Study protocol for a zinc intervention in the elderly for prevention of pneumonia, a randomized, placebo-controlled, double-blind clinical pilot trial.

Pneumonia is a major public health problem for older adults, being one of the leading causes of hospitalization and death, particularly for elderly nursing home residents. We previously conducted a clinical trial in which we demonstrated that 29% of nursing home residents had low serum zinc levels coinciding with a two-fold increase in pneumonia incidence and duration in comparison to individuals with adequate serum zinc levels. However, causality could not be inferred and necessitates a double-blind clinical trial. To determine the appropriate supplementation dose for such a trial we are conducting a randomized, placebo-controlled, double-blind clinical pilot trial aimed at delineating the optimal dosage (30 and 60 mg/day elemental Zn) and establishing safety. The results from the pilot study will be leveraged to inform our larger randomized clinical trial designed to study the effect of zinc supplementation in nursing home elderly with low serum zinc levels on respiratory infections, antibiotic use, and duration of sick days with pneumonia. In tandem with dose optimization, we will evaluate the correlation between serum zinc and pan-T cell zinc levels, given that T cells and their zinc levels are important in the response and resolution of respiratory infections but whose correlation has only been extrapolated and not demonstrated. Herein we present the study rationale and protocol, as well as discuss specific challenges we encountered in securing a manufacturer for the study agents and when recruiting from nursing home populations during the COVID-19 pandemic. In light of these experiences, we provide recommendations for future clinical trials under circumstances where supply chains are disrupted, and recruitment pools are constrained or unavailable. Clinical trial registration: https://clinicaltrials.gov/, NCT05527899.

Life-long consumption of high level of fruits and vegetables reduces tumor incidence and extends median lifespan in mice.

Objective: Epidemiological studies suggest that consumption of fruits and vegetables (FV) is negatively associated with the incidence of certain cancers and mortality. However, a causal relationship has not been demonstrated. Thus, we investigated the effect of life-long consumption of high level of FV on median lifespan, key biological functions, and pathologies in mice fed low-fat (LF) or high-fat (HF) diets and the underlying mechanisms. Methods: Using a 2 × 2 factorial design, 5 weeks-old male C57BL/6J mice were randomly assigned to one of four groups (n = 60/group): LF (LF-C, 10% kcal fat), HF (HF-C, 45% kcal fat) or each supplemented with 15% (w/w) of a unique FV mixture (LF + FV and HF + FV, respectively). Mice were euthanized when one group reached 50% mortality. Body weight and composition, tumor incidence, and death were monitored. Blood levels of lipids and pro-inflammatory cytokines were assessed. Results: After 21 months of feeding, HF-C group reached 50% mortality, at which time mice in all groups were terminated. HF-C had higher mortality (50.0%) compared to the LF-C group (18.3%, p = 0.0008). Notably, HF-FV had lower mortality (23.3%) compared to HF-C group (p = 0.008); there was no significant difference in mortality between HF-FV and LF-C groups. Tumors were found in all groups, and were predominantly present in the liver, followed by those of lung, intestine, and seminal vesicle. Tumor incidence in the HF-C group (73.3%) was higher than that in LF-C group (30.0%, p < 0.0001). HF + FV group had 23.3% lower tumor incidence compared to the HF-C group (p = 0.014). No significant difference in tumor incidence between the LF-C and LF + FV groups was observed. Long-term FV supplementation reduced systemic inflammation and blood lipids. Conclusion: We provide the first causal evidence that life-long intake of a diet, containing a high level and large variety of FV, decreases tumor incidence and extends median lifespan in mice fed a western-style high-fat diet. These effects of FV are at least in part due to reduced blood levels of pro-inflammatory cytokines and improved dyslipidemia.

Obesity, rather than high fat diet, exacerbates the outcome of influenza virus infection in influenza-sensitized mice.

