Zinc-Induced Metallothionein in Centenarian Offspring From a Large European Population: The MARK-AGE Project.

Metallothionein (MT) family are cysteine-rich proteins that regulate zinc (Zn) homeostasis and protect against oxidative damage. Studies in transgenic mice have shown that MT favorably influence longevity, although their role in human aging is not completely understood. Within the European multicenter study MARK-AGE, we analyzed MT induction after Zn treatment in peripheral blood mononuclear cells (PBMCs) and its relation with redox biomarkers in 2,936 age-stratified subjects (35-75 years) including the general population (RASIG), centenarian offspring (GO), and their spouses (SGO). We found that the lymphocyte capability to induce MT in response to Zn is not affected by aging. However, GO participants showed lower Zn-induced MT and increased basal expression of MT1A, MT1X, and ZnT-1 genes than RASIG subjects. Moreover, Zn-induced MT levels were found to be inversely related with oxidative stress markers (plasma protein carbonyls, 3-nitrotyrosine, and malondialdehyde) in the whole population, but not in GO subjects. In conclusion, our results support the hypothesis that the response to Zn is attenuated in PBMCs of centenarian offspring compared to the general population as a consequence of a tighter control of Zn homeostasis which is likely to provide them constant protection against stress stimuli over the whole lifespan.

Effect of ZIP2 Gln/Arg/Leu (rs2234632) polymorphism on zinc homeostasis and inflammatory response following zinc supplementation.

Zinc dyshomeostasis may lead to an augmented production of proinflammatory cytokines promoting chronic inflammation and increasing the susceptibility to age-related diseases. Several studies suggest that the zinc transporter protein ZIP2 may play a relevant role in the immune system especially during zinc deficiency, while a polymorphism on the coding region of ZIP2 gene (Gln/Arg/Leu) has been associated with severe carotid artery disease. The aim of this study is to investigate the role of ZIP2 SNP on zinc and inflammatory status in 1090 elderly healthy free-living subjects enrolled in the ZincAge project and to assess the effect of zinc supplementation on zinc status, inflammatory mediators, and zinc transporter expression depending on ZIP2 genotype. ZIP2 Leu- (Arg43Arg) carriers showed enhanced IL-6, TNF-α, and RANTES plasma levels associated with decreased free cytosolic zinc in PBMCs and an upregulation of zinc transporters ZIP2, ZIP8, and Znt1. Moreover, Leu- subjects displayed significant decrement of inflammatory mediators such as MCP-1, TNF-α, and RANTES following zinc supplementation. In summary, this investigation provides new evidence on the effect of ZIP2 Gln/Arg/Leu polymorphism on proinflammatory mediators and zinc homeostasis in elderly population with a more pronounced anti-inflammatory effect of zinc supplementation in subjects carrying ZIP2 Leu- (Arg43Arg) genotype. These novel findings could be useful in identifying elderly subjects who may benefit of zinc intervention to decrease the inflammatory status and to prevent or delay the development of age-related diseases.

Modulators of cellular senescence: mechanisms, promises, and challenges from in vitro studies with dietary bioactive compounds.

Cellular senescence is considered an important mechanism to prevent malignant transformation of potentially mutated cells but, persistence of senescent cells within tissues alters microenvironment in ways that can promote cancer and aging phenotype thus underlining pathophysiologic processes of different age-related diseases. Coincident with this increased knowledge, understanding and finding modulators of the dynamics that control senescent-cell formation, fate and subsequent effect on tissue function has gained critical interest in experimental gerontology and cancer research. The purpose of this review is to discuss the evidence that various dietary bioactive compounds can modulate cellular senescence in vitro and to summarize findings and mechanisms that might be useful for the development of health-promoting nutraceuticals. An overview of cellular senescence and its impact in aging and cancer is described along with the strategies and pathways that are currently being investigated to target cellular senescence. Particular emphasis is given to the mechanisms by which bioactive dietary factors (i.e., most polyphenols) can delay or induce cellular senescence in vitro and how this knowledge could be used to explain the opposite effects shown in cancer lines and primary cells by some of these compounds. In addition, the problems to translate findings from modulation of cellular senescence in vitro into experimental treatments or clinical trials able to prevent or counteract age-related diseases are briefly described. The information herein provided might be useful to design further research in the field as well as to develop new nutraceuticals to be tested in experimental models and clinical trials.

