Marco Malavolta

Dietary intake and impact of zinc supplementation on the immune functions in elderly: Nutrigenomic approach

Nutrient “zinc” is a relevant micronutrient involved in maintaining a good integrity of many body homeostatic mechanisms, including immune efficiency, owing to its requirement for the biological activity of many enzymes, proteins, and for cellular proliferation as well as genomic stability. Old people aged 60–65 years and older have zinc intakes below 50 % of the recommended dietary allowances on a given day. Many causes can be involved: among them, impaired intestinal absorption and altered subcellular processes (zinc transporters including Zip and ZnT family, metallothioneins, divalent metal transporter 1) are the most relevant. Zinc supplementation can remodel the immune alterations in elderly leading to healthy ageing. Several zinc trials have been carried out but with contradictory data on immunity, perhaps due to incorrect choice of old subjects who effectively need zinc supplementation. Old subjects with specific metallothioneins and IL-6 polymorphisms are more prone for zinc supplementation. Foods containing zinc (Mediterranean diet) may be enough to restore immunity in other elderly. We report the main causes of low zinc dietary intake in elderly and the impact of zinc supplementation upon the inflammatory/immune response on the basis of individual interleukin-6 and metallothioneins polymorphisms (nutrigenomic approach).

Nutritional Modulators of Cellular Senescence In Vitro

Cellular senescence is a complex response to stress that contributes to suppress cancer and to initialize mechanisms of repair after tissue injury. However, the accumulation of senescent cells is considered a hallmark of aging and is believed to contribute to the aging phenotype and to drive age-related pathologies. For these reasons, modulation of this response is emerging as a promising therapeutic target in cancer and aging research. In particular, it is desirable to induce cellular senescence in cancer cells for the purpose of an anticancer therapy but, conversely, it is likely that preventing excessive accumulation of senescent cells during aging could help for the purpose of health maintenance and longevity. In this chapter we review the evidence that cellular senescence can be effectively targeted in vitro by various dietary bioactive compounds and will attempt to elucidate the mechanisms involved. We also discuss the problems that hamper the translation of these findings into the development of nutraceuticals for therapeutic purposes in vivo.

Role of Zinc and Selenium in Oxidative Stress and Immunosenescence: Implications for Healthy Ageing and Longevity

Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. Some nutritional factors (zinc and selenium) may remodel these changes leading to a possible escaping of diseases with subsequent healthy ageing, because they are especially involved in improving immune functions as well as antioxidant defense. Experiments performed “in vitro” (human lymphocytes exposed to endotoxins) and “in vivo” (old mice or young mice fed with low zinc dietary intake) show that zinc is important for immune response both innate and adoptive. Selenium provokes zinc release by Metallothioneins (MT), via reduction of glutathione peroxidase. This fact is crucial in ageing because high MT may be unable to release zinc with subsequent low intracellular free zinc ion availability for immune response. Taking into account the existence of zinc transporters (ZnT and ZIP family) for cellular zinc efflux and influx, respectively, the association between ZnT and MT is important in maintaining satisfactory intracellular zinc homeostasis in ageing. Improved immune performance occur in elderly after physiological zinc supplementation, which also induces prolonged survival in old, nude and neonatal thymectomized mice. The association “zinc plus selenium” improves humoral immunity in old subjects after influenza vaccination. Therefore, zinc and selenium are relevant for immunosenescence in order to achieve healthy ageing and longevity.

Allyl Isothiocyanate Exhibits No Anticancer Activity in MDA-MB-231 Breast Cancer Cells

It was reported recently that allyl isothiocyanate (AITC) could inhibit various types of cancer cell growth. In the present study, we further investigated whether AITC could inhibit the growth of human breast cancer cells. Unexpectedly, we found that AITC did not inhibit, rather slightly promoted, the proliferation of MDA-MB-231 breast cancer cells, although it did have inhibitory effect on MCF-7 breast cancer cells. Cytofluorimetric analysis revealed that AITC (10 µM) did not induce apoptosis and cell cycle arrest in MDA-MB-231 cells. In addition, AITC significantly (p < 0.05) increased the expression of BCL-2 and mTOR genes and Beclin-1 protein in MDA-MB-231 cells. No significant changes in expression of PRKAA1 and PER2 genes, Caspase-8, Caspase-9, PARP, p-mTOR, and NF-κB p65 proteins were observed in these AITC-treated cells. Importantly, AITC displayed cytotoxic effect on MCF-10A human breast epithelial cell line. These observations suggest that AITC may not have inhibitory activity in MDA-MB-231 breast cancer cells. This in vitro study warrants more preclinical and clinical studies on the beneficial and harmful effects of AITC in healthy and cancer cells.

