Publications by authors named "John C Mathers"

302 Publications

Effect of selenium supplementation on musculoskeletal health in older women: a randomised, double-blind, placebo-controlled trial.

Lancet Healthy Longev 2021 Apr;2(4):e212-e221

Mellanby Centre for Musculoskeletal Research, University of Sheffield, Northern General Hospital, Sheffield, UK.

Background: Observational and preclinical studies show associations between selenium status, bone health, and physical function. Most adults in Europe have serum selenium below the optimum range. We hypothesised that selenium supplementation could reduce pro-resorptive actions of reactive oxygen species on osteoclasts and improve physical function.

Methods: We completed a 6-month randomised, double-blind, placebo-controlled trial. We recruited postmenopausal women older than 55 years with osteopenia or osteoporosis at the Northern General Hospital, Sheffield, UK. Participants were randomly assigned 1:1:1 to receive selenite 200 μg, 50 μg, or placebo orally once per day. Medication was supplied to the site blinded and numbered by a block randomisation sequence with a block size of 18, and participants were allocated medication in numerical order. All participants and study team were masked to treatment allocation. The primary endpoint was urine N-terminal cross-linking telopeptide of type I collagen (NTx, expressed as ratio to creatinine) at 26 weeks. Analysis included all randomly assigned participants who completed follow-up. Groups were compared with analysis of covariance with Hochberg testing. Secondary endpoints were other biochemical markers of bone turnover, bone mineral density, short physical performance battery, and grip strength. Mechanistic endpoints were glutathione peroxidase, highly sensitive C-reactive protein, and interleukin-6. This trial is registered with EU clinical trials, EudraCT 2016-002964-15, and ClinicalTrials.gov, NCT02832648, and is complete.

Findings: 120 participants were recruited between Jan 23, 2017, and April 11, 2018, and randomly assigned to selenite 200 μg, 50 μg, or placebo (n=40 per group). 115 (96%) of 120 participants completed follow-up and were included in the primary analysis (200 μg [n=39], 50 μg [n=39], placebo [n=37]). Median follow-up was 25·0 weeks (IQR 24·7-26·0). In the 200 μg group, mean serum selenium increased from 78·8 (95% CI 73·5-84·2) to 105·7 μg/L (99·5-111·9). Urine NTx to creatinine ratio (nmol bone collagen equivalent:mmol creatinine) did not differ significantly between treatment groups at 26 weeks: 40·5 (95% CI 34·9-47·0) for placebo, 43·4 (37·4-50·5) for 50 μg, and 42·2 (37·5-47·6) for 200 μg. None of the secondary or mechanistic endpoint measurements differed between treatment groups at 26 weeks. Seven (6%) of 120 participants were withdrawn from treatment at week 13 due to abnormal thyroid-stimulating hormone concentrations (one in the 200 μg group, three in the 50 μg group, and three in the placebo group) and abnormal blood glucose (one in the 50 μg group). There were three serious adverse events: a non-ST elevation myocardial infarction at week 18 (in the 50 μg group), a diagnosis of bowel cancer after routine population screening at week 2 (in the placebo group), and a pulmonary embolus due to metastatic bowel cancer at week 4 (in the 200 μg group). All severe adverse events were judged by the principal investigator as unrelated to trial medication.

Interpretation: Selenium supplementation at these doses does not affect musculoskeletal health in postmenopausal women.

Funding: UK National Institute for Health Research Efficacy and Mechanism Evaluation programme.
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http://dx.doi.org/10.1016/S2666-7568(21)00051-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020713PMC
April 2021

Acceptability and Feasibility of a 13-Week Pilot Randomised Controlled Trial Testing the Effects of Incremental Doses of Beetroot Juice in Overweight and Obese Older Adults.

Nutrients 2021 Feb 26;13(3). Epub 2021 Feb 26.

School of Life Sciences, Queen's Medical Centre,The University of Nottingham Medical School, Nottingham NG7 2UH, UK.