Introduction: Obesity is associated with impaired immune function and increased susceptibility to infection. High fat (HF) diet-induced obesity is a commonly used animal model. However, HF diet itself is known to affect immune function and infection. Thus, it is not discernable which one, HF diet or adiposity, is the major contributor to the observed impairment in immunity and susceptibility to infection in HF diet-induced obesity. We hypothesized that obesity is a major contributor to impaired immune function. Methods and results: Weight-matched outbred female CD-1 mice (1-mo) were randomly assigned to either a HF (45%) or a low fat (LF, 10%) diet group. Ten week after feeding their respective diets, weight gain in the mice fed the HF diet varied greatly. Thus, based on the average body weight, mice in HF diet group were divided into two sub-groups: HF lean (HF-L) and HF obese (HF-O). After 25-week, mice were immunized with an influenza A/Puerto Rico/8/34 vaccine and boosted 3-week later. Five week after the booster, mice were infected with influenza A/Puerto Rico/8/34 virus, and body weight was recorded daily for 1 month. HF-O mice exhibited significant weight loss after influenza virus challenge compared to LF and HF-L mice while LF and HF-L mice largely maintained their weight to a similar extent. Conclusion: Our findings suggest that obesity, rather than HF diet, per se, may impair the efficacy of influenza vaccination.

Research gaps and opportunities in precision nutrition: an NIH workshop report.

Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On 11-12 January 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The workshop proceeded in 3 parts: part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer disease, and cancer; part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health; part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.

Age-associated alterations in immune function and inflammation.

Immunosenescence is a term used to describe the age-related changes in the immune system. Immunosenescence is associated with complex alterations and dysregulation of immune function and inflammatory processes. Age-related changes in innate immune responses including alterations in chemotactic, phagocytic, and natural killing functions, impaired antigen presenting capacity, and dysregulated inflammatory response have been described. The most striking and best characterized feature of immunosenescence is the decline in both number and function of T cells. With age there is decreased proliferation, decreased number of antigen-naïve T cells, and increased number of antigen-experienced memory T cells. This decline in naïve T cell population is associated with impaired immunity and reduced response to new or mutated pathogens. While the absolute number of peripheral B cells appears constant with age, changes in B cell functions including reduced antibody production and response and cell memory have been described. However, the main alteration in cell-mediated function that has been reported across all species with aging is those observed in in T cell. These T cell mediated changes have been shown to contribute to increased susceptibility to infection and cancer in older adults. In addition to functional and phenotype alterations in immune cells, studies demonstrate that circulating concentrations of inflammatory mediators in older adults are higher than those of young. This low grade, chronic inflammatory state that occurs in the context of aging has been termed "inflammaging". This review will focus on age-related changes in the immune system including immunosenescence and inflammation as well as the functional consequences of these age-related alterations for the aged.

Dietary Fruit and Vegetable Supplementation Suppresses Diet-Induced Atherosclerosis in LDL Receptor Knockout Mice.

BACKGROUND: Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely associated with incidence of cardiovascular disease (CVD). However, evidence for causality is lacking, and the underlying mechanisms are not well understood. OBJECTIVES: We aimed to determine whether there is a causal relation between consuming high levels of F&V and prevention of atherosclerosis, the hallmark of CVD pathogenesis. Furthermore, the underlying mechanisms were determined. METHODS: Six-week-old male LDL receptor-knockout mice were randomly assigned to 3 diet groups (12 mice/group) for 20 wk: control (CON, 10% kcal fat, 0.20 g/kg cholesterol), atherogenic (Ath, 27% kcal fat, 0.55 g/kg cholesterol), and Ath supplemented with 15% F&V (Ath + FV) (equivalent to 8-9 servings/d in humans). F&V was added as a freeze-dried powder that was prepared from the 24 most commonly consumed F&Vs in the United States. Body weight, aortic atherosclerotic lesion area, hepatic steatosis area, serum lipid profile and proinflammatory cytokine TNF-α concentrations, gut microbiota, and liver TNF-α and fatty acid synthase (Fasn) mRNA concentrations were assessed. RESULTS: F&V supplementation did not affect weight gain. Mice fed the Ath + FV diet had a smaller aortic atherosclerotic lesion area (71.7% less) and hepatic steatosis area (80.7% less) than those fed the Ath diet (both P < 0.001) independent of impact on weight, whereas no difference was found between Ath + FV and CON groups in these 2 pathologic markers. Furthermore, F&V supplementation prevented Ath diet-induced dyslipidemia (high concentrations of serum TG and VLDL cholesterol and lower concentrations of HDL cholesterol), reduced serum TNF-α concentration (by 21.5%), suppressed mRNA expression of liver TNF-α and Fasn, and ameliorated Ath-induced gut microbiota dysbiosis. CONCLUSIONS: Our results indicate that consuming a large quantity and variety of F&Vs causally attenuates diet-induced atherosclerosis and hepatic steatosis in mice. These effects of F&Vs are associated with, and may be mediated through, improved atherogenic dyslipidemia, alleviated gut dysbiosis, and suppressed inflammation.

