Formononetin improved healthspan via the P53/P21/CDK4 pathway in SAMP8 mice and DAF-16/SKN-1 signaling pathway in C.elegans.

OBJECTIVE

To investigate the healthy aging effects of Formononetin and its underlying molecular mechanisms.

METHODS

SAMP8 mice were administered Formononetin (4, 8, 16 mg/kg, po) for 5 months. Behavioral tests were performed in 9-month-old mice, followed by histopathology. 5-methylcytosine (5-mC) level in the brain were detected by immunofluorescence, aging-related protein expression was measured by Western blot. In C. elegans, the lifespan, stress resistance, and aging-related gene expressions were assessed. Mutant strains (daf-16 and skn-1) were used to verify pathway dependency.

RESULTS

Formononetin dose-dependently ameliorated cognitive deficits, anxiety-like behaviors, and motor decline in SAMP8 mice, attenuated neuronal damage in the hippocampal CA1, DG and cerebral cortex, reversed 5-mC level, downregulated protein expression of P53, P21, while upregulated CDK4 and Nrf2. In C. elegans, Formononetin (37.30 μmol/L) significantly extended lifespan under normal, thermal stress, and oxidative stress conditions, improved locomotion, reduced lipofuscin accumulation, increased total SOD activity, and upregulated skn-1, sir-2.1, daf-16 and sod-3 mRNA. No lifespan extension was observed in daf-16 or skn-1 mutants.

CONCLUSION

Formononetin effectively attenuated cognitive deficits, ameliorated neuronal damage and increased 5-mC level, possibly via regulated P53, P21, CDK4 and Nrf2 protein expression in the brain of SAMP8 mice. In C. elegans, Formononetin extended lifespan, increased stress resistance, and improved locomotion and lipofuscin accumulation, possibly via regulated expression of DAF-16 and SKN-1.