Nitrate-rich food can increase nitric oxide production and improve vascular and brain functions. This study examines the feasibility of a randomised controlled trial (RCT) testing the effects of prolonged consumption of different doses of dietary nitrate (NO) in the form of beetroot juice (BJ) in overweight and obese older participants. A single-blind, four-arm parallel pilot RCT was conducted in 62 overweight and obese (30.4 ± 4 kg/m) older participants (mean ± standard deviation (SD), 66 ± 4 years). Participants were randomized to: (1) high-NO (HN: 2 × 70 mL BJ/day) (2) medium-NO (MN: 70 mL BJ/day), (3) low-NO (LN: 70 mL BJ on alternate days) or (4) Placebo (PL: 70 mL of NO-depleted BJ on alternate days), for 13 weeks. Compliance was checked by a daily log of consumed BJ, NO intake, and by measuring NO and NO concentrations in plasma, saliva, and urine samples. Fifty participants completed the study. Self-reported compliance to the interventions was >90%. There were significant positive linear relationships between NO dose and the increase in plasma and urinary NO concentration (R = 0.71, P < 0.001 and R = 0.46 P < 0.001, respectively), but relationships between NO dose and changes in salivary NO and NO were non-linear (R = 0.35, P = 0.002 and R = 0.23, P = 0.007, respectively). The results confirm the feasibility of prolonged BJ supplementation in older overweight and obese adults.
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http://dx.doi.org/10.3390/nu13030769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996834PMC
February 2021

Feasibility and acceptability of a multi-domain intervention to increase Mediterranean diet adherence and physical activity in older UK adults at risk of dementia: protocol for the MedEx-UK randomised controlled trial.

BMJ Open 2021 Feb 5;11(2):e042823. Epub 2021 Feb 5.

Department of Nutrition and Preventive Medicine, Norwich Medical School, University of East Anglia, Norwich, UK

Introduction: Dementia prevalence continues to increase, and effective interventions are needed to prevent, delay or slow its progression. Higher adherence to the Mediterranean diet (MedDiet) and increased physical activity (PA) have been proposed as strategies to facilitate healthy brain ageing and reduce dementia risk. However, to date, there have been no dementia prevention trials in the UK focussed on combined dietary and PA interventions. This study aims to: (1) assess feasibility and acceptability of a theory-underpinned digital and group-based intervention for dementia risk reduction in an 'at risk' UK cohort; (2) evaluate behaviour change responses to the intervention; and, (3) provide information on cognitive, neurological, vascular and physiological outcomes to inform the design of a follow-on, full-scale efficacy trial.

Methods: One hundred and eight participants aged 55 to 74 years with a QRISK2 score of ≥10% will be recruited to take part in this 24-week multi-site study. Participants will be randomised into three parallel arms: (1) Control; (2) MedDiet; and, (3) MedDiet+PA. The study will evaluate a personalised website, group session and food delivery intervention to increase MedDiet adherence and PA in older adults at risk of dementia. Diet and PA will be monitored prior to, during and following the intervention. Feasibility, acceptability and hypothesised mediators will be assessed in addition to measures of cognitive function, brain structure/perfusion (MRI), vascular function and metabolic markers (blood, urine and faecal) prior to, and following, the intervention.

Discussion: This trial will provide insights into the feasibility, acceptability and mechanism of effect of a multi-domain intervention focussed on the MedDiet alone and PA for dementia risk reduction in an 'at risk' UK cohort.

Ethics And Dissemination: The study has received NHS REC and HRA approval (18/NI/0191). Findings will be disseminated via conference presentations, public lectures, and peer-reviewed publications.

Trial Registration Details: ClinicalTrials.gov NCT03673722.
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http://dx.doi.org/10.1136/bmjopen-2020-042823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925921PMC
February 2021

Mediterranean diet and the hallmarks of ageing.

Eur J Clin Nutr 2021 Jan 29. Epub 2021 Jan 29.

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne,, NE2 4HH, UK.