Lack of Differences in Inflammation and T Cell-Mediated Function between Young and Older Women with Obesity.

Both obesity and aging are associated with dysregulated immune and inflammatory responses. There is limited knowledge, however, on differences in the immune system between young and older adults with obesity. The goal of this study was to compare circulating inflammatory cytokines and T cell-mediated immune response between young and older women with obesity. Twenty-three young (23-43 years) and 21 older (60-83 years) women with obesity were recruited at the Weight and Wellness Center at Tufts Medical Center. Circulating inflammatory cytokines (CRP, IL-6, and IL-1ß) and ex vivo indicators of T cell-mediated immune function were compared between the groups. Older women with obesity had significantly fewer circulating CD3+, CD8+, CD19+, and natural killer T (NKT) cells compared to young women with obesity (p = 0.016, p < 0.0001, p = 0.0003, and p < 0.0001, respectively). However, with few exceptions, there was no significant difference in inflammation markers or stimulated lymphocyte proliferation and cytokine production by peripheral blood mononuclear cells between young and older participants. These findings are in contrast to those previously reported in young and old subjects with healthy weight and call for further investigation into the impact of obesity on premature aging of the immune system.

Regulatory role of vitamin E in the immune system and inflammation.

Vitamin E, a potent lipid-soluble antioxidant, found in higher concentration in immune cells compared to other cells in blood, is one of the most effective nutrients known to modulate immune function. Vitamin E deficiency has been demonstrated to impair normal functions of the immune system in animals and humans, which can be corrected by vitamin E repletion. Although deficiency is rare, vitamin E supplementation above current dietary recommendations has been shown to enhance the function of the immune system and reduce risk of infection, particularly in older individuals. The mechanisms responsible for the effect of vitamin E on the immune system and inflammation have been explored in cell-based, pre-clinical and clinical intervention studies. Vitamin E modulates T cell function through directly impacting T cell membrane integrity, signal transduction, and cell division, and also indirectly by affecting inflammatory mediators generated from other immune cells. Modulation of immune function by vitamin E has clinical relevance as it affects host susceptibility to infectious diseases such as respiratory infections, in addition to allergic diseases such as asthma. Studies examining the role of vitamin E in the immune system have typically focused on α-tocopherol; however, emerging evidence suggests that other forms of vitamin E, including other tocopherols as well as tocotrienols, may also have potent immunomodulatory functions. Future research should continue to identify and confirm the optimal doses for individuals at different life stage, health condition, nutritional status, and genetic heterogeneity. Future research should also characterize the effects of non-α-alpha-tocopherol vitamin E on immune cell function as well as their potential clinical application. © 2018 IUBMB Life, 71(4):487-494, 2019.

Hidden Hunger: Solutions for America's Aging Populations.

