Associations of 24 h urinary excretions of α- and γ-carboxyethyl hydroxychroman with plasma α- and γ-tocopherol and dietary vitamin E intake in older adults: the Lifelines-MINUTHE Study.

BACKGROUND: Urinary metabolites of vitamin E, i.e., α- and γ-carboxyethyl hydroxychroman (α- and γ-CEHC), have gained increasing attention and have been proposed as novel biomarkers of vitamin E intake and status. However, there are insufficient data on the relationship of plasma α-tocopherol and γ-tocopherol and dietary vitamin E intake with 24 h urinary excretions of α- and γ-CEHC. OBJECTIVES: We aimed to (1) investigate the associations of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC with plasma α- and γ-tocopherol, respectively; (2) investigate the associations of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC with dietary vitamin E intake, and we hypothesize that 24 h urinary excretions of α- and γ-CEHC will better correlate with vitamin E intake than urinary α- and γ-CEHC/creatinine ratios. DESIGN: 24 h Urine and plasma samples were collected from 1519 participants (60-75 years, male: 50%) included in the Lifelines-MINUTHE Study for the assessments of urinary α- and γ-CEHC/creatinine ratios and 24 h urinary excretions of α- and γ-CEHC, and plasma α- and γ-tocopherol. Among those participants, dietary vitamin E intake data from 387 participants were available from an externally validated Flower-Food Frequency Questionnaire (FFQ). The associations of plasma α- and γ-tocopherol, dietary vitamin E intake, with urinary α- and γ-CEHC were assessed using multivariate linear regressions. RESULTS: 24 h Urinary excretion of α-CEHC (median (IQR): 0.9 (0.3-2.4) µmol) was less than that of γ-CEHC (median (IQR): 1.5 (0.5-3.5) µmol). After adjustment for covariates, we found that 24 h urinary α-CEHC excretion and urinary α-CEHC/creatinine ratio were both positively associated with plasma α-tocopherol (std.beta: 0.06, p = 0.02; std.beta: 0.06, p = 0.01, respectively). Furthermore, the sum of 24 h urinary α- and γ-CEHC excretions was positively associated with dietary vitamin E intake (std.beta: 0.08; p = 0.03), whereas there was no relation between urinary α- and γ-CEHC/creatinine ratios and vitamin E intake. No association was observed neither between plasma α- and γ-tocopherol and dietary vitamin E intake, nor between urinary γ-CEHC and plasma γ-tocopherol. CONCLUSION: Our study confirmed our hypothesis that 24 h urinary α- and γ-CEHC excretions would be a better marker for dietary vitamin E intake than urinary α- and γ-CEHC/creatinine ratios. Considering that both 24 h urinary α- and γ-CEHC excretions and α- and γ-CEHC/creatinine ratios were also associated with plasma α-tocopherol status, we suggest that 24 h urinary α- and γ-CEHC excretions could be used to assess overall vitamin E status.

Perspective: Role of Micronutrients and Omega-3 Long-Chain Polyunsaturated Fatty Acids for Immune Outcomes of Relevance to Infections in Older Adults-A Narrative Review and Call for Action.

The immune system is weakened by advancing age, often referred to as immunosenescence, increasing the vulnerability to, and frequently the severity of, infectious diseases in older people. This has become very apparent in the current coronavirus disease 2019 (COVID-19) pandemic for which older people are at higher risk of severe outcomes, even those who are fully vaccinated. Aging affects both the innate and adaptive immune systems and is characterized by an imbalanced inflammatory response. Increasing evidence shows that optimal status of nutrients such as vitamins C, D, and E and selenium and zinc as well as the omega-3 (n-3) fatty acids DHA and EPA can help compensate for these age-related changes. While inadequate intakes of these nutrients are widespread in the general population, this is often more pronounced in older people. Maintaining adequate intakes is a challenge for them due to a range of factors such as physical, physiological, and cognitive changes; altered absorption; and the presence of noncommunicable diseases. While nutritional requirements are ideally covered by a balanced diet, this can be difficult to achieve, particularly for older people. Fortified foods and nutritional complements are effective in achieving adequate micronutrient intakes and should be considered as a safe and cost-effective means for older people to improve their nutritional status and hence support their defense against infections. Complementing the diet with a combination of micronutrients, particularly those playing a key role in the immune system such as vitamins C, D, and E and selenium and zinc as well as DHA and EPA, is recommended for older people. Optimal nutrition to support the immune system in older people will remain essential, particularly in the face of the current COVID-19 pandemic and, thus, developing strategies to ensure adequate nutrition for the growing number of older adults will be an important and cost-effective investment in the future.