Ageing is a multifactorial process associated with reduced function and increased risk of morbidity and mortality. Recently, nine cellular and molecular hallmarks of ageing have been identified, which characterise the ageing process, and collectively, may be key determinants of the ageing trajectory. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Healthier dietary patterns reduce the risk of age-related diseases and increase longevity and may influence positively one or more of these hallmarks. The Mediterranean dietary pattern (MedDiet) is a plant-based eating pattern that was typical of countries such as Greece, Spain, and Italy pre-globalisation of the food system and which is associated with better health during ageing. Here we review the potential effects of a MedDiet on each of the nine hallmarks of ageing, and provide evidence that the MedDiet as a whole, or individual elements of this dietary pattern, may influence each hallmark positively-effects which may contribute to the beneficial effects of this dietary pattern on age-related disease risk and longevity. We also highlight potential avenues for future research.
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http://dx.doi.org/10.1038/s41430-020-00841-xDOI Listing
January 2021

Associations of six adiposity-related markers with incidence and mortality from 24 cancers-findings from the UK Biobank prospective cohort study.

BMC Med 2021 Jan 11;19(1). Epub 2021 Jan 11.

Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 8RZ, UK.

Background: Adiposity is a strong risk factor for cancer incidence and mortality. However, most of the evidence available has focused on body mass index (BMI) as a marker of adiposity. There is limited evidence on relationships of cancer with other adiposity markers, and if these associations are linear or not. The aim of this study was to investigate the associations of six adiposity markers with incidence and mortality from 24 cancers by accounting for potential non-linear associations.

Methods: A total of 437,393 participants (53.8% women; mean age 56.3 years) from the UK Biobank prospective cohort study were included in this study. The median follow-up was 8.8 years (interquartile range 7.9 to 9.6) for mortality and 9.3 years (IQR 8.6 to 9.9) for cancer incidence. Adiposity-related exposures were BMI, body fat percentage, waist-hip ratio, waist-height ratio, and waist and hip circumference. Incidence and mortality of 24 cancers sites were the outcomes. Cox proportional hazard models were used with each of the exposure variables fitted separately on penalised cubic splines.

Results: During follow-up, 47,882 individuals developed cancer and 11,265 died due to cancer during the follow-up period. All adiposity markers had similar associations with overall cancer incidence. BMI was associated with a higher incidence of 10 cancers (stomach cardia (hazard ratio per 1 SD increment 1.35, (95% CI 1.23; 1.47)), gallbladder (1.33 (1.12; 1.58)), liver (1.27 (1.19; 1.36)), kidney (1.26 (1.20; 1.33)), pancreas (1.12 (1.06; 1.19)), bladder (1.09 (1.04; 1.14)), colorectal (1.10 (1.06; 1.13)), endometrial (1.73 (1.65; 1.82)), uterine (1.68 (1.60; 1.75)), and breast cancer (1.08 (1.05; 1.11))) and overall cancer (1.03 (1.02; 1.04)). All these associations were linear except for breast cancer in postmenopausal women. Similar results were observed when other markers of central and overall adiposity were used. For mortality, nine cancer sites were linearly associated with BMI and eight with waist circumference and body fat percentage.

Conclusion: Adiposity, regardless of the marker used, was associated with an increased risk in 10 cancer sites.
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http://dx.doi.org/10.1186/s12916-020-01848-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798245PMC
January 2021

Challenges Associated With the Design and Deployment of Food Intake Urine Biomarker Technology for Assessment of Habitual Diet in Free-Living Individuals and Populations-A Perspective.

Front Nutr 2020 25;7:602515. Epub 2020 Nov 25.

Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, United Kingdom.

