Aging impacts immunity, zinc status, and overall health, with these factors being closely interconnected. Zinc is known to modulate protein expression and cytokine production, with new molecular mechanisms continuing to be identified. ZIP8 facilitates IFN-γ production by increasing the intracellular zinc levels; how zinc status in humans affects ZIP8 expression remains unclear. We assessed serum zinc, dietary zinc intake, proton pump inhibitor (PPI) use, phytohemagglutinin (PHA)-stimulated IFN-γ production, and ZIP8 protein expression in elderly hospitalized patients and young healthy controls. Compared to young adults, elderly participants exhibited lower zinc status and IFN-γ levels, with PPI use among the elderly correlating with zinc deficiency. Zinc-deficient elderly participants received zinc aspartate supplementation for approximately 7 days, resulting in increased serum zinc levels, IFN-γ production, and a trend toward increased ZIP8 expression; in participants taking PPIs, this increase reached statistical significance. Although we found no clear correlation between ZIP8 expression and zinc status, the observed response to supplementation warrants further investigation. These findings reinforce the relevance of zinc supplementation in the elderly, although further studies are needed to elucidate the precise mechanisms linking zinc status to IFN-γ production, particularly regarding the role of ZIP8 expression levels.

The assessment of zinc status is difficult but essential for the identification of zinc deficiency and evaluation of interventions to improve zinc status. The purpose of this systematic review (SR) and meta-analysis was to update the previously published SR of biomarkers of zinc status, conducted by the European Micronutrient Recommendations Aligned (EURRECA) network in 2009, to answer the question: Which putative measures (biomarkers) of zinc status appropriately reflect a change in zinc intake of at least 2 weeks? A structured search strategy was used to identify articles published between January 2007 and September 2022 from MEDLINE (Ovid), Embase (Ovid), Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials (CENTRAL). Relevant articles were identified using previously defined eligibility criteria. Data were extracted and combined with data from the previous SR. A random-effects model was used to calculate pooled mean differences using STATA (StataCorp). The risk of bias and the certainty of evidence for all outcomes were assessed. Additional data on 7 of the 32 previously reported biomarkers were identified, along with data on an additional 40 putative biomarkers from studies published since 2007. Pooled data analysis confirmed that, in healthy participants, both plasma/serum zinc concentration and urinary zinc excretion responded to changes in zinc intake (plasma/serum: mean effect [95% CI], controlled studies: 2.17 µmol/L [1.73, 2.61]; P < .005, I2 = 97.8; before-and-after studies: 2.87 µmol/L [2.45, 3.30]; P < .005, I2 = 98.1%; urine zinc: 0.39 mmol/mol creatinine [0.17, 0.62]; P < .005, I2 = 81.2; 3.09 µmol/day [0.16, 6.02]; P = .039, I2 = 94.3). The updated analyses support the conclusion that plasma/serum and urinary zinc respond to changes in zinc intake in studies of healthy participants. Several additional putative biomarkers were identified, but more studies are needed to assess the sensitivity and reliability. PROSPERO no. CRD42020219843.

Assessment of X-ray fluorescence capabilities for nail and hair matrices through zinc measurement in keratin reference materials

Portable X-ray fluorescence of zinc applied to human toenail clippings

Assessing zinc from a nail clipping using mono-energetic portable X-ray fluorescence

Feasibility of measuring zinc in human nails using portable x-ray fluorescence

A short 18 items food frequency questionnaire biochemically validated to estimate zinc status in humans

An initial evaluation of newly proposed biomarker of zinc status in humans - linoleic acid: dihomo-γ-linolenic acid (LA:DGLA) ratio

Zinc deficiency has serious wide-ranging health consequences and is thought to be one of the most prevalent micronutrient deficiencies in the world. However, reliable indicators or biomarkers to assess zinc status are not available at present. Indirect indicators such as the prevalence of stunting or anemia, iron deficiency, as well as more direct indicators such as plasma zinc concentrations are being used at present to estimate the prevalence of zinc deficiency in populations. However, as this paper shows by using data from a recent national micronutrient survey in Vietnam, the estimates of the prevalence of zinc deficiency using these different indicators can vary widely, leading to inconsistencies. In this paper, zinc deficiency among children is four times more prevalent than iron deficiency and 2.3 times more than stunting prevalence for example. This can lead not only to confusion concerning the real extent of the prevalence of zinc deficiency in populations, but also makes it hard to inform policy on whether action is needed or not. Moreover, evaluation of programs is hampered by the lack of a clear indicator. Efforts should be made to identify the most suitable indicator to evaluate the impact of programs aimed at improving zinc status and health of populations.

Effect of consuming hi-oleic peanuts on adiposity and cardiometabolic health

Activity of the thymus derived, immunoregulatory peptide thymulin has shown high sensitivity to zinc status in humans. However, this research has generally been done for people with the confounding effects of various health issues. In contrast, a study was done on healthy, semi‐mature growing rats where the only variable was adequate zinc status versus a short term, moderate restriction of zinc intake. After 2 weeks of being fed a diet with 5 ppm zinc, rats showed a mean serum zinc value that was 31% lower than for rats fed 27 ppm zinc. A much bigger mean percent difference of 61% was seen for serum thymulin activity. This activity was determined by a rosette formation assay that uses sheep erythrocytes plus spleen cells from thymectomized mice. Activity was restored to 100% of normal in vitro by adding zinc to the assay. Body weight was lower in the rats fed lower zinc (187 + 5 g vs 242 + 13), but total food intake was not much lower, and was the same per body weight. Serum extracellular superoxide dismutase activity was 18% lower in the low zinc group, and serum 5’‐nucleotidase activity was 26% lower. In addition, liver metallothionein in the low zinc group was about 27% lower than in the zinc adequate group. In conclusion, in rats, a marginal zinc deficiency, with no other confounding factors,produced a larger effect on thymulin activities than on a number of other parameters.