Micronutrients to Support Vaccine Immunogenicity and Efficacy.

The world has entered the third year of the coronavirus disease 2019 (COVID-19) pandemic. Vaccination is the primary public health strategy to protect against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in addition to other measures, such as mask wearing and social distancing. Vaccination has reduced COVID-19 severity and mortality dramatically. Nevertheless, incidence globally remains high, and certain populations are still at risk for severe outcomes. Additional strategies to support immunity, including potentially enhancing the response to vaccination, are needed. Many vitamins and trace minerals have recognized immunomodulatory actions, and their status and/or supplementation have been reported to correspond to the incidence and severity of infection. Furthermore, a variety of observational and some interventional studies report that adequate micronutrient status or micronutrient supplementation is associated with enhanced vaccine responses, including to COVID-19 vaccination. Such data suggest that micronutrient supplementation may hold the potential to improve vaccine immunogenicity and effectiveness, although additional interventional studies to further strengthen the existing evidence are needed. Positive findings from such research could have important implications for global public health, since deficiencies in several micronutrients that support immune function are prevalent in numerous settings, and supplementation can be implemented safely and inexpensively.

The Role of Micronutrients in Ageing Asia: What Can Be Implemented with the Existing Insights.

Life expectancy as a measure of population health does not reflect years of healthy life. The average life expectancy in the Asia-Pacific region has more than doubled since 1900 and is now above 70 years. In the Asia-Pacific region, the proportion of aged people in the population is expected to double between 2017 and 2050. Increased life expectancy leads to an increase in non-communicable diseases, which consequently affects quality of life. Suboptimal nutritional status is a contributing factor to the prevalence and severity of non-communicable diseases, including cardiovascular, cognitive, musculoskeletal, immune, metabolic and ophthalmological functions. We have reviewed the published literature on nutrition and healthy ageing as it applies to the Asia-Pacific region, focusing on vitamins, minerals/trace elements and omega-3 fatty acids. Optimal nutritional status needs to start before a senior age is reached and before the consequences of the disease process are irreversible. Based on the nutritional status and health issues in the senior age in the region, micronutrients of particular importance are vitamins A, D, E, C, B-12, zinc and omega-3 fatty acids. The present paper substantiates the creation of micronutrient guidelines and proposes actions to support the achievement of optimal nutritional status as contribution to healthy ageing for Asia-Pacific populations.

Beyond Nutrient Deficiency-Opportunities to Improve Nutritional Status and Promote Health Modernizing DRIs and Supplementation Recommendations.

The US Dietary Guidelines for Americans (DGA) provide dietary recommendations to meet nutrient needs, promote health, and prevent disease. Despite 40 years of DGA, the prevalence of under-consumed nutrients continues in the US and globally, although dietary supplement use can help to fill shortfalls. Nutrient recommendations are based on Dietary Reference Intakes (DRIs) to meet the nutrient requirements for nearly all (97 to 98 percent) healthy individuals in a particular life stage and gender group and many need to be updated using current evidence. There is an opportunity to modernize vitamin and mineral intake recommendations based on biomarker or surrogate endpoint levels needed to 'prevent deficiency' with DRIs based on ranges of biomarker or surrogate endpoints levels that support normal cell/organ/tissue function in healthy individuals, and to establish DRIs for bioactive compounds. We recommend vitamin K and Mg DRIs be updated and DRIs be established for lutein and eicosapentaenoic and docosahexaenoic acid (EPA + DHA). With increasing interest in personalized (or precision) nutrition, we propose greater research investment in validating biomarkers and metabolic health measures and the development and use of inexpensive diagnostic devices. Data generated from such approaches will help elucidate optimal nutrient status, provide objective evaluations of an individual's nutritional status, and serve to provide personalized nutrition guidance.

Strengthening the immunity of the Swiss population with micronutrients: A narrative review and call for action.

