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Polyphenol supplementation and executive functioning in overweight and obese adults at risk of cognitive impairment: A systematic review and meta-analysis.
Farag, S, Tsang, C, Murphy, PN
PloS one. 2023;18(5):e0286143
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It is recognised that overweight and obesity pose an increased risk for the development of cardiometabolic disease, and increasing evidence indicates a link to cognitive impairment associated with early onset dementia in such populations. This study's aim was to elaborate on existing knowledge of the effectiveness or otherwise of polyphenols in general to improve executive function (EFs) in an obese/ overweight population at risk of cognitive impairment. This study was a systematic review and meta-analysis of twenty-three randomised controlled trials. Results showed a nonsignificant effect of polyphenols on EFs. Authors concluded that further research should consider investigating polyphenols supplementation in a younger population at risk of cognitive impairment.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Overweight and obesity have increasing evidence that indicates a link to compromised executive functions such as memory and decision-making processes and cognitive impairment
- This meta-analysis revealed a non-significant effect of polyphenol supplementation on executive functions among overweight and/or obese populations with a susceptibility to cognitive impairment.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
A systematic review and meta-analysis were undertaken to investigate the impact of polyphenol supplementation on executive functions (cognitive functions which constitute part of the working memory and decision-making processes) among overweight and/or obese populations.
Method:
A comprehensive literature search was conducted using four electronic databases: PubMed/Medline, PsycInfo, Scopus and the Cochrane Trials Library. Inclusion criteria encompassed primary research studies which investigated the impact of polyphenols versus placebo on executive function in overweight or obese adults.
The review comprised a total of 23 randomised controlled trials (RCTs), incorporating a participant pool of N = 1,976 individuals. The mean ages of participants in all 23 studies receiving polyphenol supplementation were 62.92 years (SD = 8.06 years) and the mean BMIs ranged from 25.5 kg/m2 to 33.7 kg/m2. Various dietary polyphenols were investigated in the studies, with the main groups being isoflavones, flavonoids, resveratrol, phenolic acid, curcumin, walnuts and blueberry powder.
- The JADAD scale was employed to assess the methodological quality of the incorporated studies
- Hedges g, accompanied by 95% confidence intervals (CI) for endpoints, was computed utilising a random effects model whenever applicable
- Various statistical methods were considered for potential application in evaluating publication bias
- Sensitivity analysis was conducted to assess the robustness of the obtained results.
Results
- Meta analysis of the 23 primary studies produced a non-significant effect of polyphenol supplementation on executive function (g = 0.076, CI = -0.018 to 0.170)
- A double-blind, randomised, placebo-controlled parallel study reported significant benefits in 60 participants (mean age 67 years) taking 80mg of curcumin over placebo for digital vigilance and serial subtraction tasks (p=0.041)
- A double-blind, randomised, placebo-controlled parallel intervention trial showed significant benefits in 79 patients (mean age of 61 years) taking 150mg of resveratrol for visuospatial working memory double span and trail making test (p= 0.012).
Conclusion:
This meta-analysis revealed a non-significant effect of polyphenol supplementation on executive functions among overweight and/or obese populations.
Clinical practice applications:
- Research has documented the association between compromised executive functions and obesity/overweight, emphasising neuroinflammation and oxidative stress as potential mechanisms
- A plausible intervention involves the utilisation of polyphenols, known for their antioxidant and anti-inflammatory properties
- This systematic review and meta-analysis revealed a non-significant effect of polyphenol supplementation on executive functions
- A potential beneficial impact for 80mg of curcumin and 150mg of resveratrol was revealed in younger populations (mean ages of 67 and 61 years).
Considerations for future research:
- A potential beneficial impact of 80mg of curcumin and 150mg of resveratrol supplementation was revealed in a younger population (mean ages of 67 and 61 years), highlighting the necessity for in-depth exploration in subsequent studies
- The diversity in tasks employed for assessing executive functions and the comprehensive reporting of the phenolic composition of supplements had limitations that warrant consideration in future research
- The exact constituent and dose of supplementation needs to be described as this is necessary for the identification of the potential beneficial compounds for cognitive health and to support clinical practice.
