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.
Moving from the brain to the immune system, Ostan et al. relate their findings pertaining to the influence of dietary zinc on apoptosis in lymphocytes:
… We studied different parameters related to apoptosis (phosphatydilserine exposure, mitochondrial membrane potential, caspase 3 cleavage) and we found that zinc, while decreasing spontaneous apoptosis, can increase oxidative stress-induced apoptosis in an age-related fashion, being this effect more evident in nonagenarians than in old or young subjects. In particular, zinc can increase late apoptosis/necrosis, a phenomenon that could trigger unnecessary inflammation in vivo. We surmise that these age-associated alterations in susceptibility to apoptosis may be due to a different effect of zinc on T cell subsets, that are altered in very old people, and finally that the zinc deficiency, which is often observed in aged subjects, could be a compensatory mechanism to counteract the inflammatory status of the elderly. [Emphasis mine]
The stories in the two organs are linked by the common thread of oxidative damage: In brain, high Zn2+ causes increased mitochondrial ROS production; in blood lymphocytes, high Zn2+ sensitizes the cell to oxidative stress. In the latter case, such sensitization could certainly result from higher mitochondrial ROS production, but elucidation of the specific mechanism is beyond the scope of the paper.
I was intrigued by the idea that zinc deficiency in the elderly could be a protective measure against the oxidative/inflammatory consequences of having too much of the cation in the system. Question for the future: is this simply a way to lower the total all-causes oxidative burden — or, alternatively, are aging tissues specifically susceptible to the harmful effects of high Zn2+ in particular?