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Recent evidence suggests that high dose and/or long term use of proton pump inhibitors (PPIs) may increase the risk of adverse cardiovascular events in older patients, but mechanisms underlying these detrimental effects are not known. Taking into account that the senescent endothelial cells have been implicated in the genesis or promotion of age-related cardiovascular disease, we hypothesized an active role of PPIs in senescent cells. The aim of this study is to investigate the changes in gene expression occurring in senescent and non-senescent human coronary artery endothelial cells (HCAECs) following Omeprazole (OPZ) or Lansoprazole (LPZ) treatment. Here, we show that atherogenic response is among the most regulated processes in PPI-treated HCAECs. PPIs induced down-regulation of anti-atherogenic chemokines (CXCL11, CXCL12 and CX3CL1) in senescent but not in non-senescent cells, while the same chemokines were up-regulated in untreated senescent cells. These findings support the hypothesis that up-regulated anti-atherogenic chemokines may represent a defensive mechanism against atherosclerosis during cellular senescence, and suggest that PPIs could activate pro-atherogenic pathways by changing the secretory phenotype of senescent HCAECs. Moreover, the genes coding for fatty acid binding protein 4 (FABP4) and piezo-type mechanosensitive ion channel component 2 (PIEZO2) were modulated by PPIs treatment with respect to untreated cells. In conclusions, our results show that long-term and high dose use of PPI could change the secretory phenotype of senescent cells, suggesting one of the potential mechanisms by which use of PPI can increase adverse outcomes in older subjects. [ABSTRACT FROM AUTHOR]

Impairment of one or more parameters of circadian rhythms (CR) of body temperature (BT) and locomotor activity (LMA) are considered among the hallmarks of mammalian aging. These alterations are frequently used as markers for imminent death in laboratory mice. However, there are still contradictory data for particular strains and it is also uncertain which changes might predict senescence changes later in life, including the force of mortality. In the present paper we use telemetry to study LMA and CR of BT during aging of BALB/c mice. At our knowledge this is the first time that CR of BT and LMA are investigated in this strain in a range of age covering the whole lifespan, from young adult up to very old age. CR of BT was analyzed with a cosine model using a cross sectional approach and follow-up measurements. The results show that BT, LMA, amplitude, goodness-of-fit (GoF) to circadian cycle of temperature decrease with different shapes during chronological age. Moreover, we found that the % change of amplitude and BT in early life (5-19 months) can predict the remaining lifespan of the mice. Later in life (22-32 months), best predictors are single measurements of LMA and GoF. The results of this study also offer potential measures to rapidly identifying freely unrestrained mice with the worst longitudinal outcome and against which existing or novel biomarkers and treatments may be assessed. [ABSTRACT FROM AUTHOR]

Zinc is a relevant nutritional factor for the whole life of an organism because it affects the inflammatory/immune response and antioxidant activity, leading to a healthy state. Despite its important function, the dietary intake of zinc is inadequate in elderly. Possible interventions include food fortification because it does not require changes in dietary patterns, the cost is low and it can reach a large portion of the elderly population, including very old subjects. Studies evaluating the impact of Zn-fortified foods on functional parameters in elderly, in particular, in very old individuals, are missing. The objective of this study was to evaluate the efficacy of consumption of a zinc-fortified drinking skim milk (Zn-FMilk) for a period of 2 months in comparison to standard non-fortified milk (No-FMilk) on some biochemical parameters, zinc status, inflammatory/immune response and on a key parameter of the T cell-mediated immunity (thymulin hormone) in healthy very old subjects. The treatment with zinc-fortified milk (Zn-FMilk) is a good omen to increase the cell-mediated immunity in very old age represented by thymulin activity and some cytokine (IL-12p70, IFN-γ) release. At clinical level, a good healthy state occurs in 70 % of the subjects with no hospitalization after 1 year of the follow-up in comparison to very old control subjects that did not participate to crossover design. In conclusion, the Zn-FMilk can be considered a good functional food for elderly, including older people. It might be a good replacement to the zinc tablets or lozenges taking into account the attitude of old people to uptake milk as a preferential food. [ABSTRACT FROM AUTHOR]