Micronutrient-gene interactions related to inflammatory/immune response and antioxidant activity in ageing and inflammation. A systematic review.

Recent longitudinal studies in dietary daily intake in human centenarians have shown that a satisfactory content of some micronutrients within the cells maintain several immune functions, a low grade of inflammation and preserve antioxidant activity. Micronutrients (zinc, copper, selenium) play a pivotal role in maintaining and reinforcing the performances of the immune and antioxidant systems as well as in affecting the complex network of the genes (nutrigenomic) with anti- and pro-inflammatory tasks. Genes of pro- and anti-inflammatory cytokines and some key regulators of trace elements homeostasis, such as Metallothioneins (MT), are involved in the susceptibility to major geriatric disease/disorders. Moreover, the genetic inter-individual variability may affect the nutrients' absorption (nutrigenetic) with altered effects on inflammatory/immune response and antioxidant activity. The interaction between genetic factors and micronutrients (nutrigenomic and nutrigenetic approaches) may influence ageing and longevity because the micronutrients may become also toxic. This review reports the micronutrient-gene interactions in ageing and their impact on the healthy state with a focus on the method of protein-metal speciation analysis. The association between micronutrient-gene interactions and the protein-metal speciation analysis can give a complete picture for a personalized nutrient supplementation or chelation in order to reach healthy ageing and longevity.

Effects of human Toll-like receptor 1 polymorphisms on ageing.

BACKGROUND: Advanced age results in crucial alterations of the innate and adaptive immune system leading to functional defects resulting in infection and chronic diseases. Toll-like receptors (TLR) recognize pathogenic structures and are important in the immune response to infections and vaccination. However, the role of TLR single nucleotide polymorphisms (SNP) is poorly understood in the setting of human ageing. This study investigated the impact of the TLR1 SNPs A743G and T1805G on ageing in different age groups from two European populations. RESULTS: The TLR1 genotypes 743AA/1805GG (TLR1neg) are associated with a TLR1 negative phenotype, impaired function and susceptibility to tuberculosis. Carriers of heterozygous 743AG/1805TG and homozygous 743GG/1805TT genotypes (TLR1pos) have a TLR1 positive phenotype. By comparing healthy young and old German donors, the old group showed a tendency to carry more TLR1neg and less homozygous TLR1pos genotypes. Anti-inflammatory Interleukin (IL)-1 receptor antagonist (Ra) was significantly elevated in supernatants of mononuclear cells from old German subjects with a TLR1pos genotype in contrast to those with the 743AA genotype. Healthy old individuals and nonagenarians from Italy displayed significantly higher frequencies of TLR1pos genotypes than the old group from Germany. The data show that tumor-necrosis-factor (TNF)α, CXCL8 and CCL2 levels were higher in old donors from Germany than in plasma levels from old Italian donors. TNFα and CCL2 levels were significantly raised in old German individuals compared to Italian nonagenarians. German and Italian donors with the TLR1neg genotype basically produced more CCL2 than older European donors with TLR1pos genotypes. CONCLUSION: The higher frequency of the TLR1pos genotype in elderly Italian subjects may result from different ethnic populations. Lower inflammatory mediator release of aged Italian individuals is probably due to different background in nutrition, diet, genetics and to psychological aspects. Elderly donors carrying TLR1pos genotypes basically release more anti-inflammatory IL-1Ra and less inflammatory CCL2 suggesting a decline of the pro-inflammatory status found in ageing and, therefore, this may define an anti-inflammatory phenotype. Future studies are needed to elucidate the association of a TLRpos genotype with decreased susceptibility to infections and reduced risk to develop artherosclerosis.

