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The effect of polyphenols on DNA methylation-assessed biological age attenuation: the DIRECT PLUS randomized controlled trial.
Yaskolka Meir, A, Keller, M, Hoffmann, A, Rinott, E, Tsaban, G, Kaplan, A, Zelicha, H, Hagemann, T, Ceglarek, U, Isermann, B, et al
BMC medicine. 2023;21(1):364
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Biological age differs from chronological age and is determined by assessing our DNA, this is known as mAge. A healthy lifestyle and weight loss have been shown to be of benefit to mAge. The Mediterranean (MED) diet includes ingredients such as vitamins and naturally occurring chemicals, known as polyphenols, which may alter biological age. This randomised control trial of 256 aimed to determine the effects of a MED diet richer in green vegetables and lower in meat (Green-MED) compared to the MED diet and recommendations for healthy eating. The results showed that after 18 months of healthy eating and weight loss, none of the diets was able to lower the biological age, however the Green-MED diet and in particular the intake of green tea and the vegetable Mankai were associated with slower biological ageing compared to the other two diets. The polyphenol tyrosol was also associated with slower biological ageing. It was concluded that the diets were unable to reverse biological ageing, but a GreenMed diet rich in polyphenols, may be able to slow it. This study could be used by healthcare professionals to understand that as higher biological age is associated with poorer health outcomes, a diet rich in polyphenols may have additional benefits beyond just weight loss.
Abstract
BACKGROUND Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined. METHODS We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3-4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight). RESULTS Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e - 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = - 0.41, p = 0.004 and beta = - 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = - 1.8; p = 0.061) and green tea (beta = - 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02). CONCLUSIONS This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging. TRIAL REGISTRATION ClinicalTrials.gov, NCT03020186.
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Dietary polyphenols, metabolic syndrome and cardiometabolic risk factors: An observational study based on the DCH-NG subcohort.
Lanuza, F, Zamora-Ros, R, Bondonno, NP, Meroño, T, Rostgaard-Hansen, AL, Riccardi, G, Tjønneland, A, Landberg, R, Halkjær, J, Andres-Lacueva, C
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2023;33(6):1167-1178
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Metabolic syndrome (MetS) is a cluster of metabolic disorders that increases the risk of developing chronic diseases. Cardiometabolic risk factors include high waist circumference (WC), insulin resistance, hypertension, dysglycaemia, dyslipidaemia, and altered inflammatory markers. The aim of this study was to investigate the associations between intakes of polyphenols (total polyphenols and their main classes) and the prevalence of MetS and cardiometabolic risk factors. This study is an observational sub-cohort study of 676 Danish participants of the MAX study from the Danish Diet, Cancer and Health - Next Generations (DCH-NG) cohort. Results showed that individuals with higher total polyphenol and phenolic acid intakes, were less likely to have MetS. Furthermore, for cardiovascular risk factors, intakes of total polyphenols, flavonoids and phenolic acids were associated with a lower risk of higher systolic blood pressure and lower high-density lipoprotein cholesterol. Authors conclude by suggesting that intervention studies should be undertaken to establish whether a polyphenol-rich diet can improve some cardiometabolic risk factors and can reduce or delay the onset of cardiometabolic diseases in free-living populations.
Abstract
BACKGROUND AND AIMS Polyphenol-rich foods have beneficial properties that may lower cardiometabolic risk. We aimed to prospectively investigate the relationship between intakes of dietary polyphenols, and metabolic syndrome (MetS) and its components, in 676 Danish residents from the MAX study, a subcohort of the Danish Diet, Cancer and Health-Next Generations (DCH-NG) cohort. METHODS AND RESULTS Dietary data were collected using web-based 24-h dietary recalls over one year (at baseline, and at 6 and 12 months). The Phenol-Explorer database was used to estimate dietary polyphenol intake. Clinical variables were also collected at the same time point. Generalized linear mixed models were used to investigate relationships between polyphenol intake and MetS. Participants had a mean age of 43.9y, a mean total polyphenol intake of 1368 mg/day, and 75 (11.6%) had MetS at baseline. Compared to individuals with MetS in Q1 and after adjusting for age, sex, lifestyle and dietary confounders, those in Q4 - for total polyphenols, flavonoids and phenolic acids-had a 50% [OR (95% CI): 0.50 (0.27, 0.91)], 51% [0.49 (0.26, 0.91)] and 45% [0.55 (0.30, 1.00)] lower odds of MetS, respectively. Higher total polyphenols, flavonoids and phenolic acids intakes as continuous variable were associated with lower risk for elevated systolic blood pressure (SBP) and low high-density lipoprotein cholesterol (HDL-c) (p < 0.05). CONCLUSIONS Total polyphenol, flavonoid and phenolic acid intakes were associated with lower odds of MetS. These intakes were also consistently and significantly associated with a lower risk for higher SBP and lower HDL-c concentrations.
