MtmRNA gene expression, via IL-6 and glucocorticoids, as potential genetic marker of immunosenescence: lessons from very old mice and humans

Mocchegiani, Eugenio; Giacconi, Robertina; Cipriano, Catia; Muzzioli, Mario; Gasparini, Nazzarena; Moresi, Raffaella; Stecconi, Rosalia; Suzuki, Hisanori; Cavalieri, Elisabetta; Mariani, Erminia

doi:10.1016/s0531-5565(01)00202-9

Cited by 72 publications

(95 citation statements)

References 29 publications

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“…Therefore, the modulation of the intracellular zinc homeostasis plays a key role not only in preventing apoptosis, when oxidative stress or chronic inflammation are low, but also in inducing apoptosis especially when oxidative stress and cellular damage is high in order to down-regulate the immune response and to eliminate virally infected or malignant cells. Induction of apoptosis by zinc signalling in damaged cells, via activation of p53 pathway, is evident in young-adult age and in very old age (42) , perhaps owing to a preserved regulation of zinc homeostasis in both classes of age (16) . Experiments in thymocytes also support this point of view, since media supplemented with zinc from 50 up to 150 mM prevents old thymocyte apoptosis induced by dexamethasone or serum deprivation (43) , whereas the direct introduction of free zinc, as zinc-pyrithone, inside thymocytes provokes apoptosis because of inducing permanent oxidative stress and irreversible damage (44) , thus activating pro-apoptotic pathways.…”

Section: Rationale For Zinc Supplementation In Ageingmentioning

confidence: 99%

Zinc, metallothioneins and immunosenescence

et al. 2010

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Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. The nutritional factor, zinc, may remodel these changes with subsequent healthy ageing, because zinc improves the inflammatory/immune response as shown by in vitro and in vivo studies. The intracellular zinc homeostasis is regulated by buffering metallothioneins (MT) and zinc transporters (ZnT and ZIP families) that mediate the intracellular zinc signalling assigning to zinc a role of 'second messenger'. In ageing, the intracellular zinc homeostasis is altered, because high MT are unable to release zinc and some zinc transporters deputed to zinc influx (ZIP family) are defective leading to low intracellular zinc content for the immune efficiency. Physiological zinc supplementation in the elderly improves these functions. However, the choice of old subjects for zinc supplementation has to be performed in relation to the specific genetic background of MT and IL-6, because the latter is involved both in MTmRNA and in intracellular zinc homeostasis. Old subjects carrying GG genotypes (C-carriers) in the IL-6 -174G/C locus display high IL-6, low intracellular zinc content, impaired innate immunity and enhanced MT. Old subjects carrying GC and CC genotypes (C + carriers) display satisfactory intracellular zinc content, adequate innate immunity and are more prone to reach longevity. Zinc supplementation in old C-carriers restores natural killer cell cytotoxicity and zinc status. The genetic variations of the IL-6 -174G/C locus when associated with those of the MT1A + 647A/C locus are useful tools for the choice of old people for zinc supplementation.

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Section: Rationale For Zinc Supplementation In Ageingmentioning

confidence: 99%

Zinc, metallothioneins and immunosenescence

et al. 2010

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“…Taking into account that healthy centenarians display a low MT expression and satisfactory zinc ion availability despite pro-inflammatory cytokines (IL-6, TNF-a) increases [105], it may be suggested that this feature reflects the existence of compensatory phenomena able to counteract the effects of inflammation in these exceptional individuals. Moreover, these data suggests that a preservation of zinc homeostasis is an important feature of healthy centenarians.…”

Section: Zinc-mt Gene Interactionmentioning

confidence: 99%

“…In this context, an intriguing point is related to the low expression of the signal transducing component (gp130) of IL-6 receptor in centenarians in comparison with elderly despite high circulating levels of IL-6 [110], which in turn may be inactive in centenarians [105]. Therefore, the inflammatory status is not so detrimental in very old age as, in contrast, occurring in normal ageing.…”

Section: Zinc-interleukin-6 Gene Interactionmentioning

confidence: 99%

“…Therefore, the inflammatory status is not so detrimental in very old age as, in contrast, occurring in normal ageing. As a consequence, MTmRNA is lower and the zinc ion bioavailability is satisfactory for the immune efficiency in very old age [105]. So in ageing population, the individuals who are C-carriers, display high gp130 and have the tendency to produce elevated IL-6 quantities and therefore disadvantaged to reach the goal of extreme longevity.…”

