Effects of daily almond consumption for six months on cognitive measures in healthy middle-aged to older adults: a randomized control trial.

BACKGROUND: Age-related cognitive decline is a major public health issue. Almonds are rich in nutrients that benefit cognitive function. OBJECTIVE: To investigate the impact of almonds on cognition in elderly adults. DESIGN: In a six-month, single-blinded, randomized-controlled trial, the effects of an almond intervention on cognition in healthy, middle-aged/older adults (50-75 years) was tested. Subjects were assigned to one of three groups: 1.5 oz/d almond (n = 19), 3 oz/d almond (n = 24), or 3.5 oz/d snack (control, matched for macronutrients in 3.0 oz almonds, (n = 17). Serum analyses for tocopherols, oxidative status and inflammation, and cognition were assessed at baseline (M0), three (M3), and six (M6) months. RESULTS: At M6, serum alpha-tocopherol concentrations increased by 8% from M0 (p < 0.05) in the 3 oz almond group but did not increase in the other groups. Serum markers of inflammation and oxidative stress were not significantly different throughout the study among the groups. There was no difference in change over time in cognitive tests among the groups. However, there was a significant improvement in visuospatial working memory (p = 0.023), visual memory and learning (p = 0.017), and spatial planning and working memory (p < 0.001) in subjects receiving 3 oz/d almonds at M6, while the snack group showed no improvement. CONCLUSIONS: Almonds did not significantly improve cognitive function in cognitively intact middle-aged/older adults over six months. However, a significant improvement at M6 in cognitive measures was observed with 3 oz/d almonds. While these results are encouraging, a study of longer duration in subjects at risk for age-related cognitive decline is warranted.Trial registration: ClinicalTrials.gov identifier: NCT03093896.

The association between macular pigment optical density and visual function outcomes: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review and meta-analysis on data related to macular pigment optical density (MPOD) and visual function in adults with healthy eyes. METHODS: MEDLINE®, Cochrane, and Commonwealth of Agriculture Bureau abstracts databases were searched for English-language publications between 1946 and August 2018. Included studies examined correlation of MPOD and visual function in adults with healthy eyes at all timepoints and all designs, except for case-control, case reports, and reviews. Visual function outcomes of interest included photostress recovery, contrast sensitivity, visual acuity, glare sensitivity/disability, and dark adaptation. Random effects model meta-analyses combined study-level correlation (r). RESULTS: Twenty-two publications were included. In meta-analysis MPOD was found to be significantly correlated with contrast sensitivity at 30' (two studies, summary r: 0.37; 95% CI 0.15, 0.56), and at 1° eccentricity with a spatial frequency of 7, 11, and 21 cpd (three studies, summary r: 0.31; 95% CI 0.06, 0.52), with photostress recovery at a 1° eccentricity with a moderate background, 10 cpd, and 16% contrast (two studies, summary r: -0.17; 95% CI -0.31, -0.02), and at 30' (four studies, summary r: -0.57; 95% CI -0.78, -0.24), and with glare disability at 30' eccentricity with a log scale at 460 nm (three studies, summary r = 0.47; 95% CI 0.32; 0.59). There were insufficient data for meta-analysis for other visual functions. CONCLUSIONS: Our review identifies a link between MPOD and visual function with significant correlations with photostress recovery, glare disability, and contrast sensitivity.

Serum Carotenoids, Tocopherols, Total n-3 Polyunsaturated Fatty Acids, and n-6/n-3 Polyunsaturated Fatty Acid Ratio Reflect Brain Concentrations in a Cohort of Centenarians.

Investigating the role of nutrition on cognitive health is challenging. Human brain tissue is inaccessible in living humans and is often limited in deceased individuals. Therefore, biomarkers of brain nutrient levels are of interest. The objective of this study was to characterize the relationships between levels of fat-soluble nutrients in serum and matched brain tissues from the frontal and temporal cortices of participants in the Georgia Centenarian Study (n = 47). After adjusting for sex, race, cognitive status (Global Deterioration Scale), body mass index, and presence of hypertension and/or diabetes, there was a significant relationship (p < 0.05) between serum and brain levels of carotenoids (lutein, zeaxanthin, cryptoxanthin, ß-carotene), α-, γ-tocopherols, total n-3 polyunsaturated fatty acids (PUFAs), and n-6/n-3 PUFA ratio. The relationship between serum and brain total n-6 PUFAs was inconsistent among the two brain regions. No significant relationship was identified between serum and brain retinol, total saturated fatty acid, total monounsaturated fatty acid, and trans-fatty acid levels. These findings suggest that serum carotenoids, tocopherols, total n-3 PUFAs, and n-6/n-3 PUFA ratio reflect levels in brain and can be used as surrogate biomarkers in older population.