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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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The effects of Aronia berry (poly)phenol supplementation on arterial function and the gut microbiome in middle aged men and women: Results from a randomized controlled trial.
Le Sayec, M, Xu, Y, Laiola, M, Gallego, FA, Katsikioti, D, Durbidge, C, Kivisild, U, Armes, S, Lecomte, M, Fança-Berthon, P, et al
Clinical nutrition (Edinburgh, Scotland). 2022;41(11):2549-2561
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Over the last decades, Aronia melanocarpa, or black chokeberry, has gained increased attention for its high content of (poly)phenols, and potential protection against chronic diseases such as cardiovascular disease and diabetes. The aim of this study was to investigate the effects of 12-week aronia berry (poly)phenol consumption on cardiometabolic health and gut microbiome composition in prehypertensive middle-aged adults. This study was a 2-arm, double-blind, parallel randomised controlled trial. Participants (n = 102; 47 men and 55 women) were assigned randomly to Aronia or control groups. Results showed that there were no significant effects in blood pressure (primary outcome), endothelial function or blood lipids. However, there was a significant improvement in 24-hour ambulatory arterial indices and significant changes in gut microbiome richness, functions and composition between Aronia and control groups. Authors conclude that future studies should be conducted to investigate whether aronia supplementation may be effective in other at-risk populations such as hypertensives or people with cardiovascular disease risk.
Abstract
BACKGROUND AND AIMS Berry (poly)phenol consumption has been associated with cardioprotective benefits, however little is known on the role the gut microbiome may play on such health benefits. Our objective was to investigate the effects of aronia berry (poly)phenol consumption on cardiometabolic health and gut microbiome richness and composition in prehypertensive middle-aged men and women. METHODS A total of 102 prehypertensive participants were included in a parallel 12-week randomized double-blind placebo-controlled trial. Volunteers were randomly allocated to daily consume an encapsulated (poly)phenol-rich aronia berry extract (Aronia, n = 51) or a matched maltodextrin placebo (Control, n = 51). Blood pressure (BP) and arterial function (office and 24 h), endothelial function (measured as flow-mediated dilation), serum biochemistry (including blood lipids), plasma and urine (poly)phenol metabolites as well as gut microbiome composition through shotgun metagenomic sequencing were monitored over the study period. Relationships between vascular outcomes, (poly)phenol metabolites and gut microbiome were investigated using an integrated multi-levels approach. RESULTS A significant improvement in arterial indices measured as augmentation index (AIx) and pulse wave velocity (PWV) was found in the Aronia compared to Control group (awake Δ PWV = -0.24 m/s; 95% CI: -0.79, -0.01 m/s, P < 0.05; 24 h peripheral Δ AIx = -6.8; -11.2, -2.3, %, P = 0.003; 24 h central Δ AIx = -3.3; -5.5, -1.0, %, P = 0.006). No changes in BP, endothelial function or blood lipids were found following the intervention. Consumption of aronia (poly)phenols led to a significant increase in gut microbiome gene richness and in the abundance of butyrate-producing species such as Lawsonibacter asaccharolyticus and Intestinimonas butyriciproducens species, compared to Control group. Results from an approach including metabolomic, metagenomic and clinical outcomes highlighted associations between aronia-derived phenolic metabolites, arterial stiffness, and gut microbiome. CONCLUSIONS Aronia berry (poly)phenol consumption improved arterial function in prehypertensive middle-aged individuals, possibly via modulation of gut microbiome richness and composition based on the associations observed between these parameters. CLINICAL TRIAL REGISTRY The National Institutes of Health (NIH)-randomized trial records held on the NIH ClinicalTrials.gov website (NCT03434574). Aronia Berry Consumption on Blood Pressure.