Zinc supplementation can reduce accumulation of cadmium in aged metallothionein transgenic mice

Epidemiologic studies suggest that exposure to Cd is related to a multitude of age-related diseases. There is evidence that Cd toxicity emerges from an interference with Zn metabolism as they compete for the same binding sites of ligands. The most responsive proteins to Cd exposure are the metal-binding proteins termed metallothioneins (MTs), which display a much greater affinity for Cd than for Zn. Most studies have considered the effect of Zn on the accumulation of exogenous Cd and tissue damage, whereas observational studies have addressed the association between Zn intake and Cd levels in body fluids. However, it has not been addressed whether supplemental Zn can lower Cd levels in organs of healthy aged animals without affecting Cu stores, a question more pertinent to human aging. We therefore aimed to investigate the effect of Zn supplementation on Cd levels in liver and kidney of aged MT transgenic mice (MT1-tg) overexpressing MT1 at levels more comparable to those observed in humans than non-transgenic mice. We found a >30% reduction of kidney and liver Cd levels in Zn supplemented MT1-tg mice compared to non-supplemented controls, independently of the dose of Zn, without a significant reduction of Cu. Our data support the idea of a causal and inverse relationship between Zn intake and Cd content in organs of aged MT1-tg mice as suggested by observational studies in humans. Our work provides the rationale for interventional studies to address the effects of Zn supplementation on Cd burden in elderly people.

Zinc, Insulin and IGF-I Interplay in Aging

Zn plays an important part in many biological processes including the insulin- and insulin growth factor (IGF) signaling (IIS) pathway which, in turn, is an evolutionary conserved pathway involved in many functions that are necessary for metabolism and growth. Notably, the IIS pathway play also a major role in aging. The overall cellular response and the outcome on the longevity of the organism depends also by the mechanisms involved in the regulation of Zn homeostasis that need to act in synergy just like a symphony orchestra. A likely conductor of this orchestra is the IIS pathway, which in turn is affected itself by the different ability to modulate Zn homeostasis of each cell within the tissues. The multiple ways by which Zn action affects insulin and IGF-1 activities and how these hormones modulate Zn homeostasis is reviewed in this chapter. While the mutual interaction between Zn and IIS on the modulation of longevity appears to be still unclear and characterized by contradictory findings, there is consistent support to draw a picture where a functional cell is able to disentangle IIS-mediated “nutritional Zn signals”, which activate growth promoting pathways, functional integrity and cell division, from “stress response Zn signals” which, in turn, activate a cascade of signals to regulate transcriptionally and post-transcriptionally a multitude of cellular functions that include oxidative stress responses and the secretion of soluble factors.

Gene Expression, Oxidative Stress, and Senescence of Primary Coronary Endothelial Cells Exposed to Postprandial Serum of Healthy Adult and Elderly Volunteers after Oven-Cooked Meat Meals

Epidemiological studies have linked high consumption of meat with major age-related diseases including cardiovascular diseases. Abnormal postprandial increases in plasma lipids after a meat meal have been hypothesized among the pathogenetic mechanisms. However, it is still unknown if the postprandial serum derived after a normal meat meal is able to affect endothelial function, and if the type of meat and the age of the donors are critical factors. Here, we show the effects of postprandial sera derived from healthy adults and elderly volunteers who consumed meat meals on human coronary artery endothelial cell (HCAEC) oxidative stress, gene expression, DNA damage, and cellular senescence. We observed that a single exposure to postprandial serum induces a slight increase in ROS that is associated with modulation of gene expression pathways related to oxidative stress response and metabolism. The postprandial-induced increase in ROS is not associated with a measurable DNA oxidative damage. However, repeated exposure to postprandial serum induces an acceleration of cellular senescence. Taking into account the deleterious role of cellular senescence in age-related vascular diseases, the results suggest a new mechanism by which excessive meat consumption and time spent in postprandial state may affect health status during aging.

Vitamin E, Inflammatory/Immune Response, and the Elderly

Aging is a complex biological phenomenon in which the deficiency of the nutritional state combined with the presence of chronic inflammation and oxidative stress contribute to the development of many age-related diseases. Under this profile, the free radicals produced by the oxidative stress lead to the damage of DNA, lipids, and proteins with subsequent altered cellular homeostasis and integrity, in particular in cells of the immune system. Supplementation with vitamin E can protect against the deteriorating effects of oxidative stress, progression of degenerative diseases, altered inflammatory/immune response, and aging. Such a protective role has been well documented in immune cells from old animals describing how the vitamin E works both at cytoplasmaic and nuclear levels with an influence on many genes related to the inflammatory/immune response. All these findings have supported a lot of clinical trials in old humans and in inflammatory age-related diseases, which, however, have given contradictory and inconsistent results and even indicated a dangerous role of vitamin E in being able to affect mortality. Various factors can contribute to all the discrepancies, especially the doses and the various isoforms of vitamin E family (α, β, γ, δ) tocopherols and the corresponding tocotrienols used in different trials. However, the more plausible gap is the poor consideration of the vitamin E–gene interactions that may open new roadmaps for a correct and personalized vitamin E supplementation in aging and age-related diseases with satisfactory results in order to reach healthy aging and longevity. This peculiar nutrigenomic and/or nutrigenetic aspect is herein reported and discussed in the light of specific polymorphisms affecting vitamin E bioactivity.