Ganoderma lucidum triterpenes ameliorate age-related cognitive impairment via regulating Eubacterium lentum-mediated serine metabolism

Background Natural aging of the brain is commonly accompanied by a decline in cognitive ability, which is driven by oxidative stress, inflammation, and metabolic dysregulation. These pathological processes are further exacerbated by gut microbiota dysbiosis. Objective This study aims to investigate the therapeutic potential and underlying mechanisms of Ganoderma lucidum triterpenes (GLTs) in ameliorating cognitive impairment associated with aging. Methods The pharmacological activity of GLTs was evaluated in both in vitro and in vivo d -galactose-induced senescence models. The chemical composition of GLTs was qualitatively analyzed using an LC-Triple-TOF/MS system. Gut microbiota variation was assessed by 16S rRNA sequencing. The role of specific bacterial taxa was examined via colonization experiments, and metabolomics comparison analysis was conducted on both model animals and clinical patients of different ages to search for aging-related metabolites. Results Pharmacodynamic studies showed that GLTs significantly improved age-related cognitive deficits. A total of 43 triterpenoids were identified from GLTs, with the main ganoderic acids showing a low exposure level in the target tissue (< 100 ng/g in brain), implying a potential peripheral mechanism of action. GLT treatment effectively reversed gut microbiota dysbiosis in aged mice, particularly by increasing the abundance of Eubacterium lentum ( E. lentum ). Colonization with E. lentum markedly enhanced cognitive ability and increased serine levels in the serum and brain. Clinical metabolomics demonstrated an age-associated decline in serum serine levels. Moreover, supplementing aged mice with exogenous serine could improve cognitive function. Conclusions Our data for the first time indicate that aging leads to downregulation of E. lentum in the gut microbiota of mice, thereby reducing serine production. The decrease in serine levels in the systemic circulation mediates the decline in cognitive function. GLTs ameliorate age-related cognitive impairment by restoring E. lentum abundance and consequently increasing serine production. This work innovatively highlights GLTs as promising therapeutic candidates for aging-related neurodegeneration.