The global population, including the United States, is experiencing a demographic shift with the proportion of older adults (aged ≥ 65 years) growing faster than any other age group. This demographic group is at higher risk for developing nutrition-related chronic conditions such as heart disease and diabetes as well as infections such as influenza and pneumonia. As a result, an emphasis on nutrition is instrumental for disease risk reduction. Unfortunately, inadequate nutrient status or deficiency, often termed hidden hunger, disproportionately affects older adults because of systematic healthcare, environmental, and biological challenges. This report summarizes the unique nutrition challenges facing the aging population and identifies strategies, interventions, and policies to address hidden hunger among the older adults, discussed at the scientific symposium "Hidden Hunger: Solutions for America's Aging Population", on March 23, 2018.

Perspective: Should Vitamin E Recommendations for Older Adults Be Increased?

Current vitamin E requirements are uniformly applied across the population for those >14 y of age. However, aging is associated with alterations in cellular and physiologic functions, which are affected by vitamin E. Therefore, it is questionable whether vitamin E requirements can be uniformly applied to all adult age categories. With aging, there is dysregulation of the immune system in which there are decreased cell-mediated and pathogen defense responses coupled with an overactive, prolonged inflammatory state. Both animal and human studies in the aged suggest that intake above currently recommended levels of vitamin E may improve immune and inflammatory responses and be associated with a reduced risk of infectious disease. We review the evidence that was considered in establishing the current requirements for vitamin E and highlight data that should be considered in determining the vitamin E requirements in older adults, particularly focusing on the evidence suggesting a benefit of increased vitamin E intake on immune function and inflammatory processes and resistance to infection. The main objective of this Perspective is to initiate the discussion of whether the current Dietary Reference Intake for vitamin E should be increased for the older population. We make this suggestion on the basis of mechanistic studies showing biological plausibility, correction of a major cellular dysfunction in older adults, and strong evidence from several animal and a few human studies indicating a reduction in risk and morbidity from infections.

Naringenin is an inhibitor of T cell effector functions.

Selective inhibition of T cells has been implied to prevent and/or treat autoimmune and inflammatory diseases. Some food compounds that have such immune-modulating functions may serve as nutritional approach to this purpose. In this study, we chose naringenin, a citrus fruits-derived compound with antiinflammatory property, to test this possibility. In this in vitro study, we stimulated mouse T cells with anti-CD3/CD28 (polyclonal TCR activation) or autoantigen MOG35-55 in the presence of naringenin. We found that naringenin dose-dependently suppressed anti-CD3/CD28 and MOG35-55-induced T cell proliferation, production of T cell cytokines IFN-γ, IL-17, IL-6 and TNF-α. We further showed that inhibited T cell proliferation was associated with T cell cycle arrest at G0/G1 phase, which was in turn related to delayed degradation of the cyclin-dependent kinase inhibitor p27kip1 and the down-regulation of retinoblastoma protein phosphorylation in activated T cells. Finally, it was revealed that all these T cell-suppressive effects might be related to naringenin's interference with IL-2/IL-2R-mediated signaling pathway and STAT5 phosphorylation in activated T cells. Our results confirmed T cell-suppressive activity of naringenin previously reported by us and others, but for the first time, it was shown that the working mechanism may involve its ability to modulate cell cycle progression, cell cycle-related proteins and IL-2/IL-2R signaling pathway. Together, these results further support proposed potential of naringenin being a preventive/therapeutic agent in T-cell-mediated autoimmune inflammatory disorders.

Dysregulated 1,25-dihydroxyvitamin D levels in high-fat diet-induced obesity can be restored by changing to a lower-fat diet in mice.