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The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial.
Zelicha, H, Kloting, N, Kaplan, A, Yaskolka Meir, A, Rinott, E, Tsaban, G, Chassidim, Y, Bluher, M, Ceglarek, U, Isermann, B, et al
BMC medicine. 2022;20(1):327
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Visceral adipose tissue (VAT) accumulation is one of the main key factors that differentiate between metabolic healthy and unhealthy obese individuals. VAT is closely related to the development of multiple cardiovascular risk factors. The Mediterranean (MED) diet, high in polyphenol content and rich in plant food sources, was shown to have an enhanced effect on VAT reduction in combination with physical activity (PA), regardless of weight loss The aim of this study was to assess the effect of the MED diet, further enriched with polyphenols, and lower in red and processed meat (“green-MED diet”) on visceral adiposity in the 18-month Dietary Intervention Randomized Controlled Trial-Polyphenols, Unprocessed trial. This study is a randomised controlled trial. Participants were randomly assigned to one of three intervention groups (1:1:1 ratio): healthy dietary guidelines, MED diet, or green-MED diet, all included PA recommendations, with a free gym membership and educational sessions promoting moderate-intensity PA. Results show that participants following the green-MED diet achieved more than twice the degree of VAT reduction compared to those following the MED diet, despite similar weight loss. In fact, VAT loss was specifically related to lower red meat intake and increased walnuts, green tea, Wolfa globosa, and dietary fibre (this was reflected by higher plasma polyphenol and serum folate levels). Authors conclude that a green-MED diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the MED diet for targeted VAT reduction.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The positive health effects of the traditional MED diet, moderately high in PUFAs and MUFAs and low in red meat, are well-established
- Higher levels of total plasma polyphenol and serum folate may reflect higher consumption of “green” dietary components, which were significantly associated with greater VAT loss
- The green-MED diet, richer in dietary polyphenols and green plant-based proteins and lower in red meat, might be a more effective strategy for VAT loss than the traditional healthy MED diet, achieving more than twice the degree of VAT reduction, despite similar weight loss.
- VAT loss was specifically related to lower red meat intake and increased walnuts, green tea, Wolffia globosa, and dietary fibre and was reflected by higher plasma polyphenol and serum folate levels.
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 mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. Visceral adipose tissue (VAT) accumulation is one of the main factors that differentiate between metabolic healthy and unhealthy obese individuals.
In this Dietary Intervention Randomised Controlled Trial PoLyphenols UnproceSsed (DIRECT‐ PLUS) weight‐loss trial, 294 participants were randomised to: (A) healthy dietary guidelines (HDG), (B) MED, or (C) green‐MED diets, all combined with physical activity. The study duration was 18‐months.
This study explored the effect of the green‐MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT) and used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues.
Both isocaloric (with the same calorific value) MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green‐MED group further consumed green tea (3–4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake.
The mean weight loss (HDG: −0.4% (5.0), MED: −2.7% (5.6), green-MED: −3.9% (6.5)) and WC loss (HDG: −3.6% (5.1), MED: −4.7% (5.0), green-MED: −5.7%(5.7)) after 18 months were similar between the two MED diets (p > 0.05 for all) and higher as compared to the HDG (weight: HDG vs. MED: p = 0.02; HDG vs. green+MED: p < 0.001; WC: HDG vs. MED: p = 0.33, HDG vs. green+MED: p = 0.02).
All three abdominal fat depots decreased over 18 months of intervention (p < 0.05 vs. baseline for all). The green-MED group achieved a greater reduction in VAT than the other intervention groups (HDG: −4.2% (22.5), MED: −6.0%(31.3), green-MED: −14.1%(27.7); p < 0.05 green-MED vs. MED or vs. HDG groups). These differences in VAT loss across the groups remained significant after adjusting for age, sex, and 18-month WC change (green-MED vs. MED p = 0.023; green-MED vs. HDG p = 0.002) (Fig. 1)
Limitations of the study included a low proportion of women, and different VAT proportions at baseline across groups limit the generalisability of findings to women.
