Age-associated modification of cardiac membrane composition and related metabolic processes are major factors underlying the reduced capacity for invoking intrinsic cardioprotective survival mechanisms. In this brief review we examine some of these key membrane lipid modifications, which include alterations in the type and proportion of long-carbon chain polyunsaturated fatty acids (PUFAs). These changes have profound consequences on the efficacy of membrane proteins and lipids involved with numerous processes including ion homeostasis, intracellular signal transduction, free radical metabolism, and mitochondrial energy production. The resultant postoxidative modification of lipids, proteins, and DNA leads to a reduction in capacity for repair and ultimately worsening cellular dysfunction. However, some age-related detrimental adaptations may be counteracted by selectively manipulating membrane lipid and protein composition via dietary treatment with key omega-3 PUFAs. Such pervasive treatment results in manipulation of cellular function at multiple levels from cell membrane to the genome.