The dorsomedial prefrontal cortex (dmPFC) is critical for working memory, which declines with age. The mechanisms for aging dmPFC are oxidative stress, antioxidant defense and anatomical alterations. This study was carried out to test whether swimming training and grape seed proanthocyanidin extract (GSPE) are suitable interventions for curtailing free radical generation in the dmPFC in middle-aged male rats. The results indicated that superoxide and hydrogen peroxide increased in the middle-aged, as did lipid and protein oxidations, while superoxide dismutase and catalase activity decreased. There were positive correlations between age and lipofuscin. Importantly, the rats experienced reductions in neuronal number, volume and density in the dmPFC. Rats under combined interventions displayed more alleviation of the age changes than rats with single interventions suggesting the possibilities of utilizing GSPE as a functional supplement in conjunction with swimming exercise towards improving neuronal survivability, and preventing cognitive decline beyond middle-age. © 2019 The Authors