Sea cucumber polypeptide ameliorates aging properties via the brain-gut axis in naturally aging mice

Sea cucumber has been recognized as a traditional nutraceutical in Chinese medicine for millennia, with its derived polypeptide (SCP) demonstrating diverse bioactive properties. Nevertheless, the molecular mechanisms underlying SCP's potential geroprotective effects remain insufficiently characterized. We systematically evaluated SCP's impact on neuromotor function and cognitive performance in physiologically aged C57BL/6 J mice models using a behavioral test battery comprising open field, Y-maze, and Barnes maze paradigms. Complementary multi-omics approaches were employed to interrogate age-related perturbations in gut microbial ecology (16S rRNA sequencing) and systemic metabolism (untargeted LC-MS).H&E and immumohistochemical staining was used to evaluate the pathological features of mice brain tissues and intestinal tissue. Bulk RNA-sequencing was used to detect gene expression profiles in mice brain tissue. Behavioral assessments (open field, Y-maze, Barnes maze) demonstrated that SCP intervention effectively delayed the decline in exercise, learning and memory abilities in aging mice. SCP administration enhanced cerebral organosomatic indices and hepatic functional markers while reducing neuronal senescence biomarkers. Furthermore, SCP improved intestinal mucosal barrier function in aging mice restored gut microbial diversity metrics, effectively counteracting age-associated dysbiosis. Mechanistically, SCP induced taxonomic restructuring characterized by increased abundance of neuroprotective Eubacterium_brachy_group and Prevotellaceae genera, concomitant with suppression of dementia-linked Dubosiella. Metabolomic integration revealed SCP-mediated upregulation of steroidogenic pathways correlating with cognitive enhancement. Multi-omics validation through integrated transcriptomic profiling and immunohistochemical quantification corroborated these physiological improvements. Our findings propose a mechanism whereby SCP might exert geroprotective effects through multimodal regulation of the gut-brain axis and systemic metabolic homeostasis, establishing mechanistic foundations for its translational potential in healthy longevity promotion.