The diet in the elderly does not provide a sufficient level of nutrients needed to maintain an adequate healthy status leading to micronutrient deficiencies and impaired immune response with subsequent development of degenerative diseases. 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 and genomic stability. Old people aged 60-65 years and older have zinc intakes below 50% of the recommended daily allowance on a given day. Many causes can be involved: among them, altered intestinal absorption, inadequate mastication, psychosocial factors, drugs interactions, altered subcellular processes (zinc transporters (Zip and ZnT family), metallothioneins, divalent metal transporter-1). Zinc supplementation may remodel the immune alterations in elderly leading to healthy ageing. Several zinc trials have been carried out with contradictory data, perhaps due to incorrect choice of an effective zinc supplementation in old subjects showing subsequent zinc toxic effects on immunity. Old subjects with specific IL-6 polymorphism (GG allele carriers; named C−) are more prone for zinc supplementation than the entire old population, in whom correct dietary habits with foods containing zinc (Mediterranean diet) may be sufficient in restoring zinc deficiency and impaired immune response. We summarise the main causes of low zinc dietary intake in elderly reporting an update on the impact of zinc supplementation upon the immune response also on the basis of individual IL-6 polymorphism. [ABSTRACT FROM AUTHOR]

Ageing is an inevitable biological process associated with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. Nutritional factor, zinc, known to be involved in improving immunity, may remodel some of the age-associated changes, leading to a healthy ageing. 'In Vitro' studies involving human lymphocytes exposed to endotoxins, and 'in vivo' studies comparing old and young mice fed with low dietary zinc suggest that zinc is important for both innate and adaptive immune efficiency, and more optimal inflammatory/immune response. The intracellular zinc homeostasis is mainly regulated by Metallothioneins (MT), via ion release through the reduction of thiol groups in MT molecule. These processes are crucial because mediating the zinc signalling within the immune cells assigning to zinc a role of 'second messenger'. Zinc homeostasis is altered in ageing partly due to higher expression levels of MT, leading to an increased sequestration of zinc, resulting in less availability of free intracellular zinc. Improvement of immune functions and stress response systems occurs in elderly after physiological zinc supplementation. The main reason behind these effects seems to be related to a like 'hormetic' response induced by zinc. However, the choice of old subjects for zinc supplementation has to be performed in relationship to the specific genetic background of MT and pro-inflammatory cytokine (IL-6) because the latter is involved both in MT gene expression and in intracellular zinc homeostasis. Old subjects carrying GG genotypes (termed C− carriers) in IL-6 −174G/C locus display increased IL-6 production, low intracellular zinc ion availability, impaired innate immune response and enhanced MT. By contrast, old subjects carrying GC and CC genotypes (termed C+ carriers) in the same IL-6 −174 locus displayed satisfactory intracellular zinc and innate immune response. Moreover, male carriers of C+ allele are more prone to reach centenarian age than C− ones. Therefore, old C− subjects are likely to benefit more from zinc supplementation restoring NK cell cytotoxicity and improving the zinc status. Plasma zinc deficiency and the altered immune response is more evident when the genetic variations of IL-6 polymorphism are associated with the genetic variations of MT1A in position +647, suggesting that the genetic variations of IL-6 and MT1A are very useful tools for the identification of old people who effectively need zinc supplementation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Associations have been reported between plasma Cu and Zn levels and the incidence of the most important age-related diseases. Previously proposed methods of using plasma Cu/Zn as a predictor of all-cause mortality have been derived from populations in which old and very old subjects were underrepresented. The purpose of this paper is to estimate the usefulness of plasma Cu/Zn as a sensitive biomarker of harmful inflammatory or nutritional changes in the elderly and its incremental prognostic utility as a predictor of all-cause mortality in a functionally independent elderly Italian cohort. The association between plasma Cu/Zn and inflammatory (CRP, ESR, IL-6) or nutritional (albumin, BMI) markers was studied in 498 elderly subjects. Blood samples were taken from 164 healthy 20- to 60-year-old volunteer controls. A 3.5 years prospective follow-up study of mortality by age-related diseases was performed in n = 218 over 70-year-olds. Plasma Cu/Zn ratio was associated with all the inflammatory markers studied, as well as with serum albumin, and predicted 3.5 years mortality in subjects over 70. Plasma Cu/Zn was higher in women than men and increased with advancing age. Subjects with stable cardiovascular disease (CVD) displayed higher plasma Cu/Zn than those without, due mainly to increased plasma Cu. However, most of the age-related changes of Cu/Zn resulted from a progressive decline of plasma Zn. Cu/Zn ratio may be considered an important clinical inflammatory-nutritional biomarker as well as a significant predictor of all-cause mortality in over 70-year-olds. [ABSTRACT FROM AUTHOR]