BACKGROUND: The enormous health impact of the COVID-19 pandemic has refocused attention on measures to optimize immune function and vaccine response. Dietary deficiencies of micronutrients can weaken adaptive immunity. The aim of this review was to examine links between micronutrients, immune function and COVID-19 infection, with a focus on nutritional risks in subgroups of the Swiss population. METHODS: Scoping review on the associations between selected micronutrients (vitamins D and C, iron, selenium, zinc, and n-3 PUFAs) and immunity, with particular reference to the Swiss population. These nutrients were chosen because previous EFSA reviews have concluded they play a key role in immunity. RESULTS: The review discusses the available knowledge on links between sufficient nutrient status, optimal immune function, and prevention of respiratory tract infections. Because of the rapid spread of the COVID-19 pandemic, controlled intervention studies of micronutrients in the context of COVID-19 infection are now underway, but evidence is not yet available to draw conclusions. The anti-inflammatory properties of n-3 PUFAs are well established. In Switzerland, several subgroups of the population are at clear risk of nutrient deficiencies; e.g., older adults, multiple comorbidities, obesity, pregnancy, and institutionalized. Low intakes of n-3 PUFA are present in a large proportion of the population. CONCLUSION: There are clear and strong relationships between micronutrient and n-3 PUFA status and immune function, and subgroups of the Swiss population are at risk for deficient intakes. Therefore, during the COVID-19 pandemic, as a complement to a healthy and balanced diet, it may be prudent to consider supplementation with a combination of moderate doses of Vitamins C and D, as well as of Se, Zn and n-3 PUFA, in risk groups.

Metabolic and functional interplay between gut microbiota and fat-soluble vitamins.

Gut microbiota is a complex ecosystem seen as an extension of human genome. It represents a major metabolic interface of interaction with food components and xenobiotics in the gastrointestinal (GI) environment. In this context, the advent of modern bacterial genome sequencing technology has enabled the identification of dietary nutrients as key determinants of gut microbial ecosystem able to modulate the host-microbiome symbiotic relationship and its effects on human health. This article provides a literature review on functional and molecular interactions between a specific group of lipids and essential nutrients, e.g., fat-soluble vitamins (FSVs), and the gut microbiota. A two-way relationship appears to emerge from the available literature with important effects on human metabolism, nutrition, GI physiology and immune function. First, FSV directly or indirectly modify the microbial composition involving for example immune system-mediated and/or metabolic mechanisms of bacterial growth or inhibition. Second, the gut microbiota influences at different levels the synthesis, metabolism and transport of FSV including their bioactive metabolites that are either introduced with the diet or released in the gut via entero-hepatic circulation. A better understanding of these interactions, and of their impact on intestinal and metabolic homeostasis, will be pivotal to design new and more efficient strategies of disease prevention and therapy, and personalized nutrition.

Vitamin E status in healthy population in Asia: A review of current literature.

Vitamin E is a lipid soluble antioxidant which mainly circulates as α-tocopherol in the human plasma. Its deficiency is associated with ataxia, neuropathy, anaemia and several other health conditions. Although substantial data on vitamin E status has been published worldwide, there is paucity of data on the extent of deficiency from most Asian countries, including India. Part of the problem is lack of validated biomarkers for vitamin E and no consensus on cut offs for defining deficiency and sufficiency. Thus, interpretation of the data on the vitamin E status is difficult. Limited available data from 31 studies on vitamin E status in healthy people from Asia, the most populated continent, has been collated for the purpose of this review. Broadly, the results suggest inadequate vitamin E status in most age groups, with the prevalence of deficiency reaching 67%, 80%, 56% and 72% in infants, children and adolescents, adults, elderly and pregnant women, respectively, based on varying cut offs. The findings are not surprising as both, vitamin E intakes and its status have not received too much attention in the past. Lack of conclusive data accentuates the need for more research on the vitamin E status across all age groups and to define age, gender and physiological state specific cut offs for vitamin E levels.

Methylmalonic acid, vitamin B12, renal function, and risk of all-cause mortality in the general population: results from the prospective Lifelines-MINUTHE study.