Intrinsic and Extrinsic Factors Impacting Absorption, Metabolism, and Health Effects of Dietary Carotenoids.

Carotenoids are orange, yellow, and red lipophilic pigments present in many fruit and vegetables, as well as other food groups. Some carotenoids contribute to vitamin A requirements. The consumption and blood concentrations of specific carotenoids have been associated with reduced risks of a number of chronic conditions. However, the interpretation of large, population-based observational and prospective clinical trials is often complicated by the many extrinsic and intrinsic factors that affect the physiologic response to carotenoids. Extrinsic factors affecting carotenoid bioavailability include food-based factors, such as co-consumed lipid, food processing, and molecular structure, as well as environmental factors, such as interactions with prescription drugs, smoking, or alcohol consumption. Intrinsic, physiologic factors associated with blood and tissue carotenoid concentrations include age, body composition, hormonal fluctuations, and variation in genes associated with carotenoid absorption and metabolism. To most effectively investigate carotenoid bioactivity and to utilize blood or tissue carotenoid concentrations as biomarkers of intake, investigators should either experimentally or statistically control for confounding variables affecting the bioavailability, tissue distribution, and metabolism of carotene and xanthophyll species. Although much remains to be investigated, recent advances have highlighted that lipid co-consumption, baseline vitamin A status, smoking, body mass and body fat distribution, and genetics are relevant covariates for interpreting blood serum or plasma carotenoid responses. These and other intrinsic and extrinsic factors are discussed, highlighting remaining gaps in knowledge and opportunities for future research. To provide context, we review the state of knowledge with regard to the prominent health effects of carotenoids.

A Fresh Look at Huntingtin mRNA Processing in Huntington's Disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endocytosis, and modulate synaptic activity. Mutant HTT protein disrupts autophagy, vesicle transport, neurotransmitter signaling, and mitochondrial function. Although many of the activities of wild-type HTT protein and the toxicities of mutant HTT protein are characterized, less is known about the activities of HTT mRNA. Most putative HD therapies aim to target mutant HTT mRNA before it is translated into the protein. Therefore, it is imperative to learn as much as we can about how cells handle both wild-type and mutant HTT mRNA so that effective therapies can be designed. Here, we review the structure of wild-type and mutant HTT mRNA, with emphasis on their alternatively polyadenylated or spliced isoforms. We then consider the abundance of HTT mRNA isoforms in HD and discuss the potential implications of these findings. Evidence in the review should be used to guide future research aimed at developing mRNA-lowering therapies for HD.

Evidence of Drug-Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update.

The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug-nutrient interactions is quite limited. A comprehensive, updated review of the potential drug-nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care.

Probing the extended lipid anchorage with cytochrome c and liposomes containing diacylphosphatidylglycerol lipids.

Experiments investigating the adsorption and desorption of cytochrome c onto and from liposomes containing 50 mol% 1,2-diacylphosphatidylglycerol lipids [10:0, 12:0, 14:0, 16:0, 18:1(Δ9 cis)] with 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) in pH 7.4 buffered solutions of low to moderate ionic strength are reported. Fluorescence experiments show that cytochrome c has a similar adsorption affinity for the five labeled 50 mol% PG liposome systems investigated. Fluorescence recovery experiments reveal the extent of cytochrome c desorption upon the addition of >10× excess of unlabeled 100% 1,2-dioleoyl-sn-glycero-3-phosphatidylglycerol (DOPG) liposomes is dependent on the lipid's acyl chain length. The extent of desorption is also shown to be independent of temperature, albeit over a narrow range. The differences in the extent of cytochrome c desorption from liposomes containing PG lipids with different acyl chain lengths is attributed to the varying contribution of the binding motif involving the extended lipid anchorage in response to lipid packing stress.

The Subcellular Distribution of Alpha-Tocopherol in the Adult Primate Brain and Its Relationship with Membrane Arachidonic Acid and Its Oxidation Products.

The relationship between α-tocopherol, a known antioxidant, and polyunsaturated fatty acid (PUFA) oxidation, has not been directly investigated in the primate brain. This study characterized the membrane distribution of α-tocopherol in brain regions and investigated the association between membrane α-tocopherol and PUFA content, as well as brain PUFA oxidation products. Nuclear, myelin, mitochondrial, and neuronal membranes were isolated using a density gradient from the prefrontal cortex (PFC), cerebellum (CER), striatum (ST), and hippocampus (HC) of adult rhesus monkeys (n = 9), fed a stock diet containing vitamin E (α-, γ-tocopherol intake: ~0.7 µmol/kg body weight/day, ~5 µmol/kg body weight/day, respectively). α-tocopherol, PUFAs, and PUFA oxidation products were measured using high performance liquid chromatography (HPLC), gas chromatography (GC) and liquid chromatography-gas chromatography/mass spectrometry (LC-GC/MS) respectively. α-Tocopherol (ng/mg protein) was highest in nuclear membranes (p < 0.05) for all regions except HC. In PFC and ST, arachidonic acid (AA, µg/mg protein) had a similar membrane distribution to α-tocopherol. Total α-tocopherol concentrations were inversely associated with AA oxidation products (isoprostanes) (p < 0.05), but not docosahexaenoic acid oxidation products (neuroprostanes). This study reports novel data on α-tocopherol accumulation in primate brain regions and membranes and provides evidence that α-tocopherol and AA are similarly distributed in PFC and ST membranes, which may reflect a protective effect of α-tocopherol against AA oxidation.

