FIGURE 1.

Conceptual framework. This flow diagram outlines key concepts and hypotheses addressed in this essay and illustrate the way we propose they contribute to AMI. Many important biological processes involve redox reactions and many of life’s macromolecules are sensitive to electrophilic attacks that may impair their ability to perform their normal functional or structural roles. Few of life’s building blocks are as sensitive to oxidation as the poly-unsaturated fatty acids (PUFAs) making up much of cell and organelle membranes. Organisms generate electrophiles like reactive oxygen and nitrogen species as part of many essential live processes, including metabolism, host defense, and intercellular signaling processes. Active maintenance of an appropriate redox balance is therefore of the utmost importance for organismal function and survival. Biological aging tends to be associated with shifts in redox balance away from reducing towards oxidative conditions in many of an organism’s molecular, cellular, and organismal systems and domains, including an advanced state of membrane PUFA peroxidation that recruits PLA₂ and induces a (PLA₂-dependent) decline in neuronal excitability and activity-dependent plasticity that manifests itself as AMI.