BACKGROUND: Methylmalonic acid (MMA) is best known for its use as a functional marker of vitamin B12 deficiency. However, MMA concentrations not only depend on adequate vitamin B12 status, but also relate to renal function and endogenous production of propionic acid. Hence, we aimed to investigate to what extent variation in MMA levels is explained by vitamin B12 and eGFR and whether MMA levels are associated with mortality if vitamin B12 and eGFR are taken into account. METHODS: A total of 1533 individuals (aged 60-75 years, 50% male) were included from the Lifelines Cohort and Biobank Study. Individuals were included between 2006 and 2013, and the total follow-up time was 8.5 years. RESULTS: Median [IQR] age of the study population was 65 [62-69] years, 50% was male. At baseline, median MMA concentration was 170 [138-216] nmol/L, vitamin B12 290 [224-362] pmol/L, and eGFR 84 [74-91] mL/min/1.73 m2. Log2 vitamin B12, log2 eGFR, age, and sex were significantly associated with log2 MMA in multivariable linear regression analyses (model R2 = 0.22). After a total follow-up time of 8.5 years, 72 individuals had died. Log2 MMA levels were significantly associated with mortality (hazard ratio [HR] 1.67 [95% CI 1.25-2.22], P < 0.001). Moreover, we found a significant interaction between MMA and eGFR with respect to mortality (Pinteraction < 0.001). CONCLUSIONS: Only 22% of variation in MMA levels was explained by vitamin B12, eGFR, age, and sex, indicating that a large part of variation in MMA levels is attributable to other factors (e.g., catabolism, dietary components, or gut microbial production). Higher MMA levels are associated with an increased risk for mortality, independent of vitamin B12, eGFR, and sex. This association was more pronounced in individuals with impaired renal function.

Vitamin Status and Diet in Elderly with Low and High Socioeconomic Status: The Lifelines-MINUTHE Study.

Socioeconomic health inequalities are an important global public health problem. However, it is not well known to what extent socioeconomic inequalities culminate in impaired vitamin status and whether this is mediated by diet. We, therefore, aimed to assess vitamin status in a population already at increased risk of micronutrient deficiency, i.e., elderly with high and low socioeconomic status (SES), and to investigate whether potential differences therein were mediated by diet quality. Vitamin status in 1605 individuals (60-75 years) from the Lifelines- Micronutrients and Health inequalities in Elderly (MINUTHE) Study was assessed by measuring folic acid and the vitamins B6, B12, D, A, E, and K. Multinomial logistic and linear regression analyses were applied to test the associations between SES and vitamin status. Mediation analysis was used to explore the interrelationship between SES, diet quality, and vitamin status. Low SES was associated with poorer status of vitamin B6, vitamin B12, and, notably, folic acid. Moreover, multivitamin deficiencies were more prevalent in the low SES group. Diet quality was found to mediate the associations of SES with folic acid (for 39.1%), vitamin B6 (for 37.1%), and vitamin B12 (for 37.2%). We conclude that low SES is a risk factor for a spectrum of vitamin deficiencies. Diet quality can partially explain the socioeconomic differences in vitamin status, suggesting that policymakers can mitigate socioeconomic inequality in nutritional status through improving diet quality.

Reply to "Overstated Claims of Efficacy and Safety. Comment On: Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients 2020, 12, 1181".

We thank Vorland et al [...].

Vitamin B6, Inflammation, and Cardiovascular Outcome in a Population-Based Cohort: The Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study.

BACKGROUND: a large number of studies have linked vitamin B6 to inflammation and cardiovascular disease in the general population. However, it remains uncertain whether vitamin B6 is associated with cardiovascular outcome independent of inflammation. METHODS: we measured plasma pyridoxal 5'-phosphate (PLP), as an indicator of vitamin B6 status, at baseline in a population-based prospective cohort of 6249 participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study who were free of cardiovascular disease. As indicators of low-grade systemic inflammation, we measured high-sensitivity C-reactive protein and GlycA; Results: median plasma PLP was 37.2 (interquartile range, 25.1-57.0) nmol/L. During median follow-up for 8.3 (interquartile range, 7.8-8.9) years, 409 non-fatal and fatal cardiovascular events (composite outcome) occurred. In the overall cohort, log transformed plasma PLP was associated with the composite outcome, independent of adjustment for age, sex, smoking, alcohol consumption, body mass index (BMI), estimated glomerular filtration rate (eGFR), total cholesterol:high-density lipoprotein (HDL)-cholesterol ratio, and blood pressure (adjusted hazard ratio per increment of log plasma PLP, 0.66; 95% confidence interval (CI), 0.47-0.93). However, adjustment for high-sensitivity C-reactive protein and GlycA increased the hazard ratio by 9% and 12% respectively, to non-significant hazard ratios of 0.72 (95% confidence interval, 0.51-1.01) and 0.74 (95% confidence interval, 0.53-1.05). The association of plasma PLP with cardiovascular risk was modified by gender (adjusted Pinteraction = 0.04). When stratified according to gender, in women the prospective association with cardiovascular outcome was independent of age, smoking, alcohol consumption, high-sensitivity C-reactive protein, and GlycA (adjusted hazard ratio, 0.50, 95% confidence interval, 0.27-0.94), while it was not in men (adjusted hazard, 0.99, 95% confidence interval, 0.65-1.51). CONCLUSIONS: in this population-based cohort, plasma PLP was associated with cardiovascular outcome, but this association was confounded by traditional risk factors and parameters of inflammation. Notably, the association of low plasma PLP with high risk of adverse cardiovascular outcome was modified by gender, with a stronger and independent association in women.