Section: Zinc-interleukin-6 Gene Interactionmentioning

confidence: 99%

“…This major capacity may be largely due to a good zinc ion bioavailability, via MTs homeostasis, occurring in centenarians [105]. Indeed, short term zinc supplementation resulted in a marked increase in both basal and stress-induced HSP70 levels in lymphocytes from healthy old donors [127].…”

Section: Zinc-hsp70 Gene Interactionmentioning

confidence: 99%

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Zinc–gene interaction related to inflammatory/immune response in ageing

Mocchegiani

Malavolta

2008

Genes Nutr

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The pivotal role played by zinc-gene interaction in affecting some relevant cytokines (IL-6 and TNF-a) and heat shock proteins (HSP70-2) in ageing, successful ageing (nonagenarians) and the most common age-related diseases, such as atherosclerosis and infections, is now recognized. The polymorphisms of genes codifying proteins related to the inflammation are predictive on one hand in longevity, on the other hand they are associated with atherosclerosis or severe infections. Since the health lifespan has a strong genetic component, which in turn also affected by nutritional factors like zinc, the association of these polymorphisms with innate immune response, zinc ion bioavailability and Metallothioneins (MT) homeostasis is an useful tool to unravel the role played by zinc-gene interactions in longevity, especially due to the inability of MT in zinc release in ageing and chronic inflammation. In ageing, this last fact leads to depressed innate immune response for host defence. In contrast, in very old age the inflammation is lower with subsequent more zinc ion bioavailability, less MT gene expression and satisfactory innate immunity. Therefore, the zinc-gene (IL-6, TNF-a, Hsp70-2) interactions, via MT homeostasis, are crucial to achieve successful ageing. Human genes and longevityAgeing is a universal phenomenon that affects nearly all of animal species. According to Helfand and Rogina [69], ageing can be characterized as: (1) an inevitable consequence of being a multicellular organism; (2) associated with a random, passive decline in function; (3) leading to a global loss of homeostasis over time and (4) mortality increasing with ageing. Evolutionary studies on ageing have drawn the attention on the importance of the genetic mechanisms involved in somatic maintenance and repair that secure longevity [82]. Evidence from model organisms has indicated that subtle variation in the genes can dramatically influence lifespan. However, findings on potential candidate genetic mechanisms determining ageing and lifespan in model organisms are far to explain variations in human populations because phenotypes are critically dependent on the setting in which genes are expressed, while laboratory conditions and modern environments are markedly dissimilar [86]. Genetic analysis of human ageing is mainly approached by searching the genetic basis of susceptibility to major geriatric disorders or the allelic contributions to exceptionally long life span. It is just thanks to these last studies in centenarians populations that several candidate longevity genes or pathways including PON1 [19,130], IGF1/insulin pathway [84,120], elements of lipid metabolism [12], stress response [34] and inflammatory response have been identified [53].Genes related to inflammation and stress response, in particular the pro-inflammatory cytokines IL-1, IL-6, TNFalpha, the anti-inflammatory cytokine IL-10, the HSP70 chaperones and the regulators of trace elements homeostasis, metallothioneins (MT), seem particularly relevant taking into accoun...

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Zn and Cu alteration in connection with astrocyte metallothionein I/II overexpression in the mouse brain upon physical stress

Beltramini

Pisa

Zambenedetti

et al. 2004

Glia

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The distribution of metallothioneins I/II in the mouse brain and their specific area distribution upon physical stress were studied. To induce physical stress, groups of mice were subjected to total darkness for different periods (2 weeks, 1 month, and 2 months). The concentration of metallothioneins, evaluated by immunohistochemistry, as well as area-specific protein expression, were found in the following quantitative order: corpus striatum, cerebellum, mesencephalon, hippocampus with fornix, parts of thalamus, and pons. All other brain areas were marginally affected, or even unaffected, in terms of immunopositive metallothionein reaction. Metallothionein I/II expression was compared with the immunopositivity of glial fibrillary acidic protein (GFAP). It is noteworthy that metallothioneins and GFAP are expressed in different types of astrocytes.

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MtmRNA gene expression, via IL-6 and glucocorticoids, as potential genetic marker of immunosenescence: lessons from very old mice and humans

Cited by 72 publications

References 29 publications

Zinc, metallothioneins and immunosenescence

Zinc, metallothioneins and immunosenescence

Zinc–gene interaction related to inflammatory/immune response in ageing

Zn and Cu alteration in connection with astrocyte metallothionein I/II overexpression in the mouse brain upon physical stress

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