Abstract
BACKGROUND AND OBJECTIVES Increasing evidence indicates a link between obesity and cognitive impairment. Furthermore, there is limited literature regarding the effect of polyphenols, a plant derived compounds, on executive functioning in an overweight/obese population at-risk of cognitive impairment. The aim of the present systematic review and meta-analysis of randomized controlled trials is to examine the effect of polyphenol supplementation on executive functions in overweight and/or obese populations at risk of cognitive impairment. METHODS A comprehensive literature search was conducted from inception to March 2023 using four electronic databases: PubMed/Medline, PsycInfo, Scopus and Cochrane trials library. Published primary research studies in English that compared the effect of polyphenols with placebo on executive function in overweight/obese adults were considered eligible for the meta-analysis. Jadad scale was used for the methodological quality rating of the included studies. Hedges g with 95% confidence intervals (CI) for endpoints were calculated using random effect model where applicable. Rosenthal's Fail-safe N, funnel plots, the Begg and Mazumdar's rank correlation test (Kendall's S statistic P-Q), Egger's linear regression test, and Duval and Tweedie's trim-and-fill test were identified for potential use as appropriate, to examine publication bias. Sensitivity analysis was conducted to examine the robustness of the results. RESULTS AND CONCLUSION A total of 23 RCT studies involving N = 1,976 participants were included in the review. The results of the meta-analysis revealed a non-significant effect for polyphenol supplementation on executive function (g = 0.076, CI = -0.018 to 0.170). Observations from primary studies within the meta-analysis showed a potential positive effect of polyphenol supplementation in a younger population at-risk of cognitive impairment and it is recommended to investigate this further in future studies. Moreover, the variability of the tasks used to examine executive functions as well as the adequate reporting of supplement's phenolic composition is a limitation that future work should also consider.
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Wild blueberry (poly)phenols can improve vascular function and cognitive performance in healthy older individuals: a double-blind randomized controlled trial.
Wood, E, Hein, S, Mesnage, R, Fernandes, F, Abhayaratne, N, Xu, Y, Zhang, Z, Bell, L, Williams, C, Rodriguez-Mateos, A
The American journal of clinical nutrition. 2023;117(6):1306-1319
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The risk of developing both cardiovascular and neurodegenerative diseases increases with aging. Growing evidence from epidemiological and human intervention trials indicates that (poly)phenols may have cardioprotective properties as well as the ability to improve cognitive function. The aim of this study was to investigate the effects of daily wild blueberry (WBB) (poly)phenol consumption on vascular function and cognitive performance in healthy older individuals. This study was a randomised, double-blinded, placebo-controlled parallel design study. A total of 61 healthy older individuals were recruited and randomly assigned to one of the two arms; placebo intervention or blueberry intervention group. Results showed that long-term consumption of a dietary achievable amount of WBB enhanced vascular and cognitive function in older adults. Authors conclude that gut microbiota and vascular blood flow may play important roles in mediating the cognitive benefits shown by the consumption of (poly)phenol-rich foods.
Abstract
BACKGROUND Evidence suggests that the intake of blueberry (poly)phenols is associated with improvements in vascular function and cognitive performance. Whether these cognitive effects are linked to increases in cerebral and vascular blood flow or changes in the gut microbiota is currently unknown. METHODS A double-blind, parallel randomized controlled trial was conducted in 61 healthy older individuals aged 65-80 y. Participants received either 26 g of freeze-dried wild blueberry (WBB) powder (302 mg anthocyanins) or a matched placebo (0 mg anthocyanins). Endothelial function measured by flow-mediated dilation (FMD), cognitive function, arterial stiffness, blood pressure (BP), cerebral blood flow (CBF), gut microbiome, and blood parameters were measured at baseline and 12 wk following daily consumption. Plasma and urinary (poly)phenol metabolites were analyzed using microelution solid-phase extraction coupled with liquid chromatography-mass spectrometry. RESULTS A significant increase in FMD and reduction in 24 h ambulatory systolic BP were found in the WBB group compared with the placebo group (0.86%; 95% CI: 0.56, 1.17, P < 0.001; -3.59 mmHg; 95% CI: -6.95, -0.23, P = 0.037; respectively). Enhanced immediate recall on the auditory verbal learning task, alongside better accuracy on a task-switch task was also found following WBB treatment compared with placebo (P < 0.05). Total 24 h urinary (poly)phenol excretion increased significantly in the WBB group compared with placebo. No changes in the CBF or gut microbiota composition were found. CONCLUSIONS Daily intake of WBB powder, equivalent to 178 g fresh weight, improves vascular and cognitive function and decreases 24 h ambulatory systolic BP in healthy older individuals. This suggests that WBB (poly)phenols may reduce future CVD risk in an older population and may improve episodic memory processes and executive functioning in older adults at risk for cognitive decline. Clinical Trial Registration number in clinicaltrials.gov: NCT04084457.
