance and reduced capacity for invoking intrinsic cardioprotective mechanisms that expose a greater vulnerability to ischemic injury. Ageing involves altered gene expression of key effector proteins, including those that normally sustain Ca2+ homeostasis and antioxidant systems.
Important adaptive membrane changes also include increases in omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA and cardiolipin. These membrane lipid alterations have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, reactive oxygen species (ROS) metabolism and oxidative phosphorylation. However, some age-related detrimental adaptations may be counter-acted by substituting dietary intake of omega-6 PUFA with omega-3 PUFA.
Our experimental data shows that diet containing a high ratio of omega-3 PUFA to omega-6 PUFA leads to reversal of both the age-associated imbalance of membrane omega-3:omega-6 PUFA and dysfunctional Ca2+ regulation, thus facilitating increased efficiency of mitochondrial energy production, improved tolerance of ischaemia and reperfusion, and reduced incidence of cardiac arrhythmias. Our additional data indicate that restorative incorporation of lipophilic antioxidants such as coenzyme Q10 into mitochondrial membranes exert a potent reversal of the age-linked decline in resistance to ROS-induced mitochondrial injury.