The authors of the study did not identify the exact components responsible for the dietary effects when they compared dietary regimens and not specific nutrients.
Adherence was by a validated, self-reported dietary intake assessment tool, which the authors acknowledge is subject to error
Strengths of the study included the relatively large sample size, high retention rate, and use of 3-T MRI measurements (considered one of the gold standards tools for the quantification of specific fat depots
Clinical practice applications:
- This trial shows that, when combined with a Mediterranean diet, higher dietary consumption of green tea, walnuts, and dietary fibre and reduced red meat consumption were significantly associated with greater %VAT loss
- The authors observed a significant synergistic interaction effect between decreased red meat consumption and increased serum folate on VAT loss
- A reduction in VAT accumulation, known as a key risk factor in CVD development, may reduce metabolic complications, improve the lipid profile, and decrease cardiometabolic risk.
Considerations for future research:
- Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity.
- Future studies could explore whether the results are replicable in both male and female participants, as this sample was largely male.
Abstract
BACKGROUND Mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT). METHODS In the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3-4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues. RESULTS Participants (age = 51 years; 88% men; body mass index = 31.2 kg/m2; 29% VAT) had an 89.8% retention rate and 79.3% completed eligible MRIs. While both MED diets reached similar moderate weight (MED: - 2.7%, green-MED: - 3.9%) and waist circumference (MED: - 4.7%, green-MED: - 5.7%) loss, the green-MED dieters doubled the VAT loss (HDG: - 4.2%, MED: - 6.0%, green-MED: - 14.1%; p < 0.05, independent of age, sex, waist circumference, or weight loss). Higher dietary consumption of green tea, walnuts, and Wolffia globosa; lower red meat intake; higher total plasma polyphenols (mainly hippuric acid), and elevated urine urolithin A polyphenol were significantly related to greater VAT loss (p < 0.05, multivariate models). CONCLUSIONS A green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression. TRIAL REGISTRATION ClinicalTrials.gov , NCT03020186.
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Consumption of flavonoids and risk of hormone-related cancers: a systematic review and meta-analysis of observational studies.
Liu, F, Peng, Y, Qiao, Y, Huang, Y, Song, F, Zhang, M, Song, F
Nutrition journal. 2022;21(1):27
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Hormone-related cancers (HRCs) are greatly influenced by hormone levels and generally respond to hormone regulation, which plays an indispensable role in tumour growth. Encouragingly, diets rich in vegetables, fruits and tea are found to reduce the cancer risk, having the potential to exert chemo-preventive effects with the presence of anticarcinogenic phytochemicals. The aim of this study was to elucidate the association between flavonoids intake and HRCs risk. This study is a meta-analysis of fifty-one studies. It consisted of 22 prospective cohort studies, 1 nested case–control study, 18 population-based case–control studies and 10 hospital-based case–control studies. Results show that higher consumption of total flavonoids was only associated with an increased risk of men-specific cancers, mainly prostate cancer. Furthermore, the subclasses, flavanols, flavones, and isoflavones, and the three main individual compounds of isoflavones (daidzein, genistein and glycitein) may have protective effects on women-specific cancers, whereas flavones and flavanones have been found to cause potentially dangerous effects in thyroid cancer. Additionally, there was no evidence in support of any role for anthocyanidins in HRCs. Authors conclude that there is a small amount of evidence that total flavonoids, flavanols, flavones, flavanones, flavan-3-ols and isoflavones may be associated with a lower or higher risk of certain HRCs, which may provide guidance for dietary guidelines to a certain extent in the future.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Dietary flavonoids are widely available in plant-based foods such as vegetables, citrus fruits, green tea and berries
- Menopausal status may be an important consideration for flavonoid intake when considering breast cancer risk
- Differences in results for Asians and non-Asians need to be considered for the use of flavonoids in women-specific hormonal cancers and prostate cancer in men
- Caution should be exercised when considering flavones and flavanones and thyroid cancer risk until further research is available
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:
Background
Hormone-related cancers (HRCs) are the most frequently diagnosed cancers globally , accounting for more than a quarter of new cancer cases worldwide in 2018. They include breast, ovarian, endometrial, prostate, testicular and thyroid cancer which share a similar carcinogenic mechanism. Diets rich in vegetables, fruit, legumes and tea may reduce cancer risk due to anticarcinogenic phytochemicals, such as flavonoids. Flavonoids are claimed to have many different physiological and pathological functions in the cancer process, including tumour cell proliferation, inflammation, angiogenesis, invasion and metastasis.. This study aimed to summarise the relationships between consumption of flavonoids with the risk of HRC.
