Sustained hippocampal neurogenesis and improved memory performance in senescent p66Shc-/-mice

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 decreased incidence of age-related pathologies and reduced signs of behavioral aging, in addition to an overall increased metabolic rate and to reduced OS. We hypothesized that p66Shc-/- mutants might show greater 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 of 24 month-old p66Shc-/- (knock-out - KO) and p66Shc+/+ (wild-type - WT) male and female mice. Spatial learning abilities and spontaneous behavior were also investigated in a multifunctional behavioral system - IntelliCages. Results indicate greater cell proliferation in females compared to male subjects, p66Shc-/- females being in addition protected from precursor cells loss/quiescence. Furthermore, all female subjects were characterized by an elevated number of young neurons, while the number of dying cells was not affected by genotype or sex. Greater hippocampal cell proliferation was accompanied, in females, by greater spatial learning abilities than males. Overall data suggest that hippocampal function is protected in the female gender, an effect amplified by reduced oxidative stress in the p66Shc-/- mutant mice.