Zinc-Binding Proteins and Immunosenescence: Implications as Biological and Genetic Markers

Abstract

A review. The ageing process is defined as a decline in performance and fitness with advancing age. The progressive decrease in physiol. capacity and the reduced ability to respond to environmental stress leads to increased vulnerability to disease. Consequently, the incidence of many diseases and the mortality rate increases with ageing. Conversely, human centenarians escape many age-related diseases with subsequent healthy ageing and longevity. In order to explain increased mortality with advancing age and at the same time the reasons of an exceptional longevity of centenarians, many theories have been proposed. Among them, "Antagonistic Pleiotropy" seems to fit best with one of the causes of immunosenescence, such as chronic inflammatory status, because some genes related to the inflammatory response, from useful mediators devoted to the neutralization of dangerous/harmful agents early in life and in adulthood, become detrimental in aging where the antigenic load is chronic, resulting in a dangerous self-destructive response. As an example in this context, we discuss here two zinc-binding stress-related proteins, Metallothioneins (MT) and alpha-2 macroglobulin (α2-M). We propose that these alter function from a role in protection against oxidative stress and inflammation in young-adult age, to become harmful agents in ageing, mainly due to their continuous sequestration of zinc allowing low zinc ion bioavailability for a satisfactory inflammatory/immune response. Some MT genetic polymorphisms are related to low zinc status and innate immune dysfunction and with the appearance of cardiovascular diseases and type II diabetes, whereas α-2M polymorphisms are assocd. with the appearance of Alzheimer's disease and myocardial infarction. Therefore MT and α-2M may be considered as biol. and genetic markers of ageing. Their assocn. with zinc transporters (ZnT and Zip family), which are in turn involved in the correct maintenance of intracellular zinc homeostasis, is crucial in order to better understand the genes and the mechanisms involved in longevity and immunosenescence. [on SciFinder(R)]