Purpose <p>Age-related cognitive decline and synaptic loss are associated with alterations in hippocampal synaptic protein phosphorylation and signaling pathways. Natural compounds from marine sources, such as <i>Capsosiphon fulvescens</i> glycopeptides (Cf-tPep), have shown potential neuroprotective properties. This study aimed to investigate the effects of trypsinized glycopeptides from <i>C. fulvescens</i> on synaptic protein phosphorylation and cognitive function in aging hippocampal neurons and rats.</p> Methods <p>The research employed both in vitro and in vivo experimental models to evaluate the impact of Cf-tPep on aged hippocampal neurons and cognitive function in rats. Primary hippocampal neurons from rats were cultured for 49&#xa0;days to model aging. Synaptic protein expression and phosphorylation were analyzed through Western blotting, immunoprecipitation, and double-immunofluorescence. In vivo, aged rats received Cf-tPep via hippocampal microinjection using osmotic pumps. Cognitive function was assessed using the Morris water maze test.</p> Results <p>Cf-tPep treatment restored phosphorylation levels of synaptic proteins, including PSD95 (S295) and GluN2B (Y1472), in aged neurons. This effect was mediated through inhibition of the calcineurin-STEP signaling pathway and activation of CaMKII-ERK1/2 signaling, enhancing synaptic plasticity and reducing neuronal senescence. In aged rats, Cf-tPep improved spatial learning and memory retention by modulating synaptic protein phosphorylation.</p> Conclusion <p>Trypsinized glycopeptides from <i>C. fulvescens</i> show promise as a therapeutic agent for alleviating age-related cognitive decline through regulation of synaptic signaling pathways. These findings suggest their potential for promoting brain health in the elderly.</p>