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Polyphenol Intake in Pregnant Women on Gestational Diabetes Risk and Neurodevelopmental Disorders in Offspring: A Systematic Review.
Salinas-Roca, B, Rubió-Piqué, L, Montull-López, A
Nutrients. 2022;14(18)
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In Europe, gestational diabetes affects approximately 10.9% of pregnant women. According to previous research, the cardiometabolic health of the mother and the mother's dietary habits during pregnancy may affect the foetus' neurodevelopment. Taking polyphenol supplements and eating foods rich in polyphenols is beneficial for promoting health across generations. In this systematic review, fourteen studies were included in order to evaluate the effects of polyphenols on gestational diabetes and mental health in the offspring. A higher prevalence of neurodevelopmental diseases in offspring is associated with gestational diabetes. The results of this systematic review revealed that polyphenol intake during pregnancy might have a beneficial effect on improving cardiometabolic health, reducing inflammation, DNA methylation and oxidative stress, thus reducing the risk of developing fetal neurodevelopmental disorders, such as attention deficit hyperactivity disorder, autism spectrum disorder and learning disorders. There is a need for further robust research, as the existing evidence regarding the safety of long-term polyphenol supplementation and its effects on gestational diabetes and fetal neurodevelopment is very limited. In spite of this, healthcare professionals can use the findings of this systematic review to learn more about the positive health benefits of polyphenols in pregnant women.
Abstract
The intake of foods containing polyphenols can have a protective role to avoid comorbidities during pregnancy and, at the same time, promote transgenerational health. This review aims to describe the effect of polyphenol intake through supplements or polyphenol-rich foods during pregnancy on the incidence and evolution of gestational diabetes mellitus (GDM), as well as the link with the neurodevelopment of the fetus. Using PRISMA procedures, a systematic review was conducted by searching in biomedical databases (PubMed, Cinahl and Scopus) from January to June 2022. Full articles were screened (n = 419) and critically appraised. Fourteen studies were selected and were divided into two different thematic blocks considering (i) the effect of polyphenols in GDM and (ii) the effect of GDM to mental disorders in the offspring. A positive relationship was observed between the intake of polyphenols and the prevention and control of cardiometabolic complications during pregnancy, such as GDM, which could be related to thwarted inflammatory and oxidative processes, as well as neuronal factors. GDM is related to a greater risk of suffering from diseases related to neurodevelopment, such as attention deficit hyperactivity disorder, autism spectrum disorder and learning disorder. Further clinical research on the molecule protective mechanism of polyphenols on pregnant women is required to understand the transgenerational impact on fetal neurodevelopment.
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Effects of Polyphenol-Rich Interventions on Cognition and Brain Health in Healthy Young and Middle-Aged Adults: Systematic Review and Meta-Analysis.
Ammar, A, Trabelsi, K, Boukhris, O, Bouaziz, B, Müller, P, M Glenn, J, Bott, NT, Müller, N, Chtourou, H, Driss, T, et al
Journal of clinical medicine. 2020;9(5)
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Literature shows that (poly)phenols are a brain-friendly intervention that may prevent and delay age-associated decline in cognitive function. The main aim of this study was to systematically review the literature and conduct a meta-analysis of all trials investigating the acute and chronic effects of (poly)phenol-rich supplementation on cognitive functions and brain health in young and middle-aged healthy adults. This study is a systemic review and meta-analysis which included 16 studies. The pooled analysis of the acute/chronic administration (4 weeks) of (poly)phenol-rich supplementation suggests a beneficial effect on the majority of the assessed cognitive functions. These beneficial effects appear to depend on the administration type (acute or chronic) and the supplementation protocols (dose and bioavailability) with more significant effects observed following acute supplementation. Authors conclude that rich polyphenol supplementation may be highly useful as an inexpensive, long-term preventive intervention on neurodegenerative diseases and cognitive decline especially in young and middle-aged adults.