Altered regulation of vitamin D metabolites, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (1,25[OH]2D), was observed in high-fat diet (HFD)-induced obesity. We hypothesized that these HFD-induced changes in vitamin D metabolism would be reversed by decreasing fat mass through dietary intervention. Four-week-old C57BL/6J mice were assigned to 1 of 3 experimental diet groups: (1) the LL group was fed a control diet for 31 weeks, (2) the HH group was fed an HFD for 31 weeks, and (3) the HL group was fed HFD for 15 weeks then switched to the control diet for the remaining 16 weeks. The fat mass of the HL group decreased by 15% from the 14th to the 30th week. Serum 1,25(OH)2D level was significantly higher in the HH group than the LL group, whereas that of the HL group was intermediate to the 2 groups. Serum parathyroid hormone and renal 1-hydroxylase (Cyp27b1) mRNA levels, which are known to stimulate renal 1,25(OH)2D production, were significantly higher in the HH group than the LL group. After losing fat mass, the HL group had significantly lower renal Cyp27b1 mRNA levels than the HH group. No differences were found in serum 25-hydroxyvitamin D levels and mRNA levels of hepatic 25-hydroxylases. In adipose tissue, mRNA levels of 25-hydroxylase and vitamin D receptor were elevated in parallel to the adiposity. In conclusion, serum 1,25(OH)2D levels were closely associated with body adiposity, and reducing fat mass by changing to a lower-fat diet can reverse this obesity-associated increase in circulating 1,25(OH)2D levels.

Dietary naringenin supplementation attenuates experimental autoimmune encephalomyelitis by modulating autoimmune inflammatory responses in mice.

Autoimmune disease is highly prevalent in humans. Since conventional therapies have limited efficacy and often come with significant side effects, nutrition may provide an alternative and complementary approach to improving autoimmune disorders. Naringenin, a flavonoid found in citrus fruits, has been shown to have anti-inflammatory and antioxidant properties. Using the experimental autoimmune encephalomyelitis (EAE), a rodent model of human multiple sclerosis, we determined the effect of dietary naringenin (0.5%) on autoimmune disease. We found that naringenin reduced the incidence, delayed the onset, and attenuated the symptoms of EAE, which were accompanied by reduced immune cell infiltration and demyelination in the spinal cord. Additionally, the pro-inflammatory CD4+ T cell subsets Th1, Th9, and Th17 cells together with their respective transcription factors T-bet, PU.1, and RORγt were reduced in both the central nervous system (CNS) and lymph nodes of EAE mice fed naringenin while no difference was found in Th2 and regulatory T cell (Treg) populations in either CNS or lymph nodes between the two groups. We further showed that pathologic T cell proliferation induced by ex vivo re-stimulation with MOG35-55 and proinflammatory cytokines IL-6 and TNF-α were lower in naringenin-fed mice than in the control mice. Additionally, we found that naringenin treatment inhibited mRNA expression of CXCL10 (Th1 recruiting chemokine), vascular cell adhesion molecule-1 (VCAM-1), and VLA-4 (VCAM-1 ligand) in the CNS of EAE mice. Altogether, these results indicate that naringenin may have a potential to ameliorate autoimmune disease by favorably modulating autoimmune response.

Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance.

It is well-established that the nutritional deficiency or inadequacy can impair immune functions. Growing evidence suggests that for certain nutrients increased intake above currently recommended levels may help optimize immune functions including improving defense function and thus resistance to infection, while maintaining tolerance. This review will examine the data representing the research on prominent intervention agents n-3 polyunsaturated fatty acids (PUFA), micronutrients (zinc, vitamins D and E), and functional foods including probiotics and tea components for their immunological effects, working mechanisms, and clinical relevance. Many of these nutritive and non-nutritive food components are related in their functions to maintain or improve immune function including inhibition of pro-inflammatory mediators, promotion of anti-inflammatory functions, modulation of cell-mediated immunity, alteration of antigen-presenting cell functions, and communication between the innate and adaptive immune systems. Both animal and human studies present promising findings suggesting a clinical benefit of vitamin D, n-3 PUFA, and green tea catechin EGCG in autoimmune and inflammatory disorders, and vitamin D, vitamin E, zinc, and probiotics in reduction of infection. However, many studies report divergent and discrepant results/conclusions due to various factors. Chief among them, and thus call for attention, includes more standardized trial designs, better characterized populations, greater consideration for the intervention doses used, and more meaningful outcome measurements chosen.

