Aging is accompanied by poor learning and memory abilities and by decreased hippocampal neurogenesis, a process that is also modulated by oxidative stress (OS). P66Shc has recently emerged as a novel mammalian gerontogene able to affect healthspan during aging. Deletion of this gene in mice leads to reduced OS accompanied by decreased incidence of age-related pathologies and reduced signs of behavioral aging. We hypothesized that p66Shc−/− mutants might show increased neurogenesis in the hippocampus, a brain region involved in learning and memory processes. To this aim, granule cell number, proliferation, neuronal differentiation, and cell death were assessed in the hippocampus in senescent p66Shc−/− [knock out (KO)] and p66Shc+/+ [wild type (WT)] male and female mice. Spatial learning abilities and spontaneous activity were also investigated in a multifunctional behavioral system—IntelliCages. The behavioral analysis revealed that females in general perform better in spatial learning tasks, with genotype effects being apparent in the activity pattern only. Likewise, all females showed increased neuronal differentiation, whereas increased proliferation was found only in those belonging to the p66Shc−/− genotype, indicating that they might be protected from precursor cell loss. The number of dying cells was not affected by genotype or sex; however, all KO mice showed less granule cells than WT. Overall, our data suggest that hippocampal function is protected in the female gender at older age, an effect amplified by reduced OS in the p66Shc−/− mutant. © 2012 Wiley Periodicals, Inc.