Improvement of diet at the population level is a cornerstone of national and international strategies for reducing chronic disease burden. A critical challenge in generating robust data on habitual dietary intake is accurate exposure assessment. Self-reporting instruments (e.g., food frequency questionnaires, dietary recall) are subject to reporting bias and serving size perceptions, while weighed dietary assessments are unfeasible in large-scale studies. However, secondary metabolites derived from individual foods/food groups and present in urine provide an opportunity to develop potential biomarkers of food intake (BFIs). Habitual dietary intake assessment in population surveys using biomarkers presents several challenges, including the need to develop affordable biofluid collection methods, acceptable to participants that allow collection of informative samples. Monitoring diet comprehensively using biomarkers requires analytical methods to quantify the structurally diverse mixture of target biomarkers, at a range of concentrations within urine. The present article provides a perspective on the challenges associated with the development of urine biomarker technology for monitoring diet exposure in free-living individuals with a view to its future deployment in "real world" situations. An observational study ( = 95), as part of a national survey on eating habits, provided an opportunity to explore biomarker measurement in a free-living population. In a second food intervention study ( = 15), individuals consumed a wide range of foods as a series of menus designed specifically to achieve exposure reflecting a diversity of foods commonly consumed in the UK, emulating normal eating patterns. First Morning Void urines were shown to be suitable samples for biomarker measurement. Triple quadrupole mass spectrometry, coupled with liquid chromatography, was used to assess simultaneously the behavior of a panel of 54 potential BFIs. This panel of chemically diverse biomarkers, reporting intake of a wide range of commonly-consumed foods, can be extended successfully as new biomarker leads are discovered. Towards validation, we demonstrate excellent discrimination of eating patterns and quantitative relationships between biomarker concentrations in urine and the intake of several foods. In conclusion, we believe that the integration of information from BFI technology and dietary self-reporting tools will expedite research on the complex interactions between dietary choices and health.
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http://dx.doi.org/10.3389/fnut.2020.602515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745244PMC
November 2020

Does Personalized Nutrition Advice Improve Dietary Intake in Healthy Adults? A Systematic Review of Randomized Controlled Trials.

Adv Nutr 2020 Dec 12. Epub 2020 Dec 12.

Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia.

Personalized nutrition (PN) behavior-change interventions are being used increasingly in attempts to improve dietary intake; however, the impact of PN advice on improvements in dietary intake has not been reviewed systematically. The aim of this systematic review was to evaluate the effect of PN advice on changes in dietary intake compared with generalized advice in healthy adults. Three databases (EMBASE, PubMed, and CINAHL) were searched between 2009 and 2020 for randomized controlled trials (RCTs) that tested the effect of PN and tailored advice based on diet, phenotype, or genetic information. The Evidence Analysis Library Quality Criteria checklist was used to conduct a risk-of-bias assessment. Information on intervention design and changes in nutrients, foods, and dietary patterns was extracted from the 11 studies meeting the inclusion criteria. Studies were conducted in the United States, Canada, or Europe; reported outcomes on 57 to 1488 participants; and varied in follow-up duration from 1 to 12 mo. Five studies incorporated behavior-change techniques. The risk of bias for included studies was low. Overall, the available evidence suggests that dietary intake is improved to a greater extent in participants randomly assigned to receive PN advice compared with generalized dietary advice. Additional well-designed PN RCTs are needed that incorporate behavior-change techniques, a broader range of dietary outcomes, and comparisons between personalization based on dietary, biological, and/or lifestyle information.
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http://dx.doi.org/10.1093/advances/nmaa144DOI Listing
December 2020

Design and Characterisation of a Randomized Food Intervention That Mimics Exposure to a Typical UK Diet to Provide Urine Samples for Identification and Validation of Metabolite Biomarkers of Food Intake.

Front Nutr 2020 21;7:561010. Epub 2020 Oct 21.

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom.

