Zinc, metallothioneins, immune responses, survival and ageing.

Zinc is required as a catalytic, structural (zinc fingers) and regulatory ion. In this capacity, it is involved in many homeostatic mechanisms, including immune responses. Metallothioneins (MTs) may play key roles because of their preferential binding to zinc especially in ageing. MTs protect from oxidative damage during transient stress conditions at young-adult age. This protection no longer exists in ageing and in age-related diseases (cancer and infections) because the stress condition is constant. As such, MTs may constantly deplete zinc from plasma and tissues. This phenomenon causes increased MTs levels on the one hand, but on the other hand induces low zinc ion bioavailability for normal immune responses. This may be particularly relevant for thymic functions and natural killer activity. Therefore MTs which are protective in young-adults may become dangerous in immune responses during ageing. Physiological supplementation of zinc in ageing corrects central and peripheral immune defects, resulting prolonged survival and decreased mortality (50%) from infections and tumours, especially during middle age. Because of increased MT gene expression and protein levels in the liver and atrophic thymus of old mice, MTs are proposed as genetic markers of immunosenescence.