Genistein ameliorates glucose-induced β-amyloid toxicity, oxidative stress, and aging in the C. elegans model of Alzheimer's disease.

Alzheimer's disease (AD) has been considered a kind of diabetic encephalopathy due to the shared molecular mechanisms found between type 2 diabetes mellitus (T2DM) and AD. However, the specific mechanism and therapy of diabetic encephalopathy remain underexplored, particularly the neuroprotective potential of dietary polyphenols in conditions of glucose enrichment. In this study, glucose enrichment-induced potentially harmful effects regarding (neuro)toxicity, apoptosis, oxidative stress, and impaired lipid metabolism were reported for the first time in the AD Caenorhabditis elegans model (CL4176 and CL2355). Genistein intervention prolonged the lifespan and mitigated AD-like symptoms in C. elegans. Further results from network pharmacology, RNA sequencing, RT-qPCR, and lipidomic analysis revealed that the anti-aging, antioxidative, and neuroprotective effects of genistein involve the regulation of sphingolipids, glycerophospholipids, and glycerolipids, which are likely mediated via the PI3K/AKT signaling pathway. These findings provide novel insights into the role of dietary polyphenols in preventing cognitive impairment and aging.