Metallothioneins (MTs) are involved in metal-related cell homeostasis because of their high affinity for metals forming clusters. The main functional role of MTs is to sequester and/or dispense zinc participating in zinc homeostasis, which is relevant in normal immune response. Consistent with this role, MTs gene expression (MTmRNA) is transcriptionally induced by a variety of stressing agents to protect cells from reactive oxygen species. In order to accomplish this task, MTs gene expression is affected by glucocorticoids and IL-6 for a prompt immune response. This protection is peculiar in young-adult age during transient stress and inflammatory condition, but not in ageing because stress-like condition and inflammation are constant for the whole circadian cycle. This may lead MTs to turn-off from role of protection in young age to deleterious one in ageing. The aim is to suggest MTmRNA as potential genetic marker of immunosenescence. Liver MTmRNA, IL-6 and glucocorticoids levels are high, whereas the bioavailability of zinc ions is low and natural killer cells activity is depressed in old and very old mice during the light period as compared to young in the same period. An inversion of nutritional-endocrine-immune profile exclusively occurs in young mice during the night showing the existence of immune plasticity. No inversion occurs in old mice during the night. As a consequence, no immune plasticity in old mice ensues. By contrast, very old mice remodel the altered MTmRNA and immune-endocrine profile during the night up to values of young ones observed during the light period. Therefore, the remodelling of MTmRNA may be involved in the maintenance of immune plasticity with subsequent successful ageing. Thus, MTmRNA, via IL-6 and glucocorticoids, may be potential genetic marker of immunosenescence. This assumption is reinforced by low MTmRNA in lymphocytes of nonagenarians and young-adult people in comparison with elderly and Down's syndrome subjects.