E. Mocchegiani, R. Giacconi, M. Muzzioli, C. Cipriano

Extrathymic immune pasticity is pivotal for health ageing. Extrathymic T-cell subsets display age-different patterns during the circadian cycle. Immune remodelling occurs in young and very old age leading individuals as "high responders" to external noxae. Limited remodelling appears in old age. Therefore, old individuals are "low responders" with the appearance of age-related diseases. NKT and CD4+ cells alpha/beta and gamma/delta are pivotal because involved in polarising Th1/Th2 response. Different pattern of extra-thymic NKT cell exists during the circadian cycle. NKTgamma/delta, rather than alpha/beta, display major peaks in the dark in young and very old mice, not in old, coupled with increased IFN-gamma and NKT cell cytotoxicity, suggesting Tgamma/delta as marker of immunosenescence. Indeed, CD4+gamma/delta cells maintain immune plasticity because of their lack in elderly and in old infected patients, not in nonagenarians. Zinc-bound MT homeostasis, via IL-6, is involved because high IL-6 provokes no zinc release by MT in elderly and old infected patients with subsequent low zinc ion biovailability for immune response. Zinc supplementation corrects the defect. Nonagenarians show instead low MTmRNA, good zinc ion bioavailability and satisfactory immune performances. In this context, iNOS and PARP-1 are crucial because MT affects them with subsequent immune cell-death, rather than DNA-repair, by PARP-1 due to persistent inflammation in ageing. By contrast, the inflammation is less detrimental in very old age because of low gp130 (target of IL-6) despite high IL-6. Therefore, Tgamma/delta is marker of immunosenescence downstream. Zinc-bound-MT is the marker upstream affecting functional biochemical cascade involved in immune plasticity maintenance.

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