Dietary guidance for lutein: consideration for intake recommendations is scientifically supported.

Lutein, a yellow xanthophyll carotenoid found in egg yolks and many colorful fruits and vegetables, has gained public health interest for its putative role in visual performance and reducing the risk of age-related macular degeneration. The National Academies of Sciences, Engineering and Medicine's recommended Dietary Reference Intakes (DRIs) focus on preventing deficiency and toxicity, but there is a budding interest in establishing DRI-like guidelines for non-essential bioactives, like lutein, that promote optimal health and/or prevent chronic diseases. Lupton et al. developed a set of nine criteria to determine whether a bioactive is ready to be considered for DRI-like recommendations. These criteria include: (1) an accepted definition; (2) a reliable analysis method; (3) a food database with known amounts of the bioactive; (4) cohort studies; (5) clinical trials on metabolic processes; (6) clinical trials for dose-response and efficacy; (7) safety data; (8) systematic reviews and/or meta-analyses; (9) a plausible biological rationale. Based on a review of the literature supporting these criteria, lutein is ready to be considered for intake recommendations. Establishing dietary guidance for lutein would encourage the consumption of lutein-containing foods and raise public awareness about its potential health benefits.

Lutein accumulates in subcellular membranes of brain regions in adult rhesus macaques: Relationship to DHA oxidation products.

OBJECTIVES: Lutein, a carotenoid with anti-oxidant functions, preferentially accumulates in primate brain and is positively related to cognition in humans. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), is also beneficial for cognition, but is susceptible to oxidation. The present study characterized the membrane distribution of lutein in brain regions important for different domains of cognitive function and determined whether membrane lutein was associated with brain PUFA oxidation. METHODS: Adult rhesus monkeys were fed a stock diet (~2 mg/day lutein or ~0.5 µmol/kg body weight/day) (n = 9) or the stock diet plus a daily supplement of lutein (~4.5 mg/day or~1 µmol/kg body weight/day) and zeaxanthin (~0.5 mg/day or 0.1 µmol/kg body weight/day) for 6-12 months (n = 4). Nuclear, myelin, mitochondrial, and neuronal plasma membranes were isolated using a Ficoll density gradient from prefrontal cortex (PFC), cerebellum (CER), striatum (ST), and hippocampus (HC). Carotenoids, PUFAs, and PUFA oxidation products were measured using HPLC, GC, and LC-GC/MS, respectively. RESULTS: All-trans-lutein (ng/mg protein) was detected in all regions and membranes and was highly variable among monkeys. Lutein/zeaxanthin supplementation significantly increased total concentrations of lutein in serum, PFC and CER, as well as lutein in mitochondrial membranes and total DHA concentrations in PFC only (P<0.05). In PFC and ST, mitochondrial lutein was inversely related to DHA oxidation products, but not those from arachidonic acid (P <0.05). DISCUSSION: This study provides novel data on subcellular lutein accumulation and its relationship to DHA oxidation in primate brain. These findings support the hypothesis that lutein may be associated with antioxidant functions in the brain.

Almonds ameliorate glycemic control in Chinese patients with better controlled type 2 diabetes: a randomized, crossover, controlled feeding trial.

BACKGROUND: Almonds can decrease glycemic index of co-consumed foods and are a rich source for oleic acid and α-tocopherol. The aim of the randomized, crossover, controlled feeding trial was to examine whether as compared to NCEP step II diet as control (CON), ~60 g/d almonds (ALM) added to CON would improve glucoregulation and cardiovascular disease (CVD) risk factors in 33 Chinese T2DM patients. METHODS: Forty T2DM patients were enrolled and randomly assigned to receive CON or ALM for 12 wks after a 2-wk. run-in period. Blood and urine samples were collected in the beginning and at the end of each dietary intervention phase for the assessment of biomarkers of glucoregulation, lipid profile, inflammation, and oxidative stress. RESULTS: While ALM had a better overall nutritional quality than CON, neither ALM nor CON improved the glycemic status as the primary study outcome and other CVD risk factors, except the circulating nitric oxide being decreased by ALM compared to CON. Among 27 of 33 patients with the baseline HbA1c ≤8, ALM decreased post-interventional fasting serum glucose and HbA1c by 5.9% and 3.0% as compared to that of CON, respectively (P = 0.01 and 0.04). Mean total and LDL-cholesterol concentrations were not changed by both diets. CONCLUSIONS: These results suggest almonds incorporated into healthful diets can improve glycemic status in diabetic patients with a better glycemic control. TRIAL REGISTRATION: NCT01656850, registered 13 January 2012.