Attachment style and immunity: a 1-year longitudinal study.

Previous cross-sectional studies suggested an association between attachment-related avoidance and altered immune function. We aimed at testing this hypothesis with longitudinal data. A random sample of 65 female nurses provided a blood sample and completed measures of perceived stress, social support, alexithymia, and attachment style. Immune assays included lymphocyte proliferative response (LPR) to Phytohemagglutinin and NK cell cytotoxicity (NKCC). State measures (perceived stress and support) and immune measures were collected again after 4, 8, and 12 months. Linear mixed effects models were used to examine the relationship between attachment and immunity. While low to moderate levels of attachment-related avoidance were not associated with NKCC, there was a significant negative association (beta -.35; p=.005) between high levels of avoidance and NKCC. No association was observed between NKCC and attachment-related anxiety, and between LPR and both attachment dimensions. While our findings should be interpreted with caution due to study limitations such as the relatively small sample size and the inclusion of only female participants, they corroborate the notion that attachment is linked to physiology and health.

Metallothioneins, ageing and cellular senescence: a future therapeutic target.

In ageing, the accumulation of damaged molecules provoked by oxidative stress and inflammation contributes to altered gene expressions and cellular dysfunction. The antioxidant system is crucial in order to prevent damage to intracellular molecules including DNA and, consequently, to avoid cellular dysfunction or neoplastic transformation. However, during serious DNA damage, the cells can activate a response characterized by cell cycle arrest and production of factors (mainly chemokines and cytokines) named "senescent associated secretory phenotype" (SASP) with the putative function to attract immune cells involved in the clearance of the senescent cells. This phenomenon named "cellular senescence" is, by one side, an important tumor suppressive mechanism but, on the other side, it contributes to impair tissue regenerative capacity and to possible transformation of neighbouring cells to cancer cells if a rapid clearance of the senescent cell doesn't occur. Therefore, preventing DNA damage via an optimal intracellular antioxidant defence is the key to reduce risk of cancer while keeping senescent changes at minimum. Zinc-bound Metallothioneins (MT), could play a key role in this prevention because they are antioxidant proteins and release zinc ions for several proteins and enzymes involved in antioxidant and DNA-repair responses. Reduced MT expression and intracellular zinc occur in some models of senescent cells. This process is of relevance since zinc ions released from MT could be implicated in the modulation of SASP. In chronic inflammation, such as in ageing, the dysfunction in zinc release from MT occurs, suggesting a potential contribution to the onset of senescent cells. Hence, MT could be directly or indirectly involved in the modulation of cellular senescent state and might represent a possible therapeutic target against the accumulation of dysfunctional senescent cells.

Disturbed zinc homeostasis in diabetic patients by in vitro and in vivo analysis of insulinomimetic activity of zinc.

Disturbances of zinc homeostasis have been observed in several diseases, including diabetes mellitus. To further characterize the association between zinc and diabetes, we recruited 75 patients with type 1 or type 2 diabetes and 75 nondiabetic sex-/age-matched control subjects in order to analyze differences concerning human zinc transporter 8 (hZnT-8) expression, single nucleotide polymorphisms (SNPs) in the genes of hZnT-8 as well as metallothionein 1A and serum/intracellular zinc. Furthermore, we investigated the relation between insulin and zinc homeostasis in type 2 diabetic subjects and consolidated our results by in vitro analysis of the effect of insulin on cellular zinc status and by analysis of the modulation of insulin signal transduction by intracellular zinc homeostasis. Concerning the expression of hZnT-8 and the SNPs analyzed, we did not observe any differences between diabetic and control subjects. Serum zinc was significantly lower in diabetic patients compared to controls, and intracellular zinc showed the same tendency. Interestingly, type 2 diabetes patients treated with insulin displayed lower serum zinc compared to those not injecting insulin. In vitro analyses showed that insulin leads to an increase in intracellular zinc and that insulin signaling was enhanced by elevated intracellular zinc concentrations. In conclusion, we show that type 1 and type 2 diabetic patients suffer from zinc deficiency, and our results indicate that zinc supplementation may qualify as a potential treatment adjunct in type 2 diabetes by promoting insulin signaling, especially in zinc-deficient subjects.