Substituting whole grains for refined grains in a 6-wk randomized trial has a modest effect on gut microbiota and immune and inflammatory markers of healthy adults.

Background: Observational studies suggest an inverse association between whole-grain (WG) consumption and inflammation. However, evidence from interventional studies is limited, and few studies have included measurements of cell-mediated immunity.Objective: We assessed the effects of diets rich in WGs compared with refined grains (RGs) on immune and inflammatory responses, gut microbiota, and microbial products in healthy adults while maintaining subject body weights.Design: After a 2-wk provided-food run-in period of consuming a Western-style diet, 49 men and 32 postmenopausal women [age range: 40-65 y, body mass index (in kg/m2) <35] were assigned to consume 1 of 2 provided-food weight-maintenance diets for 6 wk.Results: Compared with the RG group, the WG group had increased plasma total alkyresorcinols (a measure of WG intake) (P < 0.0001), stool weight (P < 0.0001), stool frequency (P = 0.02), and short-chain fatty acid (SCFA) producer Lachnospira [false-discovery rate (FDR)-corrected P = 0.25] but decreased pro-inflammatory Enterobacteriaceae (FDR-corrected P = 0.25). Changes in stool acetate (P = 0.02) and total SCFAs (P = 0.05) were higher in the WG group than in the RG group. A positive association was shown between Lachnospira and acetate (FDR-corrected P = 0.002) or butyrate (FDR-corrected P = 0.005). We also showed that there was a higher percentage of terminal effector memory T cells (P = 0.03) and LPS-stimulated ex vivo production of tumor necrosis factor-α (P = 0.04) in the WG group than in the RG group, which were positively associated with plasma alkylresorcinol concentrations.Conclusion: The short-term consumption of WGs in a weight-maintenance diet increases stool weight and frequency and has modest positive effects on gut microbiota, SCFAs, effector memory T cells, and the acute innate immune response and no effect on other markers of cell-mediated immunity or systemic and gut inflammation. This trial was registered at clinicaltrials.gov as NCT01902394.

Lower hepatic iron storage associated with obesity in mice can be restored by decreasing body fat mass through feeding a low-fat diet.

High-fat diet (HFD)-induced obesity has been reported to result in low hepatic iron storage. In the current study, we tested the hypothesis that these obesity-related changes in hepatic iron status could be reversed by decreasing adiposity by feeding a low-fat diet. Five-week-old C57BL/6 mice were assigned to 3 groups: the LL group was fed a control diet for 31 weeks, the HH group was fed a HFD for 31 weeks, and the HL group was fed the HFD for 15 weeks and then switched to the control diet for 16 weeks. The fat mass of the HL group decreased by 3.2 g from the 14th to the 30th weeks. Fat mass was significantly different among the groups (11.4, 15.8, and 37.5 g in the LL, HH, and HL groups, respectively; P< .001). The liver iron concentration of the HL group was similar to that of the LL group, which was about 30% higher than that of the HH group (74.2, 72.7, and 55.7 µg/g in the LL, HL, and HH groups, respectively; P< .05). Duodenal cytochrome b messenger RNA (mRNA) levels were higher in the HL group than in the HH group. Although bone morphogenetic protein 6 (Bmp6) mRNA levels showed no significant differences in the liver, duodenal Bmp6 mRNA levels were significantly lower in the HH group compared with the LL and HL groups. Liver Smad1/5 proteins were differentially activated: the HH group had significantly less phosphorylated Smads than did the LL and HL groups. Our data demonstrate that hepatic iron storage levels are closely related to body adiposity, and reducing body fat mass through feeding a lower-fat diet to HFD-induced obese mice restores liver iron storage.

The rise, the fall and the renaissance of vitamin E.