Abstract
CONTEXT Affecting older and even some younger adults, neurodegenerative disease represents a global public health concern and has been identified as a research priority. To date, most anti-aging interventions have examined older adults, but little is known about the effects of polyphenol interventions on brain-related aging processes in healthy young and middle-aged adults. OBJECTIVE This systematic review and meta-analysis aimed to evaluate the acute and chronic effects of (poly)phenol-rich diet supplementation on cognitive function and brain health in young and middle-aged adults. In July 2019, two electronic databases (PubMed and Web of Science) were used to search for relevant trials examining the effect of acute or chronic (poly)phenol-rich supplementation on cognitive function and neuroprotective measures in young and middle-aged adults (<60 years old). A total of 4303 records were screened by two researchers using the PICOS criteria. Fifteen high quality (mean PEDro score = 8.8 ± 0.58) trials with 401 total participants were included in the final analyses. Information on treatment, study design, characteristics of participants, outcomes and used tools were extracted following PRISMA guidelines. When items were shown to be sufficiently comparable, a random-effects meta-analysis was used to pool estimates across studies. Effect size (ES) and its 95% confidence interval (CI) was calculated. The meta-analysis indicated that (poly)phenol supplementation significantly increased brain-derived neurotrophic factor (ES = 3.259, p = 0.033), which was accompanied by higher performance in serial (7s) subtraction (ES = 1.467, p = 0.001) and decreases in simple reaction time (ES = -0.926, p = 0.015) and mental fatigue (ES = -3.521 p = 0.010). Data related to cognitive function were skewed towards an effect from acute compared to chronic polyphenol intervention; data related to BDNF were skewed toward an effect from higher bioavailability phenolic components. CONCLUSION This meta-analysis provides promising findings regarding the usefulness of polyphenol-rich intervention as an inexpensive approach for enhancing circulation of pro-cognitive neurotrophic factors. These beneficial effects appear to depend on the supplementation protocols. An early acute and/or chronic application of low- to high-dose phenolic components with high bioavailability rates (≥30%) at a younger age appear to provide more promising effects.
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A Review of Dietary (Phyto)Nutrients for Glutathione Support.
Minich, DM, Brown, BI
Nutrients. 2019;11(9)
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Glutathione is made up of 3 amino acids (cysteine, glutamic acid and glycine) and plays important roles in the body, including oxidative stress reduction, supporting the immune system and contributing to detoxification processes. Evidence suggests that it is an important marker and target for treatment in many chronic, age-related diseases. This review article explores the evidence of nutritional strategies to improve glutathione status. The authors examine the evidence for supplementation of the precursors of glutathione as well as with various forms of supplemental glutathione itself, and the impacts on glutathione status and clinical impacts. Crucially, the review article provides information on dietary sources of precursors of glutathione and glutathione itself, which will provide Nutrition Practitioners with compelling information for use in clinic. Lean protein, brassica vegetables, polyphenol-rich fruits and vegetables, green tea, herbs and spices and omega-3 rich foods are all discussed in detail.
Abstract
Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse roles of glutathione in physiology are relevant to a considerable body of evidence suggesting that glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Yet, proper personalized balance in the individual is key as well as a better understanding of antioxidants and redox balance. Optimizing glutathione levels has been proposed as a strategy for health promotion and disease prevention, although clear, causal relationships between glutathione status and disease risk or treatment remain to be clarified. Nonetheless, human clinical research suggests that nutritional interventions, including amino acids, vitamins, minerals, phytochemicals, and foods can have important effects on circulating glutathione which may translate to clinical benefit. Importantly, genetic variation is a modifier of glutathione status and influences response to nutritional factors that impact glutathione levels. This narrative review explores clinical evidence for nutritional strategies that could be used to improve glutathione status.
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Dietary Diversity Was Positively Associated with Psychological Resilience among Elders: A Population-Based Study.
