Lactoferrin ameliorates cognitive impairment in D-galactose-induced aging mice by regulating the PI3K/Akt/mTOR signaling pathway and the microbiome-gut-brain axis.

Lactoferrin (LF) has been shown to be effective in attenuating oxidative stress, neuroinflammation, but its potential and mechanisms in alleviating brain aging remain to be clarified. In this study, the effect of different doses of LF (L: 50, M: 500 and H: 2000 mg/kg) on D-galactose (D-gal)-induced brain aging C57BL/6 mice was evaluated. The results showed that body weight, mobility, and spatial memory capacity of aging mice were restored after LF (M & H) intervention. It also attenuated hippocampal neuronal damage and intestinal barrier damage in aging mice. LF (M & H) increased brain and serum levels of antioxidant defense enzymes (SOD, GSH, CAT) and decreased colon and serum levels of inflammatory factors (IL-1β, IL-6 and TNF-α). Western blotting results showed that LF (M & H) increased LC3II/I, Beclin1 expression, decreased p-mTOR, p-akt, and p62 expression, and restored autophagy through the PI3K/Akt/m-TOR pathway. Furthermore, LF (M & H) protected the intestinal barrier by regulating the ratio of Firmicutes/Bacteroidetes and increased levels of the beneficial metabolites short chain fatty acids (SCFAs). Notably, LF (H) exhibited the best anti-aging potential. 500 mg/kg/day LF intervention may be cost-effective in prevents brain aging by regulating the autophagy pathway and the microbiome-gut-brain axis.