Poor dietary choices are major risk factors for obesity and non-communicable diseases, which places an increasing burden on healthcare systems worldwide. To monitor the effectiveness of healthy eating guidelines and strategies, there is a need for objective measures of dietary intake in community settings. Metabolites derived from specific foods present in urine samples can provide objective biomarkers of food intake (BFIs). Whilst the majority of biomarker discovery/validation studies have investigated potential biomarkers for single foods only, this study considered the whole diet by using menus that delivered a wide range of foods in meals that emulated conventional UK eating patterns. Fifty-one healthy participants (range 19-77 years; 57% female) followed a uniquely designed, randomized controlled dietary intervention, and provided spot urine samples suitable for discovery of BFIs within a real-world context. Free-living participants prepared and consumed all foods and drinks in their own homes and were asked to follow the protocols for meal consumption and home urine sample collection. This study also assessed the robustness, and impact on data quality, of a minimally invasive urine collection protocol. Overall the study design was well-accepted by participants and concluded successfully without any drop outs. Compliance for urine collection, adherence to menu plans, and observance of recommended meal timings, was shown to be very high. Metabolome analysis using mass spectrometry coupled with data mining demonstrated that the study protocol was well-suited for BFI discovery and validation. Novel, putative biomarkers for an extended range of foods were identified including legumes, curry, strongly-heated products, and artificially sweetened, low calorie beverages. In conclusion, aspects of this study design would help to overcome several current challenges in the development of BFI technology. One specific attribute was the examination of BFI generalizability across related food groups and across different preparations and cooking methods of foods. Furthermore, the collection of urine samples at multiple time points helped to determine which spot sample was optimal for identification and validation of BFIs in free-living individuals. A further valuable design feature centered on the comprehensiveness of the menu design which allowed the testing of biomarker specificity within a biobank of urine samples.
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http://dx.doi.org/10.3389/fnut.2020.561010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609501PMC
October 2020

Diet-Associated Inflammation Modulates Inflammation and WNT Signaling in the Rectal Mucosa, and the Response to Supplementation with Dietary Fiber.

Cancer Prev Res (Phila) 2020 Oct 28. Epub 2020 Oct 28.

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.

Inflammation drives colorectal cancer development, and colorectal cancer risk is influenced by dietary factors, including dietary fiber. Hyperactive WNT signaling occurs in colorectal cancer and may regulate inflammation. This study investigated (i) relationships between the inflammatory potential of diet, assessed using the Energy-adjusted Dietary Inflammatory Index (E-DII), and markers of WNT signaling, and (ii) whether DII status modulated the response to supplementation with two types of dietary fiber. Seventy-five healthy participants were supplemented with resistant starch and/or polydextrose (PD) or placebo for 50 days. Rectal biopsies were collected before and after intervention and used to assess WNT pathway gene expression and crypt cell proliferation. E-DII scores were calculated from food frequency questionnaire data. High-sensitivity C-reactive protein (hsCRP) and fecal calprotectin concentrations were quantified. hsCRP concentration was significantly greater in participants with higher E-DII scores [least square means (LSM) 4.7 vs. 2.4 mg/L, = 0.03]. Baseline E-DII score correlated with ( = 0.503, = 0.003) and ( = 0.472, = 0.006) expression, after adjusting for age, gender, body mass index, endoscopy procedure, and smoking status. expression was more than 2-fold greater in individuals with higher E-DII scores (LSM 0.131 vs. 0.059, = 0.002). Baseline E-DII modulated the effects of PD supplementation on expression ( = 0.04). More proinflammatory diets were associated with altered WNT signaling and appeared to modulate the effects of PD supplementation on expression of . This is the first study to investigate relationships between the E-DII and molecular markers of WNT signaling in rectal tissue of healthy individuals. PREVENTION RELEVANCE: Our finding that more inflammatory dietary components may impact large bowel health through effects on a well-recognised pathway involved in cancer development will strengthen the evidence base for dietary advice to help prevent bowel cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0335DOI Listing
October 2020

From lifespan to healthspan: the role of nutrition in healthy ageing.

J Nutr Sci 2020 24;9:e33. Epub 2020 Aug 24.

International and Scientific Affairs, Council for Responsible Nutrition-International, Washington, DC 20036, USA.