Methods:
The meta-analysis was carried out following PRISMA guidelines and registered on PROSPERO. A literature search in PubMed and Embase was conducted using the keywords flavonoids, flavanols and isoflavones and breast, ovarian, endometrial, prostate, testicular and thyroid cancer. 51 studies published between 1999 and 2022 consisted of 22 prospective cohort, 18 population-based and 10 hospital-based case-control studies. On the Newcastle-Ottawa Scale assessment all studies were of medium or high methodological quality.
Results:
Results were analysed using Stata 15.1 software and ORs with 95% CIs used to measure the association between flavonoid intake and HRCs risk. Statistical I2 evaluated heterogeneity among the studies.
Funnel plots were inspected for publication bias and calculated by Begg’s/Egger’s regression tests. Sensitivity analyses were performed to explore the source of heterogeneity. Subgroup analysis was performed on study design and region, as well as menopausal status.
Higher consumption of flavonoids was associated with a decreased risk of women-specific cancers but a significant elevated risk of prostate cancer as seen below.
Women specific cancers:
For flavonoid sub-classes, higher consumption of flavanols (OR=0.85; 95% CI, 0.76–0.94; I2=75.5%; p<0.001), flavones (OR=0.85; 95% CI, 0.77–0.95; I2=76.3%; p<0.001) and isoflavones (OR=0.87; 95% CI, 0.82–0.92; I2=73.8%; p<0.001) was associated with a decreased risk of women-specific cancers (breast, ovarian and endometrial), especially among the case–control studies. Similar results were seen in the main compounds of isoflavones: daidzen, genistein and glycitein. There were differences in the association between isoflavones in Asian and non-Asian regions.
Men-specific cancers:
The higher consumption of total flavonoids (OR=1.11; 95% CI, 1.02–1.21; I2 = 0%; p = 0.484) was associated with an increased risk of prostate cancer and this was only found in non-Asian populations.
Conclusion:
Despite limitations of the meta-analysis, such as the use of observational studies and small sample sizes of the included studies, this systematic review may provide some preliminary dietary evidence for the use of flavonoids in HRCs.
Clinical practice applications:
- The promotion of a plant-based diet, rich in vegetables, fruits, green tea and legumes may have protective effects on women-specific cancers due to the rich presence of flavanols, flavones and isoflavones, as well as the compounds genistein, glycitein and daidzein.
- Results show no associations between total flavonoids intake and women-specific cancer however, the sub-groups of flavanols, flavones and isoflavones were associated with a decreased risk in women-specific cancers. Similar results were seen in the individual compounds of isoflavones: genistein, glycitein and daidzein. These results may guide decision-making when recommending the inclusion of these compounds for protective benefits in women-specific cancers.
- The positive association between total flavonoids and prostate cancer risk was only seen in non-Asians, and between higher consumption of flavones and flavanones and thyroid cancer risk albeit in limited studies (n=3) may provide important guidelines when considering which foods to include from a plant-based diet.