Brain xanthophyll content and exploratory gene expression analysis: subspecies differences in rhesus macaque.

BACKGROUND: The dietary xanthophylls, lutein and zeaxanthin, accumulate in primate retina and brain, and emerging evidence indicates neural lutein content may be beneficial for cognition. Neural xanthophyll content in primates varies greatly among individuals, and genetic factors are likely to be significant contributors. Subspecies of rhesus macaques originating from different geographic locations are known to differ genetically, but the effect of origin on gene expression and carotenoid status has not been determined. The study objective was to determine whether xanthophyll status and expression of carotenoid-related genes, as well as genes with known variants between subspecies, differ between the brains of adult rhesus monkeys of Indian and Chinese origin. METHODS: Samples of prefrontal cortex, cerebellum, and striatum were collected from adult monkeys (n = 9) fed a standard stock diet containing carotenoids. Serum and brain carotenoids were determined using reverse-phase high-performance liquid chromatography. For each brain region, RNA sequencing and real-time quantitative polymerase chain reaction were used to determine differentially expressed genes between the subspecies. RESULTS: Indian-origin monkeys had higher xanthophyll levels in brain tissue compared to Chinese-origin monkeys despite consuming similar amounts of dietary carotenoids. In a region-specific manner, four genes related to carotenoid and fatty acid metabolism (BCO2, RPE65, ELOVL4, FADS2) and four genes involved in the immune response (CD4, CD74, CXCL12 LTBR) were differentially expressed between Indian- and Chinese-origin monkeys. Expression of all four genes involved in carotenoid and fatty acid metabolism were correlated with brain xanthophyll concentration in a region-specific manner. CONCLUSIONS: These results indicate that origin is related to differences in both gene expression and xanthophyll content in the brain. Findings from this study may have important implications regarding genetic diversity, lutein status, and cognition in primates.

Lutein and Brain Function.

Lutein is one of the most prevalent carotenoids in nature and in the human diet. Together with zeaxanthin, it is highly concentrated as macular pigment in the foveal retina of primates, attenuating blue light exposure, providing protection from photo-oxidation and enhancing visual performance. Recently, interest in lutein has expanded beyond the retina to its possible contributions to brain development and function. Only primates accumulate lutein within the brain, but little is known about its distribution or physiological role. Our team has begun to utilize the rhesus macaque (Macaca mulatta) model to study the uptake and bio-localization of lutein in the brain. Our overall goal has been to assess the association of lutein localization with brain function. In this review, we will first cover the evolution of the non-human primate model for lutein and brain studies, discuss prior association studies of lutein with retina and brain function, and review approaches that can be used to localize brain lutein. We also describe our approach to the biosynthesis of 13C-lutein, which will allow investigation of lutein flux, localization, metabolism and pharmacokinetics. Lastly, we describe potential future research opportunities.

Interactions of cytochrome C with N-acylated phosphatidylethanolamine lipids.

N-acylphosphatidylethanolamines (NAPEs) are naturally occurring derivatives of phosphatidylethanolmine (PE) in which the PE amino group is attached to an acyl chain. Given their occurrence in natural systems, there is interest in knowing the effect of NAPEs on membrane dynamic structure and function. This study examines the ability of NAPEs to affect the association of the cytochrome c and Zn-heme cytochrome c with the surface of bilayer membranes. Fluorescence titration experiments show that cationic cytochrome c has the same high affinity for the surfaces of anionic vesicles that are rich in NAPEs or diplalmitoyphosphatidylglycerol (DPPG) but the protein/membrane interaction in each case is quite different. Cytochrome c adsorption to DPPG membranes is relatively irreversible due to the DPPG molecules adopting an extended conformation that promotes strong hydrophobic contact with the adsorbed protein. In contrast, cytochrome c association with N-acyl DPPE membranes is due primarily to reversible electrostatic interactions with the anionic headgroup, and not hydrophobic contact with the N-acyl chain. The presence of a small mole fraction of an N-propionyl derivative of DPPE (N-C3:0-DPPE) diminishes cytochrome c affinity for vesicles containing a large amount of DPPG apparently by relieving the membrane packing strain that drives the extended DPPG conformation.