Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin.

Multiple factors have been implicated in the age-related declines in brain function. Thus, it is unlikely that modulating only a single factor will be effective at slowing this decline. A better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Over the last few years, we have identified an orally active, novel neuroprotective and cognition-enhancing molecule, the flavonoid fisetin. Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant. Fisetin can also maintain mitochondrial function in the presence of oxidative stress. In addition, it has anti-inflammatory activity against microglial cells and inhibits the activity of 5-lipoxygenase, thereby reducing the production of lipid peroxides and their pro-inflammatory by-products. This wide range of actions suggests that fisetin has the ability to reduce the age-related decline in brain function.