Abstract
The capacity of the remodelling immune responses during stress (named immune plasticity) is fundamental to reach successful ageing. We herein report two pivotal experimental models in order to demonstrate the relevance of the immune plasticity in ageing and successful ageing. These two experimental models will be compared with the capacity in remodelling the immune response in human centenarians. With regard to experimental models, one model is represented by the circadian rhythms of immune responses, the other one is the immune responses during partial hepatectomy/liver regeneration (pHx). The latter is suggestive because it mimics the immunosenescence and chronic inflammation 48 h after partial hepatectomy in the young through the continuous production of IL-6, which is the main cause of immune plasticity lack in ageing. The constant production of IL-6 leads to abnormal increments of zinc-bound Metallothionein (MT), which is in turn unable in zinc release in ageing. As a consequence, low zinc ion bioavailability appears for thymic and extrathymic immune efficiency, in particular of liver NKT cells bearing TCR γδ. The remodelling during the circadian cycle and during pHx of zinc-bound MT confers the immune plasticity of liver NKT γδ cells and NK cells in young and very old mice, not in old mice. With regard to human centenarians and their capacity in remodelling the immune response with respect to elderly, these exceptional individuals display low zinc-bound MT associated with: a) satisfactory intracellular zinc ion availability, b) more capacity in zinc release by MT, c) less inflammation due to low gene expression of IL-6 receptor (gp130), d) increased levels of IFN-gamma and number of NKT cell bearing TCR γδ. Moreover, some polymorphisms for MT tested in PBMCs from human donors are related to successful ageing. In conclusion, zinc-bound MT homeostasis is fundamental to confer the immune plasticity that is a condition "sine qua non" to achieve healthy ageing and longevity.
Highlights
Immune plasticity is a condition "sine qua non" for health ageing
Consistent with these findings, zinc and MT homeostasis is crucial in conferring immune plasticity during ageing taking into account that satisfactory zinc ion bioavailability is observed in human centenarians [1]
The choice of these two experimental models is based by previous findings showing the impact that the thymic circadian variations [13] and the liver extrathymic T-cell pathway [1] have in the economy of the immune response in ageing and successful ageing
Summary
Immune plasticity is a condition "sine qua non" for health ageing. The absence of the plasticity leads the organism to be a "low responder" to oxidative stress with subsequent appearance of age-related diseases. The zinc release by MT does not occur in ageing because stress-like condition is chronic leading to low zinc ion bioavailability for immune efficiency and for zinc-dependent biological functions, such as enzyme antioxidant activity and DNA-repair [10].
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