Depression is common and medically relevant illness that has been associated to a state of "accelerated aging" and can significantly compromise successful aging. In recent years, the concept of "brain reserve" has emerged to describe some individuals having an increased "baseline adaptive neuroplasticity", providing greater dynamic capacity for adjusting and remodeling cortical circuits to various stressors. We hypothesize that brain reserve may have neuroprotective effects against late life depression. Here, we discuss the modulatory capacity of stress and corticosteroid hormones on hippocampal plasticity and neuronal viability in late life depression as well as the anti-depressive of ketamine and scopolamine mediated by stimulation of the mammalian target of rapamycin, increased inhibitory phosphorylation of GSK-3β, and increased synaptogenesis. This review shall shed light on complex neurobiological mechanisms that underpin late life depression and help to better understand neural correlates of resilience. Investigating how rat models of increased cognitive reserve mitigate a chronic mild stress-elicited depression will afford new insights in the search for new therapeutic targets to treat this neuropsychiatric disorder.