Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice

Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age. [Display omitted] •Cyclic KD preserves memory in aged mice even when administered later in life•KD improves LTP and increases dendritic tree complexity•KD upregulates the cAMP signaling pathway in the synaptic proteome of aged mice•β-Hydroxybutyrate activates PKA and stimulates BDNF expression KD improves memory in aged mice; however, the molecular effects governing such changes at synaptic level remain unknown. Acuna-Catalan et al. reveal that a KD improves short- and long-term memory and strengthens synapses of aged mice. Moreover, KD upregulates the cAMP signaling in the cortical synaptic proteome, thus promoting BDNF expression.