Across the globe, there has been a marked increase in longevity, but significant inequalities remain. These are exacerbated by inadequate access to proper nutrition and health care services and to reliable information to make the decisions related to nutrition and health care. Many in economically developing as well as developed societies are plagued with the double-burden of energy excess and undernutrition. This has resulted in mental and physical deterioration, increased non-communicable disease rates, lost productivity, increased medical costs and reduced quality of life. While adequate nutrition is fundamental to good health at all stages of the life course, the impact of diet on prolonging good quality of life during ageing remains unclear. For progress to continue, there is need for new and/or innovative approaches to promoting health as individuals age, as well as qualitative and quantitative biomarkers and other accepted tools that can measure improvements in physiological integrity throughout life. A framework for progress has been proposed by the World Health Organization in their Global Strategy and Action Plan on Ageing and Health. Here, we focused on the impact of nutrition within this framework, which takes a broad, person-centred emphasis on healthy ageing, stressing the need to better understand each individual's intrinsic capacity, their functional abilities at various life stages, and the impact of their mental, and physical health, as well as the environments they inhabit.
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http://dx.doi.org/10.1017/jns.2020.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550962PMC
August 2020

Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis.

Nat Cancer 2020 Oct 21;1(10):976-989. Epub 2020 Sep 21.

Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.
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http://dx.doi.org/10.1038/s43018-020-00112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116185PMC
October 2020

Effects of a Mediterranean diet on blood pressure: a systematic review and meta-analysis of randomized controlled trials and observational studies.

J Hypertens 2021 Apr;39(4):729-739

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne.

Objective: To conduct a systematic review and meta-analysis investigating effects of MedDiet on blood pressure in randomized controlled trials (RCTs) and associations of MedDiet with risk of hypertension in observational studies.

Methods: PubMed, The Cochrane Library and EBSCOhost were searched from inception until January 2020 for studies that met the following criteria: participants aged at least 18 years, RCTs investigating effects of a MedDiet versus control on BP, observational studies exploring associations between MedDiet adherence and risk of hypertension. Random-effects meta-analyses were conducted. Meta-regression and subgroup analyses were performed for RCTs to identify potential effect moderators.

Results: Nineteen RCTs reporting data on 4137 participants and 16 observational studies reporting data on 59 001 participants were included in the meta-analysis. MedDiet interventions reduced SBP and DBP by a mean -1.4 mmHg (95% CI: -2.40 to -0.39 mmHg, P = 0.007, I2 = 53.5%, Q = 44.7, τ2 = 1.65, df = 19) and -1.5 mmHg (95% CI: -2.74 to -0.32 mmHg, P = 0.013, I2 = 71.5%, Q = 51.6, τ2 = 4.72, df = 19) versus control, respectively. Meta-regression revealed that longer study duration and higher baseline SBP was associated with a greater decrease in BP, in response to a MedDiet (P < 0.05). In observational studies, odds of developing hypertension were 13% lower with higher versus lower MedDiet adherence (95% CI: 0.78--0.98, P = 0.017, I2 = 69.6%, Q = 41.1, τ2 = 0.03, df = 17).

Conclusion: Data suggest that MedDiet is an effective dietary strategy to aid BP control, which may contribute towards the lower risk of CVD reported with this dietary pattern. This study was registered with PROSPERO: CRD42019125073.
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http://dx.doi.org/10.1097/HJH.0000000000002667DOI Listing
April 2021

Calystegines are Potential Urine Biomarkers for Dietary Exposure to Potato Products.

Mol Nutr Food Res 2020 10 29;64(20):e2000515. Epub 2020 Sep 29.

Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, SY23 3DA, UK.

Scope: Metabolites derived from specific foods present in urine samples can provide objective biomarkers of food intake (BFIs). This study investigated the possibility that calystegines (a class of iminosugars) may provide BIFs for potato (Solanum tuberosum L.) product exposure.

Methods And Results: Calystegine content is examined in published data covering a wide range of potato cultivars. Rapid methods are developed for the quantification of calystegines in cooked potato products and human urine using triple quadrupole mass spectrometry. The potential of calystegines as BFIs for potato consumption is assessed in a controlled food intervention study in the United Kingdom and validated in an epidemiological study in Portugal. Calystegine concentrations are reproducibly above the quantification limit in first morning void urines the day after potato consumption, showing a good dose-response relationship, particularly for calystegine A . The design of the controlled intervention mimicks exposure to a typical UK diet and showed that neither differences in preparation/cooking method or influence of other foods in the diet has significant impact on biomarker performance. Calystegine biomarkers also perform well in the independent validation study.

