This chapter describes specific neuroprotective lipid mediators that sustain connectivity and plasticity of neuronal circuits. Since synapse dysfunctions lead to unsuccessful aging, potential synaptic deconstruction pathways are described, including ferroptosis. The molecular logic that sustains neuronal survival when confronted with neurodegenerations is expounded. Lipid mediators, by inducing protective cell phenotypes, modulate calcium signaling, mitochondrial function, and uncompensated oxidative stress (UOS). Studies using experimental stroke led to the discovery of 10,17S-docosatriene (Neuroprotectin D1; NPD1) that inhibits apoptosis, mediates preconditioning rescue, and restores aberrant neuronal networks in experimental epileptogenesis. DHA is necessary for photoreceptor integrity, requiring specific receptors for uptake and retention, which play a role in AMD. NPD1’s protective bioactivity in PD models is described as well. NPD1’s synthesis downregulation in the hippocampus of AD patients is presented. Elovanoids (ELVs) thwart ischemic stroke brain damage, while lipid mediators limit inflammation and slow down the course of disruptions in AD hippocampal circuits. There is redundancy and synergies of inflammation-homeostatic mediators that target systemic inflammation in AD. Thus, protective pro-homeostatic NPD1 and ELVs contribute to successful aging. The unraveling of molecular principles for neuronal survival when confronted with adversities has shed potential mechanisms to sustain successful aging.