The past two decades have seen remarkable progress in our understanding of the multifactorial drivers of hippocampal aging and cognitive decline. Recent findings have also raised the possibility of functional rejuvenation in the aged hippocampus. In this review, we aim to synthesize the mechanisms that drive hippocampal aging and evaluate critically the potential for rejuvenation. We discuss the functional changes in synaptic plasticity and regenerative potential of the aged hippocampus, followed by mechanisms of microglia aging, and assess the cross talk between these proaging processes. We then examine proyouth interventions that demonstrate significant promise in reversing age-related impairments in the hippocampus and, finally, attempt to look ahead toward novel therapeutics for brain aging.

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