Comparison of intracellular zinc signals in nonadherent lymphocytes from young-adult and elderly donors: role of zinc transporters (Zip family) and proinflammatory cytokines.

Intracellular zinc homeostasis is crucial in regulating the inflammatory/immune response at any age. It is tightly regulated by zinc transporters that control influx, efflux and compartmentalization of zinc within the cells. Specific methods for detecting the age-related differences in intracellular zinc signaling are poorly described. We report a novel assay induced after the in vitro zinc addition in peripheral blood mononuclear cells (PBMCs) and in lymphocytes from young and old donors in the absence/presence of in vitro zinc depletion (using EDTA). The intracellular labile zinc variations are monitored over time by flow cytometry using Fluozin-3 AM probe. The best curve fit of the data is calculated using a nonlinear regression model defined as follows: pr3/[1+Exp(-pr1-pr2*Xt)]. Pr1 depends on the initial free zinc value (time 0); pr2 describes the rate of the speed in reaching the maximum intracellular free zinc concentration; pr3 represents the maximum intracellular zinc increment (plateau curve); Xt is the time course. Age-related intracellular free zinc variations occur in PBMCs and lymphocytes incubated in EDTA-supplemented medium. The higher plateau of the curve (pr3) was observed in younger subjects. An up-regulation of Zip genes (Zip1, Zip2, Zip3), influencing zinc influx, is more pronounced in the young than old donors. Interleukin-6 and tumor necrosis factor-α overproduction was enhanced in old individuals, suggesting the presence of more marked zinc deficiency and chronic inflammation. In conclusion, the determination of intracellular zinc signals induced by in vitro zinc addition using logistic parameters may be useful to estimate the rate of intracellular zinc homeostasis and its role in inflammatory/immune response in aging.

Cu to Zn ratio, physical function, disability, and mortality risk in older elderly (ilSIRENTE study).

Associations between copper to zinc ratio (CZr) and mortality have suggested CZr as a biomarker of aging. Nevertheless, very limited data exist on the association between serum CZr and physical or functional status of very old people. We examined the relationship between serum CZr and physical performance, muscle strength, functional status, and survival from the ilSIRENTE Study: a longitudinal study of persons aged 80 years or older (n = 346). An adjusted linear regression model was subsequently performed to calculate the regression coefficients of the associations between baseline physical and functional measures (dependent variable) with CZr or "Cu and Zn" alone taking also into account the influence of other relevant factors, including hematological (albumin, cholesterol, and urea) and inflammatory biomarkers (IL-6 and CRP) that were significantly different across CZr tertiles. CZr showed significant and stronger relationships than Cu or Zn alone with all baseline physical and functional measures in models that did not include adjustments for inflammatory parameters. CZr was also associated with physical decline, measured as "SPPB% decline" at 2 years of follow-up and mortality at 4 years of follow-up. Subjects in the high CZr tertile had a higher risk of death with an adjusted hazard ratio of 1.92 (95% CI, 1.12-3.29; p = 0.02). In conclusion, we have confirmed the role of CZr as a predictor of mortality, whereas the role of CZr as a biomarker or predictor of physical or functional performance seems to be the consequence of its strict relationships with inflammatory parameters. In this context, further investigations need to be carried out.

A genetic variant near the equine interleukin 6 gene associated with copper:zinc ratio.

