Oxidative stress and brain aging: is zinc the link?

Zn2+ dyshomeostasis has been strongly linked to neuronal injury in many neurological conditions. Toxic accumulation of intracellular free Zn2+ ([Zn2+](i)) may result from either flux of the cation through glutamate receptor-associated channels, voltage-sensitive calcium channels, or Zn2+-sensitive membrane transporters. Injurious [Zn2+](i) rises can also result from release of the cation from intracellular sites such as metallothioneins (MTs) and mitochondria. Chronic inflammation and oxidative stress are hallmarks of aging. Zn2+ homeostasis is affected by oxidative stress, which is a potent trigger for detrimental Zn2+ release from MTs. Interestingly, Zn2+ itself is a strong inducer of oxidative stress by promoting mitochondrial and extra-mitochondrial production of reactive oxygen species. In this review, we examine how Zn2+ dyshomeostasis and oxidative stress might act synergistically to promote aging-related neurodegeneration.