Sn-2 palmitate attenuates neuroinflammation in aged mice via sex-specific modulation of the microbiota-gut-brain axis

Previous studies have demonstrated that sn-2 palmitate promotes neurodevelopment in early-life hosts (e.g., infants and newly weaned mice). However, its neuroprotective effects in aged mice and the underlying mechanisms remain unclear. In this study, we employed 18-month-old C57BL/6 mice as an aging model. After six months of dietary supplementation with sn-2 palmitate at varying concentrations (47.62 %, 59.15 % or 75.79 %), both male and female aged mice exhibited attenuated neuroinflammation accompanied by the reduced expression of glial activation markers (IBA-1 and GFAP). Notably, this neuroprotective effect was mediated by regulating the microbiota-gut-brain axis in a sex-dependent manner and was most pronounced in aged mice supplemented with 75.79 % sn-2 palmitate. In females, it enriched gut microbiota belonging to the genera Lachnoclostridium, Dubosiella, and Muribaculum, up-regulated phenylalanine, tyrosine and tryptophan biosynthesis, and phenylalanine metabolism pathways in serum and enhanced fecal sphingolipid excretion, collectively reducing systemic inflammation. Meanwhile, the up-regulation of arginine and proline metabolism in the hippocampus enhanced its energy buffering capacity and stress resilience. In males, sn-2 palmitate increased the abundances of Akkermansia, Parabacteroides, and Blautia genera, which enhanced tryptophan metabolism and elevated its serum derivatives, while reducing circulating glycerolipid levels and promoting their fecal excretion. The tryptophan-glycerolipid metabolic regulation exerted a dual anti-inflammatory effect, suppressing systemic inflammation and directly attenuating neuroinflammation. Together, our findings provide novel insights into the neuroprotective potential of dietary sn-2 palmitate in aged models and establish a foundation for developing precision dietary interventions tailored to sex differences, with potential implications for improving brain health in aging populations.