Aging predominates over an MFGM/EV-rich supplement in modulating the brain lipidome and cognitive decline of aged rats

Intake of nutraceuticals containing milk fat globule membranes (MFGMs) and extracellular vesicles (EVs) are purported to ameliorate age-related cognitive decline, which varies from mild cognitive impairment to dementia and is a growing burden for healthcare systems worldwide. This study explored whether intake of an MFGM/EV-based ingredient, rich in polar milk lipids, mitigates cognitive decline in aged rats and modulates their brain lipidome. To do so, we carried out a 25-week long intervention study where 88-week-old rats were supplemented with the MFGM/EV-rich ingredient or a control milk lipid-deficient ingredient. At the end of the study, the rats were subjected to the Morris water maze test to assess their cognitive performance and biopsies of hippocampus, cerebral cortex and cerebellum were analyzed by in-depth MS ALL lipidomics. For comparative purposes, we also included young 8-week-old rats in the study. Altogether, we found that the MFGM/EV-rich ingredient did not ameliorate age-related cognitive decline and mitigated only to a minor extent the age-driven remodeling of the brain lipidome. Furthermore, we provide the community with a comprehensive lipidomic resource detailing the lipid landscape and metabolic changes that occur in the brain as rats age. This resource can serve as a valuable reference for designing future nutritional therapies to rejuvenate the brain lipidome and improve cognitive function. • Dietary supplementation with an MFGM/EV-rich ingredient does not mitigate age-related cognitive decline in old rats. • Cognitive decline correlates with reduced levels of 22:6-containing glycerophospholipids and mitochondrial lipids. • Aging concurs with increased levels of sphingolipids with hydroxylated fatty acyl chains. • Comprehensive lipidomic resource of lipid molecules in hippocampus, cerebral cortex and cerebellum of aged and young rats.