Conclusion: It is concluded that calystegines have many of the characteristics needed to be considered as specific BFIs for potato product intake.
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http://dx.doi.org/10.1002/mnfr.202000515DOI Listing
October 2020

The Association between 25-Hydroxyvitamin D Concentration and Disability Trajectories in Very Old Adults: The Newcastle 85+ Study.

Nutrients 2020 Sep 9;12(9). Epub 2020 Sep 9.

Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

: Low vitamin D status is common in very old adults which may have adverse consequences for muscle function, a major predictor of disability. : To explore the association between 25-hydroxyvitamin D [25(OH)D] concentrations and disability trajectories in very old adults and to determine whether there is an 'adequate' 25(OH)D concentration which might protect against a faster disability trajectory. : A total of 775 participants from the Newcastle 85+ Study for who 25(OH)D concentration at baseline was available. Serum 25(OH)D concentrations of <25 nmol/L, 25-50 nmol/L and >50 nmol/L were used as cut-offs to define low, moderate and high vitamin D status, respectively. Disability was defined as difficulty in performing 17 activities of daily living, at baseline, after 18, 36 and 60 months. : A three-trajectory model was derived (low-to-mild, mild-to-moderate and moderate-to-severe). In partially adjusted models, participants with 25(OH)D concentrations <25 nmol/L were more likely to have moderate and severe disability trajectories, even after adjusting for sex, living in an institution, season, cognitive status, BMI and vitamin D supplement use. However, this association disappeared after further adjustment for physical activity. : Vitamin D status does not appear to influence the trajectories of disability in very old adults.
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http://dx.doi.org/10.3390/nu12092742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551468PMC
September 2020

Dietary Selenium Intakes and Musculoskeletal Function in Very Old Adults: Analysis of the Newcastle 85+ Study.

Nutrients 2020 Jul 12;12(7). Epub 2020 Jul 12.

The MRC-Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Newcastle upon Tyne NE2 4HH, UK.

: Selenium is a trace element essential for health. Severe selenium deficiencies are associated with poor musculoskeletal (MSK) function. However, the effects of moderate deficiency on MSK function, especially in older adults, is unclear. : To determine the associations between selenium intake and MSK function in very old adults. : Selenium intake at baseline and, hand-grip strength (HGS) and timed-up-and-go (TUG) at four phases over 5 years, were available in 791 participants in the Newcastle 85+ Study, a community-based, longitudinal cohort of ≥85 year old individuals. We investigated relationships between selenium intake and HGS and TUG in cross-sectional analyses at baseline using multivariate analyses and, prospectively using linear mixed models to explore HGS and TUG changes over 5 years in association with baseline selenium intake. : At baseline, 53% of participants had selenium intakes that were classified as low. These individuals had 2.80 kg lower HGS and were 2.30 s slower performing the TUG, cross-sectionally. In multivariate, baseline analyses, selenium intake had no significant impact on HGS or TUG. Selenium intake had no significant effect on MSK function, prospectively. : Low selenium intake is common among very old adults and, in cross-sectional analyses, is associated with poorer MSK function.
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http://dx.doi.org/10.3390/nu12072068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400825PMC
July 2020

Paving the way to better population health through personalised nutrition.

Authors:
John C Mathers

EFSA J 2019 Jul 8;17(Suppl 1):e170713. Epub 2019 Jul 8.

Human Nutrition Research Centre Institute of Cellular Medicine and Newcastle University Institute for Ageing Newcastle University Newcastle on Tyne NE2 4HH UK.