The aim of this study was to validate an A/T single nucleotide polymorphism (SNP) corresponding to a LINE2 sequence located ∼1.1kb downstream of the IL-6 gene (SNP BIEC2-911738) and to determine if this variant is correlated with interleukin 6 (IL-6) modulation or with different plasma concentrations of Zn, Cu, Se and Fe. The frequency of the newly described variant T ranged from 0 to 23.1% among different breeds of horses. SBIEC2-911738 was not associated with changes in IL-6 plasma levels. Increased Cu:Zn ratios were observed in horses carrying the AT genotype independently of breed when stabled for 24h after physical exercise.

Metalloproteases/anti-metalloproteases imbalance in chronic obstructive pulmonary disease: genetic factors and treatment implications.

PURPOSE OF REVIEW: The aim is to describe the involvement of matrix metalloprotease (MMP), A Disintegrin And Metalloproteases (ADAM), tissue inhibitors of MMP (TIMP) polymorphisms and the role of α-2 Macroglobulin (α-2M) in chronic obstructive pulmonary disease (COPD) development and progression, with a focus on interventions with synthetic MMP inhibitors alone or associated with current drugs used in COPD therapy in order to restore MMPs/TIMPs imbalance. RECENT FINDINGS: COPD is one of the major causes of death in the elderly. It is characterized by progressive development of airflow limitation manifested by decreased forced expiratory volume in one second (FEV1) and reduction in the percentage of FEV1/forced vital capacity. The major pathogenic role is played by metalloproteases (MMPs, ADAMs)/anti-metalloproteases (TIMPs, α-2M) imbalance, which is responsible for MMP overproduction not sufficiently counteracted by TIMPs or α-2M. As a consequence, the lung extracellular matrix is destroyed with obstruction of small airways and appearance of emphysema. SUMMARY: The disease is mainly caused by exposure to cigarette smoke or noxious gases and air pollutants, but also genetic factors are involved. Among them, polymorphisms of MMPs (MMP1, MMP2, MMP9, MMP12), ADAMs (ADAM33) and TIMPs (TIMP1, TIMP2) are relevant, in which the inflammation and the smoking habit play key roles especially in unfavorable allele carriers. The association between these polymorphisms and the current drugs paves the way for personalized therapy with a great impact at clinical level.

In vivo effect of alpha-bisabolol, a nontoxic sesquiterpene alcohol, on the induction of spontaneous mammary tumors in HER-2/neu transgenic mice.

Breast cancer represents the most commonly diagnosed invasive malignancy in pre- and postmenopausal women in both developed and underdeveloped countries. Taking into account that treatment options, including surgery, have not been able to deal with the growing incidence of breast malignancy, it is required to develop mechanism-based novel agents for its prevention. Wide interest in some natural compounds as antiinflammatory agents and as alternative to the traditional medicines is increasing because they do not provoke any adverse effects and are effective in multiple organs, alpha-Bisabolol (BISA), a small oily sesquiterpene alcohol, was reported as chemopreventive agent in induced rat mammary carcinogenesis. The aim of the present study is to investigate the role played by two doses of BISA (via intramammary infusion) on the induction and development of mammary tumor in HER-2/neu transgenic mice as well as the BISA effect after tumor surgical resection. The main data show that (a) optimal dosage of BISA is 10 mg/mouse rather than 3.6 mg/mouse with no adverse effects (e.g., alopecia); (b) the number of the palpable tumor masses decreases in mice treated with 10 mg/mouse of BISA; (c) mice after surgical resection of the primary tumor and treatment with BISA (10 mg) are free from tumor for more weeks, after the surgical treatment; (d) using array analysis, some genes implicated in carcinogenesis mechanisms (NF-kappaBia, Map2k, Mapkl4, and HER2/ neu), angiogenesis process (Fgf), and inhibition of apoptosis (Birc5) are differently regulated after BISA treatment, with a downregulation of the HER2/neu as well as of Fgf and Birc5 genes; (e) the NK cell cytotoxicity increases in tumor-treated mice, especially after the removal of the first tumor mass. Such effectiveness could be important to achieve goals for a possible combination of BISA to conventional therapies in breast cancer and to tumor surgical removal (adjuvant therapy), as suggested for other sesquiterpene analogs.

