Trehalose has been widely used as a food and drug additive for a long time, and its effects on antioxidant stress, autophagy, and anti-aging have been gradually studied. However, the molecular mechanism by which trehalose exerts anti-oxidative stress and anti-aging effects has not been fully clarified. Our anti-aging cell phenotype study based on trehalose validates its intrinsic mechanisms of anti-oxidative stress and anti-inflammation in cells. We analyzed publicly available transcriptomic data (GSE76643) to identify molecular pathways regulated by trehalose, and then validated the key findings in our own cellular and animal experiments. The results indicate that trehalose alleviates oxidative stress-induced senescence, and that this effect is associated with remodeling of cell cycle progression, including down-regulation of selected cell-cycle regulators. The D-Gal-induced premature aging mouse model demonstrated that trehalose can effectively alleviate aging phenotypes in the hair, liver metabolic abnormalities, lung, and kidney of mice. Trehalose treatment reversed the D‑galactose‑induced upregulation of P16, P21, and P53 proteins in the liver, lung, and kidney, further supporting its anti‑aging effects in vivo. Additionally, the down-regulated expression of BIRC5, CCNE2, and CDK2 mRNA in certain tissues suggests that trehalose regulates or intervenes in the cell cycle. Based on the cell-cycle remodeling phenotype, we hypothesized that trehalose may modulate P65, STAT3, Keap1-Kelch, and CDK2. Molecular docking predicted potential interactions between trehalose and these proteins; these predictions require experimental validation. In conclusion, this study provides evidence that trehalose may alleviate oxidative stress-induced senescence in association with cell-cycle remodeling. These findings lay a foundation for further development of trehalose as an anti-aging intervention, but direct causality remains to be established.