Considerations for future research:
- Further meta-analysis of prospective studies with larger sample sizes
- The use of a validated and reliable questionnaire for measuring flavonoid intake
- Intervention studies evaluating flavonoid subclasses
- Comparisons between Asian and non-Asian populations
- Consideration of menopausal status as an effect modifier
Abstract
BACKGROUND Flavonoids seem to have hormone-like and anti-hormone properties so that the consumption of flavonoids may have potential effects on hormone-related cancers (HRCs), but the findings have been inconsistent so far. This meta-analysis was aimed to explore the association between flavonoids intake and HRCs risk among observational studies. METHODS Qualified articles, published on PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) from January 1999 to March 2022 and focused on relationships between flavonoids (total, subclass of and individual flavonoids) and HRCs (breast, ovarian, endometrial, thyroid, prostate and testicular cancer), were retrieved for pooled analysis. Random effects models were performed to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Funnel plots and Begg's/Egger's test were used to evaluate the publication bias. Subgroup analyses and sensitivity analyses were conducted to explore the origins of heterogeneity. RESULTS All included studies were rated as medium or high quality. Higher consumption of flavonols (OR = 0.85, 95% CI: 0.76-0.94), flavones (OR = 0.85, 95% CI: 0.77-0.95) and isoflavones (OR = 0.87, 95% CI: 0.82-0.92) was associated with a decreased risk of women-specific cancers (breast, ovarian and endometrial cancer), while the higher intake of total flavonoids was linked to a significantly elevated risk of prostate cancer (OR = 1.11, 95% CI: 1.02-1.21). A little evidence implied that thyroid cancer risk was augmented with the higher intake of flavones (OR = 1.24, 95% CI: 1.03-1.50) and flavanones (OR = 1.31, 95% CI: 1.09-1.57). CONCLUSIONS The present study suggests evidence that intake of total flavonoids, flavonols, flavones, flavanones, flavan-3-ols and isoflavones would be associated with a lower or higher risk of HRCs, which perhaps provides guidance for diet guidelines to a certain extent. TRIAL REGISTRATION This protocol has been registered on PROSPERO with registration number CRD42020200720 .
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A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.
Basak, SK, Bera, A, Yoon, AJ, Morselli, M, Jeong, C, Tosevska, A, Dong, TS, Eklund, M, Russ, E, Nasser, H, et al
Cancer. 2020;126(8):1668-1682
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APG-157 is a botanical drug containing multiple polyphenols that delivers the active components to oromucosal tissues near the tumour target. APG-157 slowly disintegrates in the oral cavity over 15 to 20 minutes to release the drug substance. The drug substance is a precise, rational combination of multiple molecules derived from Curcuma longa wherein curcumin is the principal component. The main aim of this study was to determine the pharmacokinetics and safety of the orally delivered pastille (APG-157) when used by normal subjects and patients with cancer. This study is a randomised, double-blind, placebo-controlled trial. A total of 32 subjects were enrolled, and 25 completed the study (13 normal individuals and 12 patients with oral cancer). Results demonstrated that transoral APG-157 treatment leads to systemic absorption of curcumin and its analogs. There was a statistically significant concentration reduction in inflammatory cytokines and Bacteroides species noted in the salivary cells. Pre-treatment and post-treatment tumour samples from patients with cancer demonstrated T-cell recruitment to the tumour microenvironment. Authors conclude that APG-157 is absorbed well, reduces inflammation, and attracts T-cells to the tumour thus, it can be potentially used in combination with immunotherapy drugs. Furthermore, a long-term evaluation of immune checkpoint blockade with and without APG-157 could provide a clear understanding of the usefulness of APG-157 as either an adjuvant or neoadjuvant therapeutic agent for patients with advanced or recurrent head and neck cancer.
Abstract
BACKGROUND Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
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Probiotic fruit beverages with different polyphenol profiles attenuated early insulin response.
Xu, J, Jönsson, T, Plaza, M, Håkansson, Å, Antonsson, M, Ahrén, IL, Turner, C, Spégel, P, Granfeldt, Y
Nutrition journal. 2018;17(1):34
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Elevated levels of blood glucose after eating, known as postprandial hyperglycaemia, contribute to the development of cardiovascular disease and type 2 diabetes. Postprandial hyperglycaemia is a condition that can be improved through lifestyle and diet modifications. The aim of the study was to investigate and compare the postprandial glycaemic and insulin responses after consuming five different probiotic fruit or vegetable beverages. A secondary aim was to analyse beverages for their polyphenol content and antioxidative capacity. The study is a randomised, controlled, crossover study which included twelve healthy young adults (6 men and 6 women) with a BMI of 24.3 +/- 2.4kg/m2. Results indicate that Bilberry showed the most profound insulin lowering effect, followed by Rose hip. The analysis also showed that Bilberry had the highest values of the total phenolic compounds and flavonols, whereas Mango had the lowest. The highest values of antioxidative capacity were found in Bilberry and Beetroot. Authors conclude that consumption of food products that induce a lower insulin response may enhance insulin sensitivity.