Diet (zinc)-gene interaction related to inflammatory/immune response in ageing: possible link with frailty syndrome?

The pivotal role played by zinc-gene interaction in affecting the inflammatory response mediated by IL-6 in ageing, successful ageing (nonagenarians) and the most common age-related diseases is now recognized. Contradictory data emerging from association studies of IL-6 polymorphisms with longevity and chronic age-related diseases seem to arise from the interaction of this inflammatory pathway with dietary habits. Similar conclusions are expected to arise from association studies with the frailty syndrome. Some polymorphisms of genes related to vitamin B12 availability have been already found to be associated with frailty suggesting a possible link among diet-gene interaction and frailty in old age. Other studies in this field are urgently required because of their high potential for suggesting strategies in the care and prevention of frailty in ageing through dietary interventions, in which nutrient zinc may play a pivotal role taking into account that the high copper to zinc ratio is a significant index of the mortality in older people.

Assessment of gene-nutrient interactions on inflammatory status of the elderly with the use of a zinc diet score--ZINCAGE study.

Although zinc plays an important role in health status of the elderly, their dietary habits in relation to zinc intake are not well documented. The main objective of the current study was the assessment of dietary zinc intake in European old populations and the investigation of its impact on plasma zinc and inflammatory cytokines concentrations, in relation to genetic markers. Within the ZINCAGE study, 819 healthy old Europeans (>or=60 years old) were recruited. Plasma zinc, interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured. Genotype data were obtained for the -174G/C polymorphism in the IL-6 gene. Dietary data were collected with a food frequency questionnaire and were used to calculate a zinc diet score. Zinc score was validated using additional dietary data (24-h recalls), in a subsample of 105 subjects. Zinc score was different among most of the European centres (P<.001), while an age-dependent decline was documented (P=4.4x10(-12)). Plasma zinc concentrations were significantly correlated with the zinc score (standardized beta=0.144, P=8.8x10(-5)). The minor allele frequency for the -174G/C polymorphism was f(C) 0.31. There was a significant interaction of zinc diet score and GG (-174G/C) genotype on higher plasma IL-6 levels (beta+/-S.E.=0.014+/-0.0, P=.008). The main finding of our study was the detection of gene-nutrient and biochemical-nutrient interactions in a multiethnic cohort based on a common dietary assessment tool.

Noninvasive neonatal thymus graft into the axillary cavity extends the lifespan of old mice.

Neonatal thymus grafts exert a rejuvenating action on various immunological and nonimmunological functions found altered in old mice. Commonly, half of a thymus is grafted under the kidney capsule. The invasiveness of the surgical procedure and the use of limited thymus tissue may explain why precedent survival kinetics remain unaffected. In this trial, we grafted two neonatal thymi into the axillary cavity of old mice, thus reducing the invasiveness of the intervention and increasing the amount of grafted neonatal tissue. Using a Piantanelli parametric model of survivorship, we found a significant change in mortality rate between the two groups (thymus graft and controls).

Accumulation of cells with short telomeres is associated with impaired zinc homeostasis and inflammation in old hypertensive participants.

Critical shortening of telomeres, likely associated with a considerable increase of senescent cells, can be observed in PBMC of individuals aged 80 and older. We investigated the relationship between critical telomere shortening and zinc status in healthy or hypertensive participants with or without cardiovascular disease in old and very old participants. Telomere shortening and accumulation of cells with short telomeres (percent of cells with short telomeres) in advancing age was evident in patients and healthy controls, but exacerbated in those patients aged 80 and older. Moreover, in very old patients, the accumulation of % CST may impair intracellular zinc homeostasis and metallothioneins expression, which itself is linked to an increased number of inflammatory agents, thereby suggesting the existence of a possible causal relationship between % CST and zinc homeostasis. The determination of % CST could be a more reliable means than the simple measure of telomere length as fundamental parameter in ageing to determine whether individuals are still able to respond to stress.

Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis.

Several studies have assessed changes in frequency of -174 interleukin (IL)-6 single nucleotide polymorphism (SNP) with age. If IL-6 tracks with disability and age-related diseases, then there should be reduction, in the oldest old, of the frequency of homozygous GG subjects, who produce higher IL-6 levels. However, discordant results have been obtained. To explore the relationship between this polymorphism and longevity, we analyzed individual data on long-living subjects and controls from eight case-control studies conducted in Europeans, using meta-analysis. There was no significant difference in the IL-6 genotype between the oldest old and controls (Odds Ratio [OR]=0.96; 95% C.I.: 0.77-1.20; p=0.71), but there was significant between-study heterogeneity (I2=55.5%). In a subgroup analyses when male centenarians from the three Italian studies were included, the frequency of the IL-6 -174 GG genotype was significantly lower than the other genotypes (OR=0.49; 95% C.I.: 0.31-0.80; p=0.004), with no evidence of heterogeneity (I2=0%). Our data supports a negative association between the GG genotype of IL-6 SNP and longevity in Italian centenarians, with males who carry the genotype being two times less likely to reach extreme old age compared with subjects carrying CC or CG genotypes. These findings were not replicated in other European groups suggesting a possible interaction between genetics, sex and environment in reaching longevity.

Possible new antiaging strategies related to neuroendocrine-immune interactions.

The aging process demonstrates gradual and spontaneous changes, resulting in maturation through childhood, puberty and young adulthood, and then decline through middle and late age. However, animals and humans are capable of reaching the extreme limit of life span characteristic for the species with a very efficient network of antiaging mechanisms. Among them, neuroendocrine-immune interactions play a pivotal role. The loss of the capacity of the organism in remodeling the neuroendocrine-immune response leads to the appearance of age-associated pathologies. We herein report some substances which can be proposed as new antiaging strategies because of their capacity to remodel some biological functions in old animals and humans. These substances are: L-deprenyl, leptin, ghrelin, carnosine and NO donors. Their role as possible antiaging strategies in healthy people in relation to neuroendocrine-immune responses and zinc ion bioavailability is reported and discussed.

Mediterranean diet and plasma concentration of inflammatory markers in old and very old subjects in the ZINCAGE population study.

BACKGROUND: Aging is associated with low-grade elevation of circulating inflammatory markers, leading to increased risk of morbidity and mortality. The Mediterranean diet has been suggested as a determinant of longevity. In the current study, we investigated the impact of the Mediterranean diet on inflammatory status in old subjects. METHODS: Within the ZINCAGE study, 957 healthy old subjects (>or=60 years old) from five European countries were recruited. Plasma interleukin (IL)-6, IL-8, monocyte chemoattractant protein, tumor necrosis factor-alpha, high-density lipoprotein cholesterol (HDL-C) and erythrocyte sedimentation rate (ESR) were measured. Dietary data were collected applying a food frequency questionnaire and were used to estimate adherence to the Mediterranean diet. RESULTS: The Italians presented the greatest adherence to the Mediterranean diet, while the Polish the poorest. In females, higher diet score was significantly associated with lower body mass index and ESR and higher HDL-C levels (beta=-0.127, p=0.003; beta=-0.144, p=0.001; beta=0.144, p=0.029, respectively). In males, diet score was negatively associated with IL-8 levels (beta=-0.101, p=0.044). The Mediterranean diet was associated with reduced IL-8 concentrations in Greeks (beta=-0.213, p=0.007). CONCLUSIONS: There were significant effects of the components of the Mediterranean diet on inflammation markers. The Mediterranean diet score is useful in assessing nutritional influence on immune status.