Yin, Z, Brasher, MS, Kraus, VB, Lv, Y, Shi, X, Zeng, Y
Nutrients. 2019;11(3)
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There's a growing interest by researchers in the relationship between the diversity of people's diets and their health, including their psychological resilience. This study looked at the associations between dietary diversity (DD) and psychological resilience in 8571 elderly individuals in China. Frequency and variety of food groups was collected in order to produce an average (mean) DD score. The psychological resilience of participants was assessed using a validated research tool known as "simplified resilience score" (SRS). The statistical analysis of the data collected showed that those elders with the poorest psychological resilience scores were also eating the least diverse diets. Based on separate analyses by age group, the association of a low SRS with poor DD was more prominent in the younger elderly than the oldest old. Compared with younger participants with good DD, the risk of a low SRS was greater for younger participants with poor DD, the oldest old with good DD, and the oldest old with poor DD, with OR respectively. The greatest contribution to DD was from a high consumption of vegetables, fruits, and nuts. Our study suggested that poor DD was associated with a low psychological resilience among the Chinese elderly, especially the younger elderly. These findings suggest that eating a diet rich in a variety of vegetables, fruits, and nuts might promote psychological resilience.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Dietary polyphenols abundant in fruits, vegetables and nuts have been associated with improved psychological resilience.
- Healthcare practitioners working on the dietary diversity of their clients should focus attention on these phenolic-rich foods in the interests of psychological resilience.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
This is a population-based study involving 8571 community-based elderly individuals, where dietary diversity (DD) was assessed by means of food frequency questionnaires, and correlated with psychological resilience, assessed by a validated simplified resilience score (SRS). Low DD has been previously correlated with a high level of oxidative stress mediating oxidative damage to mitochondria and lipids in neuronal circuits, as seen in affective (anxiety, depression) and neurodegenerative conditions (Alzheimer's and Parkinson's Diseases). Conversely, dietary polyphenols, a group of phenolic compounds abundant in fruits, vegetables, and other plant sources, have been associated with improved psychological resilience.
Clinical practice applications:
The greatest contribution to dietary diversity from the totality of food groups was from a high consumption of vegetables, fruits, and nuts. This can help nutrition practitioners inform their clinical decisions when supporting individuals wanting to improve the diversity of their diet.
Considerations for future research:
Future work is necessary to further assess these findings in longitudinal studies and clinical trials, and to ascertain what the mechanisms of action are in this process. It would be particularly interesting to find out whether the gut microbiota and its communication with the brain via the gut-brain axis is part of the process.
Abstract
The association between dietary diversity (DD) and psychological resilience among older people is an underdeveloped area of research. This cross-sectional study explored the associations of DD with psychological resilience among 8571 community-based elderly individuals. The intake frequencies of food groups were collected, and dietary diversity was assessed based on the mean DD score. Psychological resilience was assessed using a simplified resilience score (SRS). Data were analyzed using multiple linear regression and logistic regression models. Poor DD was significantly associated with psychological resilience, with a β (95% CI) of -0.94 (-1.07, -0.81) for the SRS (p < 0.01) and an odds ratio (95% CI) of 1.83 (1.66, 2.01) for low SRS status. The interaction effects of age with DD were observed for the SRS (p < 0.001) and low SRS status (p < 0.001). Based on separate analyses by age group, the association of a low SRS with poor DD was more prominent in the younger elderly than the oldest old, with OR (95% CI) 2.32 (1.96, 2.74) and 1.61 (1.43, 1.82), respectively. Compared with younger participants with good DD, the risk of a low SRS was greater for younger participants with poor DD, the oldest old with good DD, and the oldest old with poor DD, with OR (95% CI) 2.39 (2.02, 2.81), 1.28 (1.09, 1.51), and 2.03 (1.72, 2.39), respectively. The greatest contribution to DD was from a high consumption of vegetables, fruits, and nuts. Our study suggested that poor DD was associated with a low psychological resilience among the Chinese elderly, especially the younger elderly. These findings suggest that augmentation of DD might promote psychological resilience.
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Bridging the Reciprocal Gap between Sleep and Fruit and Vegetable Consumption: A Review of the Evidence, Potential Mechanisms, Implications, and Directions for Future Work.