Abstract
BACKGROUND Consumption of polyphenol-rich fruits and vegetables may improve postprandial glucose and insulin levels and hence promote well-being. Previously it has been observed that consumption of bilberry decreases the postprandial insulin demand. The intention with the present study was to compare the impact of different supplements with various polyphenol profiles, on the postprandial glucose and insulin responses in healthy young adults. METHODS In a randomized, controlled, crossover study the postprandial glycemic and insulin responses were observed in eleven healthy adults after intake of five different beverages containing bilberry (European blueberry), blackcurrant, beetroot, mango and rose hip, respectively; all drinks were enriched with the same composition of fermented oatmeal and probiotics. The control was a glucose drink. The profile and content of the polyphenols in the different beverages were determined by HPLC-DAD analysis. The antioxidative capacity of the different beverages were measured by TEAC and DPPH assays. RESULTS Beverages containing bilberry, blackcurrant, mango or rose hip significantly attenuated the early postprandial insulin response (0-90 min), but showed no effect on glucose response. Drinks with bilberry or rose hip reduced the insulin response from the very early phase (0-30 min), and had significantly lower insulin index compared with the control. The efficiency of the bilberry and rose hip to decrease early postprandial insulin responses correlated with higher phenolic contents. CONCLUSIONS Supplements with bilberry, blackcurrant, mango or rose hip in the tested probiotic and oatmeal enriched beverage attenuated early-phase insulin response, but had no effect on the postprandial glycemic response. The improved ability of bilberry and rose hip to lower the very early phase of insulin response seems to be due to a higher phenolic content. TRIAL REGISTRATION The study was retrospectively registered at ClinicalTrials.gov with number NCT03159065 .
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The effect of green tea extract supplementation on exercise-induced oxidative stress parameters in male sprinters.
Jówko, E, Długołęcka, B, Makaruk, B, Cieśliński, I
European journal of nutrition. 2015;54(5):783-91
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High intensity exercise generates reactive oxygen species (ROS), which help with muscle recovery. However, when produced in excess, ROSs cause oxidative stress and cellular damage. Antioxidants produced in the body or taken in through the diet are able to make ROSs inactive. This double blind, randomised controlled trial aimed to evaluate the effects of Green tea extract supplementation on oxidative stress in 16 male sprinters. The study found no significant difference between the group given the supplement and the placebo group in terms of muscle damage recovery and exercise performance. However, an increased levels of polyphenols were observed in the supplement group post-exercise in comparison to the placebo group.
Abstract
BACKGROUND Although research suggests that antioxidant supplementation can protect against exercise-induced muscle damage and oxidative stress, also delayed post-exercise muscle recovery and hindered adaptation to training were reported in the supplemented athletes. PURPOSE The purpose of the study was to evaluate the effects of green tea extract (GTE) supplementation on selected blood markers of oxidative stress and muscle damage in sprinters during preparatory phase of their training cycle. METHODS Sixteen sprinters participated in a double-blind, randomized, placebo (PL)-controlled crossover study, including two 4-week treatment periods with PL and GTE (980 mg polyphenols daily). The sprinters performed two repeated cycle sprint tests (RST; 4 × 15 s, with 1-min rest intervals), after PL and GTE supplementation. Blood was sampled before (at rest), 5 min after RST, and after the 24-h recovery. The activities of superoxide dismutase (SOD) and glutathione peroxidase were measured in erythrocytes, and total polyphenols, total antioxidant capacity (TAC), uric acid (UA), albumin (AL), malondialdehyde (MDA), and creatine kinase (CK) were determined in blood plasma. RESULTS Repeated cycle sprint test performed after PL induced an increase in MDA, TAC, and SOD. Moreover, an increase in UA, AL, and CK was observed after RST irrespective of experimental conditions (PL, GTE). Supplementation with GTE caused an increase in total polyphenols and TAC at rest, and a decrease in MDA and SOD after RST. No significant changes in sprint performance were noted after GTE, as compared to PL. CONCLUSIONS Supplementation with GTE prevents oxidative stress induced by RST in sprinters. Furthermore, GTE supplementation does not seem to hinder training adaptation in antioxidant enzyme system. On the other hand, neither prevention of exercise-induced muscle damage, nor an improvement in sprint performance is noted after GTE administration.