The brain, particularly the hippocampus, is sensitive to age-related cellular changes, leading to cognitive deficits. Recent work by our laboratory has demonstrated that autophagy, a catabolic lysosomal-dependant process, is reduced in aged hippocampal neurons, and that restoring autophagy levels is sufficient to improve age-related memory impairment. Nonetheless, the regulatory mechanisms involved in neuronal autophagy decline during aging remain largely unknown. Exploring this question, we found that WD repeat domain phosphoinositide-interacting protein 2 (WIPI2), an important driver of autophagosome biogenesis, is significantly reduced in the hippocampus of aged mice. Employing a viral-based strategy to selectively downregulate WIPI2 in mature hippocampal neurons in vivo, we revealed that WIPI2 plays a key role in regulating autophagy-dependent control of learning and memory. Moreover, using gain and loss of function models, we found that WIPI2 could mediate the induction of autophagy by systemic factors involved in the maintenance of neuronal homeostasis. Taken together, our results reveal the importance of WIPI2 in autophagy-dependent regulation of cognitive fitness, and as a mediator of the impact of systemic factors on neuronal homeostasis, opening the possibility for new therapies for age-related cognitive deficits.