Noorwali, E, Hardie, L, Cade, J
Nutrients. 2019;11(6)
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Both sleep disruption and a low intake of fruit and vegetables (FV) are associated with higher rates of premature death and chronic disease. This review looked at previous studies in order to determine whether there is a link between sleep and FV consumption. A recent meta-analysis found that shorter sleep duration is consistently associated with low fruit and vegetable intake in children, but in adults the association is less clear. Studies looking at the effect of sleep on FV intake had variable results. Tart cherries and kiwi fruits were the most commonly studied fruits for their effect on sleep measures. Observational studies tended to find that both short- and long-sleepers tend to eat less FV than those that sleep for 7-8 hours. A lot of evidence shows that people who go to sleep later (‘owls’) tend to consume unhealthier diets with lower intakes of FV than people who go to bed earlier (‘larks’). The researchers also looked at potential mechanisms for the association between sleep and FV intake. Polyphenols in FV may influence sleep by increasing neurotransmitters via the gut-brain axis, improving energy metabolism and through alterations in circadian rhythms and the CLOCK genes. Ways in which disrupted sleep may affect FV consumption included changes in hunger hormones, emotional stress and impaired decision making. With further research, interactions between sleep measures and FV consumption may be clarified and potentially reduce the burden of chronic diseases and premature deaths.
Abstract
A substantial burden of disease and mortality globally is attributable to both sleep disruption and low intakes of fruit and vegetable (FV) and there is increasing mechanistic and epidemiological evidence to support a reciprocal relationship between the two. This review provides an overview of experimental and observational studies assessing the relations between sleep and FV consumption from 52 human adult studies. Experimental studies are currently limited and show inconsistent results. Observational studies support a non-linear association with adults sleeping the recommended 7-9 hours/day having the highest intakes of FV. The potential mechanisms linking sleep and FV consumption are highlighted. Disrupted sleep influences FV consumption through homeostatic and non-homeostatic mechanisms. Conversely, FV consumption may influence sleep through polyphenol content via several potential pathways. Few human experimental studies have examined the effects of FV items and their polyphenols on sleep and there is a need for more studies to address this. An appreciation of the relationship between sleep and FV consumption may help optimize sleep and FV consumption and may reduce the burden of chronic diseases. This review provides implications for public health and directions for future work.
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Mechanisms Underlying the Anti-Depressive Effects of Regular Tea Consumption.
Rothenberg, DO, Zhang, L
Nutrients. 2019;11(6)
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Previous research suggests that tea consumption is linked to a lower risk of depression, but it is not understood why. This meta-analysis and literature review looked at previous human, animal and laboratory studies that might give an indication of the mechanisms by which drinking tea can lead to a reduced depression risk. Tea contains many different active compounds such as L-theanine, various polyphenols and polyphenol metabolites that have effects on the immune system, stress response, brain neurotransmitters such as serotonin and dopamine, and gut bacteria. Different types of tea such as black, green or oolong tea contain different amounts of active compounds. The authors found that these compounds are capable of functioning through multiple pathways simultaneously that together reduce the risk of depression. The authors concluded that daily consumption of moderate amounts of different types of tea may offer significant potential benefit in the risk reduction of depression.
Abstract
This article is a comprehensive review of the literature pertaining to the antidepressant effects and mechanisms of regular tea consumption. Meta-data supplemented with recent observational studies were first analyzed to assess the association between tea consumption and depression risk. The literature reported risk ratios (RR) were 0.69 with 95% confidence intervals of 0.62-0.77. Next, we thoroughly reviewed human trials, mouse models, and in vitro experiments to determine the predominant mechanisms underlying the observed linear relationship between tea consumption and reduced risk of depression. Current theories on the neurobiology of depression were utilized to map tea-mediated mechanisms of antidepressant activity onto an integrated framework of depression pathology. The major nodes within the network framework of depression included hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, inflammation, weakened monoaminergic systems, reduced neurogenesis/neuroplasticity, and poor microbiome diversity affecting the gut-brain axis. We detailed how each node has subsystems within them, including signaling pathways, specific target proteins, or transporters that interface with compounds in tea, mediating their antidepressant effects. A major pathway was found to be the ERK/CREB/BDNF signaling pathway, up-regulated by a number of compounds in tea including teasaponin, L-theanine, EGCG and combinations of tea catechins and their metabolites. Black tea theaflavins and EGCG are potent anti-inflammatory agents via down-regulation of NF-κB signaling. Multiple compounds in tea are effective modulators of dopaminergic activity and the gut-brain axis. Taken together, our findings show that constituents found in all major tea types, predominantly L-theanine, polyphenols and polyphenol metabolites, are capable of functioning through multiple pathways simultaneously to collectively reduce the risk of depression.