Vascular complications, including ischaemic cardiomyopathy, are the major causes of death in old diabetic patients. Chronic inflammation due to high IL-6 production occurs in type 2 diabetes (NIDDM) and atherosclerosis. High levels of IL-6 are associated with hyperglycaemia, dyslipidemia and provoke insulin resistance. In ageing and inflammation, IL-6 affects Metallothionein (MT) homeostasis, which in turn is involved in zinc turnover. Zinc deficiency is an usual event in ageing, inflammation, type 2 diabetes and atherosclerosis. No genetic study exists on MT polymorphisms in NIDDM-atherosclerotic patients. The aim of the present study is to screen a single nucleotide polymorphism in the promoter region of the MT2A gene in relation to inflammation (IL-6) and plasma zinc in NIDDM-atherosclerotic patients. The -209 A/G MT2A polymorphism is associated with chronic inflammation (higher plasma levels of IL-6), hyperglycaemia, enhanced HbA1c and more marked zinc deficiency in AA than AG genotype carrying patients. Analysing patients and controls subdivided in AA and AG genotypes, significant interactions existed between disease status and genotypes for glucose and zinc. AA patients are more at risk of developing NIDDM in association with atherosclerosis ( p = 0.0015 odds ratio = 2.617) and its complications, such as ischaemic cardiomyopathy ( p = 0.0050 odds ratio = 12.6). In conclusion, high levels of IL-6 unmask the phenotypes (higher insulin resistance and zinc deficiency) in relation to the genotypes with subsequent risk of developing ischaemic cardiomyopathy in NIDDM-atherosclerotic patients carrying AA genotype. Hence, the novel -209A/G MT2A polymorphism may be a further useful tool for the prevention, diagnosis and therapy of these combined pathologies in the elderly. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the peripheral representation and the clonogenic capacity of CD34+ progenitor cells from 130 healthy subjects (80 females and 50 males) ranging in age from 16 to 100 years. We demonstrated that the absolute number of circulating CD34+ cells progressively and significantly decreased with advancing age, with a 2–fold reduction in subjects aged more than 80 years. The number of granulocyte-macrophagic (CFU-GM), erytroid (BFU-E), and mixed (CFU-GEMM) colonies which developed from the number of CD34+ purified cells per ml, progressively and significantly decreased with advancing age. The reduction of both CD34+ cell number and clonogenic capacity during aging was statistically significant in males but not in females. When evaluated on a per cell bases, a significant age-related decrease in the number of CFU-GM colonies was observed in female but not in male subjects. Our study demonstrates the influence of gender on age-related alterations of the number and clonogenic capacity of CD34+ cells in the peripheral blood. This evidence deserves particular consideration for the future planning of stem cell therapy in age-associated debilitating diseases. [ABSTRACT FROM AUTHOR]