Reply to "Comment on: Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients 2020, 12, 1181".

We thank Tsoupras and Zabetakis for their interest in our recent publication [...].

Expert Opinion on Benefits of Long-Chain Omega-3 Fatty Acids (DHA and EPA) in Aging and Clinical Nutrition.

Life expectancy is increasing and so is the prevalence of age-related non-communicable diseases (NCDs). Consequently, older people and patients present with multi-morbidities and more complex needs, putting significant pressure on healthcare systems. Effective nutrition interventions could be an important tool to address patient needs, improve clinical outcomes and reduce healthcare costs. Inflammation plays a central role in NCDs, so targeting it is relevant to disease prevention and treatment. The long-chain omega-3 polyunsaturated fatty acids (omega-3 LCPUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are known to reduce inflammation and promote its resolution, suggesting a beneficial role in various therapeutic areas. An expert group reviewed the data on omega-3 LCPUFAs in specific patient populations and medical conditions. Evidence for benefits in cognitive health, age- and disease-related decline in muscle mass, cancer treatment, surgical patients and critical illness was identified. Use of DHA and EPA in some conditions is already included in some relevant guidelines. However, it is important to note that data on the effects of omega-3 LCPUFAs are still inconsistent in many areas (e.g., cognitive decline) due to a range of factors that vary amongst the trials performed to date; these factors include dose, timing and duration; baseline omega-3 LCPUFA status; and intake of other nutrients. Well-designed intervention studies are required to optimize the effects of DHA and EPA in specific patient populations and to develop more personalized strategies for their use.

Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections.

Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, were responsible for approximately 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: (1) supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; (2) supplementation above the Recommended Dietary Allowance (RDA), but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and (3) public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.

Duality of Tocopherol Isoforms and Novel Associations with Vitamins Involved in One-Carbon Metabolism: Results from an Elderly Sample of the LifeLines Cohort Study.

Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60-75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of α-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of γ-tocopherol were often opposite to those of α-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for α-tocopherol and γ-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied.

Plasma versus Erythrocyte Vitamin E in Renal Transplant Recipients, and Duality of Tocopherol Species.

Redox imbalance is an adverse on-going phenomenon in renal transplant recipients (RTR). Vitamin E has important antioxidant properties that counterbalance its deleterious effects. However, plasma vitamin E affinity with lipids challenges interpretation of its levels. To test the hypothesis that erythrocyte membranes represent a lipids-independent specimen to estimate vitamin E status, we performed a cross-sectional study in a cohort of adult RTR (n = 113) recruited in a university setting (2015-2018). We compared crude and total lipids-standardized linear regression-derived coefficients of plasma and erythrocyte tocopherol species in relation to clinical and laboratory parameters. Strongly positive associations of fasting lipids with plasma tocopherol became inverse, rather than absent, in total lipids-standardized analyses, indicating potential overadjustment. Whilst, no variables from the lipids domain were associated with the tocopherol species measured from erythrocyte specimens. In relation to inflammatory status and clinical parameters with antioxidant activity, we found associations in directions that are consistent with either beneficial or adverse effects concerning α- or γ-tocopherol, respectively. In conclusion, erythrocytes offer a lipids-independent alternative to estimate vitamin E status and investigate its relationship with parameters over other biological domains. In RTR, α- and γ-tocopherol may serve as biomarkers of relatively lower or higher vulnerability to oxidative stress and inflammation, noticeably in opposite directions.