Zinc deficiency has an estimated prevalence of 31% globally, and can lead to poor pregnancy outcomes, immune dysfunction, and increased risk for chronic disorders. A barrier to elucidating the exact role of zinc in human health is a lack of reliable clinical biomarkers for zinc status in humans. Currently used plasma zinc levels, lack both sensitivity and specificity to zinc status. To probe for novel biomarkers, metabolome profiles were studied in healthy, adult male subjects that underwent dietary zinc depletion and repletion. Plasma samples were analyzed following baseline (2 wk, 11mg Zn/d), zinc‐depletion (0.6mg Zn/d for 1 wk and 4mg Zn/d for 5 wk), and zinc‐repletion (4 wk, 11mg Zn/d) phases using untargeted, unbiased metabolomic LC‐MS/MS. Principle component analysis demonstrated metabolite clustering during each dietary phase of the study. A total of 12 different metabolites were significantly (P&lt;0.05) up or down regulated (log2 fold change) during dietary zinc depletion relative to baseline and were reversed with zinc repletion. Methylhistidine was identified as the most significantly altered metabolite (8.59‐fold change) and may indicate protein degradation to replenish plasma zinc. This research is a significant first step in utilizing metabolomics to establish novel consequences and biomarkers of zinc deficiency. Funding: USANA Health Sciences, T32 ES007060 &amp; P30 ES000210

Diminished taste acuity (hypogeusia) has been linked to zinc deficiency in humans and animals. This phenomenon has been exploited in the Zinc Taste Test (ZTT), a taste acuity test commonly employed by Australian naturopaths. However, its validity has not yet been firmly established. A systematic search of several key databases was conducted. Only studies in which there were full reports of clinical trials comparing the ZTT to at least one other zinc test within the same sample population were included. Three (3) studies matched the criteria for inclusion. Study I compared the ZTT with sweat zinc in patients with food intolerance, reporting moderate correlation. Study II recruited pregnant women using the ZTT and serum zinc to assess zinc status, with above 70% congruence between the two tests at the start of the trial and 100% congruence at the end. Study III also recruited pregnant women at three stages during gestation, assessing ZTT and leukocyte zinc initially, later adding dietary zinc intake and at delivery cord blood zinc. No significant correlation was found between the results of these different methods; however, statistically significant differences in the ZTT responders (tasters and nontasters) were found for pregnancy outcomes. The methodology of the three studies is critically discussed. Although depletion of zinc leads to decreased taste acuity, it does not explain all cases of hypogeusia. Various other influences on taste perception are discussed in relation to the validity of the ZTT. Stringent exclusion criteria are therefore mandatory to increase specificity. Large variations from the original test design have been identified. The laboratory assays of zinc in these studies are also lacking sensitivity to accurately assess zinc status. To date, there are no tests that are both sensitive and specific that accurately assess marginal zinc status in humans. The ZTT, albeit widely used, does not fill this void, and further research is needed.

Proteomic analysis shows the upregulation of erythrocyte dematin in zinc-restricted human subjects

Methods of assessment of zinc status in humans: a systematic review

Investigation of Lymphocyte Gene Expression for Use as Biomarkers for Zinc Status in Humans

Low dietary zinc alters indices of copper function and status in postmenopausal women

Assessment of Marginal Zinc Status in Humans

Changes in dietary zinc and copper affect zinc-status indicators of postmenopausal women, notably, extracellular superoxide dismutase and amyloid precursor proteins

The present study focused on whether serum extracellular superoxide dimutase (EC-SOD) activity can be used as a functional indicator of marginal zinc deficiency in humans. Subjects in this study were 444 healthy adults over 30 yr of age living a normal rural life in Kyunggi province, Korea. The mean dietary zinc intake of subjects obtained from one 24-h recall was 6.41 +/- 4.35 mg and the average serum zinc concentration of the subjects was 11.06 +/- 2.44 micromol/L. Subjects were divided into three groups by serum zinc concentrations: adequate (serum zinc >10.7 micromol/L), low (serum zinc 9.0-10.7 micromol/L), and very low (serum zinc <9.0 micromol/L) groups. A total of 50 subjects were selected from the three groups for analysis of EC-SOD activities. The EC-SOD activity of subjects increased with increasing serum zinc concentrations, and the activities of the three groups were significantly different as indicated by the Kruskal-Wallis test (p = 0.0239). Also, serum EC-SOD activities were significantly correlated with serum zinc concentrations (r = 0.289, p = 0.04). Serum EC-SOD activities, however, were not significantly correlated to the dietary zinc intakes. In conclusion, these results show that EC-SOD activities are decreased in subjects with low serum zinc concentrations and suggest that EC-SOD activity may be a functional indicator of zinc nutritional status in humans.