This review deals with the expectations of vitamin E ability of preventing or curing, as a potent antioxidant, alleged oxidative stress based ailments including cardiovascular disease, cancer, neurodegenerative diseases, cataracts, macular degeneration and more. The results obtained with clinical intervention studies have highly restricted the range of effectiveness of this vitamin. At the same time, new non-antioxidant mechanisms have been proposed. The new functions of vitamin E have been shown to affect cell signal transduction and gene expression, both in vitro and in vivo. Phosphorylation of vitamin E, which takes place in vivo, results in a molecule provided with functions that are in part stronger and in part different from those of the non-phosphorylate compound. The in vivo documented functions of vitamin E preventing the vitamin E deficiency ataxia (AVED), slowing down the progression of non-alcoholic steato-hepatitis (NASH), decreasing inflammation and potentiating the immune response are apparently based on these new molecular mechanisms. It should be stressed however that vitamin E, when present at higher concentrations in the body, should exert antioxidant properties to the extent that its chromanol ring is unprotected or un-esterified.

High folic acid intake reduces natural killer cell cytotoxicity in aged mice.

Presence of unmetabolized folic acid in plasma, which is indicative of folic acid intake beyond the metabolic capacity of the body, is associated with reduced natural killer (NK) cell cytotoxicity in postmenopausal women ≥50years. NK cells are cytotoxic lymphocytes that are part of the innate immune system critical for surveillance and defense against virus-infected and cancer cells. We determined if a high folic acid diet can result in reduced NK cell cytotoxicity in an aged mouse model. Female C57BL/6 mice (16-month-old) were fed an AIN-93M diet with the recommended daily allowance (1× RDA, control) or 20× RDA (high) folic acid for 3months. NK cytotoxicity was lower in splenocytes from mice fed a high folic acid diet when compared to mice on control diet (P<.04). The lower NK cell cytotoxicity in high folic acid fed mice could be due to their lower mature cytotoxic/naïve NK cell ratio (P=.03) when compared to the control mice. Splenocytes from mice on high folic acid diet produced less interleukin (IL)-10 when stimulated with lipopolysaccharide (P<.05). The difference in NK cell cytotoxicity between dietary groups was abolished when the splenocytes were supplemented with exogenous IL-10 prior to assessment of the NK cytotoxicity, suggesting that the reduced NK cell cytotoxicity of the high folic acid group was at least partially due to reduced IL-10 production. This study demonstrates a causal relationship between high folic acid intake and reduced NK cell cytotoxicity and provides some insights into the potential mechanisms behind this relationship.

Cardio-metabolic and immunological impacts of extra virgin olive oil consumption in overweight and obese older adults: a randomized controlled trial.

BACKGROUND: Both aging and obesity are related to dysregulated immune function, which may be responsible for increased risk of infection and also chronic non-infectious diseases. Dietary lipids have been shown to impact immune and inflammatory responses and cardio-metabolic risk factors. No information on the impact of olive oil on immune responses of overweight and obese older adults is available. OBJECTIVE: We aimed to determine the effect of replacing oils used in a typical American diet with extra virgin olive oil for 3 months on immune responses and cardio-metabolic risk factors in overweight and obese older adults. METHODS: This was a randomized, single-blinded and placebo-controlled trial in 41 overweight or obese participants (aged ≥ 65) who consumed a typical American diet. Participants in the control (CON, n = 21) group were provided with a mixture of corn, soybean oil and butter, and those in the olive oil (OO, n = 20) group, with extra virgin olive oil, to replace substitutable oils in their diet. At baseline and 3 months, we measured blood pressure, biochemical and immunological parameters using fasting blood, and delayed-type hypersensitivity (DTH) skin response. RESULTS: Compared to the CON group, the OO group showed decreased systolic blood pressure (P < 0.05), a strong trend toward increased plasma HDL-C concentrations (P = 0.06), and increased anti-CD3/anti-CD28 -stimulated T cell proliferation (P < 0.05). No differences were found in T cell phenotype, cytokine production, and DTH response between the two groups. CONCLUSIONS: Our results indicate that substitution of oils used in a typical American diet with extra virgin olive oil in overweight and obese older adults may have cardio-metabolic and immunological health benefits. This trial was registered at clinicaltrials.gov as NCT01903304.