As each individual person differs from the next in multiple ways, it is a beguiling idea that our individual nutritional needs also differ. In support of this idea, findings from nutritional intervention studies provide ample evidence of considerable interindividual variation in response to the same dietary exposure. We have a limited understanding of the mechanisms responsible for this variation but, following sequencing of the human genome, the role of genes in explaining interindividual differences has been centre stage. In addition, evidence of diet-gene interactions that influence phenotype, including health, emphasises the importance of both nature and nurture. Eating patterns are major determinants of health, so public health advice to reduce the risk of common complex diseases focuses on diet. However, most dietary interventions are relatively ineffective and personalised approaches that tailor the intervention to the individual may be more acceptable and more effective. That idea was tested in the Food4Me study in which adults from seven European countries were randomised to one of four treatment groups in an internet-delivered dietary intervention. Compared with the Control (standardised healthy eating advice), those people randomised to a personalised nutrition intervention had bigger, sustained changes, in eating behaviour after 6 months. However, including more complex phenotypic and/or genotypic information in developing the personalised nutrition advice had no added benefit. Research in personalised nutrition is broadening its scope to consider effects mediated by the gut microbiome as well as multiple aspects of genotype and phenotype. Such research has the potential to explain interindividual differences in the response to specific dietary factors and may provide a scientific basis for more refined approaches to personalised nutrition. However, if this research is to make a significant contribution to improving public health, it will need to address the psychological, social, economic and cultural factors that influence eating patterns to ensure that advice is converted into action and that improved dietary habits are sustained in perpetuity.
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http://dx.doi.org/10.2903/j.efsa.2019.e170713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015519PMC
July 2019

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.

Lancet 2020 06;395(10240):1855-1863

Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.

Background: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population.

Methods: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990.

Findings: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43-0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39-0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34-0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31-0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43-0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously.

Interpretation: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results.

Funding: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.
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http://dx.doi.org/10.1016/S0140-6736(20)30366-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294238PMC
June 2020

DNA methylation patterns of LINE-1 and Alu for pre-symptomatic dementia in type 2 diabetes.

PLoS One 2020 11;15(6):e0234578. Epub 2020 Jun 11.

Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.

The identification of early markers of dementia is important for higher-risk populations such as those with type 2 diabetes (T2D). Retrotransposons, including long interspersed nuclear element 1 (LINE-1) and Alu, comprise ~40% of the human genome. Although dysregulation of these retrotransposons can induce aberrant gene regulation and genomic instability, their role in the development of pre-symptomatic dementia (PSD) among T2D patients is unknown. Here, we examined locus-specific changes in LINE-1 and Alu methylation in PSD and the potential to offset these changes via supplementation with folate and vitamin B12. We interrogated DNA methylation patterns corresponding to 22,352 probes for LINE-1 and Alu elements using publicly-available Illumina Infinium 450K methylation datasets from i) an 18-month prospective study in 28 T2D patients (GSE62003) and ii) an intervention study in which 44 individuals were supplemented with folic acid (400 μg/day) and vitamin B12 (500 μg/day) over two years (GSE74548). We identified 714 differentially methylated positions (DMP) mapping to retrotransposons in T2D patients who developed PSD in comparison to those who did not (PFDR < 0.05), comprised of 2.4% (228 probes) of all LINE-1 probes and 3.8% (486 probes) of all Alu probes. These loci were enriched in genes with functions related to Alzheimer's disease and cognitive decline, including GNB5, GNG7 and PKN3 (p < 0.05). In older individuals supplemented with folate/vitamin B12, 85 (11.9%) PSD retrotransposon loci showed significant changes in methylation (p < 0.05): participants with the MTHFR CC genotype predominantly showed hypermethylation at these loci, while hypomethylation was observed more frequently in those with the TT genotype. In T2D patients, LINE-1 and Alu elements are differentially methylated in PSD in a locus-specific manner and may offer clinical utility in monitoring risk of dementia. Further work is required to examine the potential for dietary supplementation in lowering the risk of PSD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234578PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289438PMC
August 2020

Developing community-based urine sampling methods to deploy biomarker technology for the assessment of dietary exposure.

Public Health Nutr 2020 12 11;23(17):3081-3092. Epub 2020 Jun 11.

Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, AberystwythSY23 3DA, UK.

Objective: Obtaining objective, dietary exposure information from individuals is challenging because of the complexity of food consumption patterns and the limitations of self-reporting tools (e.g., FFQ and diet diaries). This hinders research efforts to associate intakes of specific foods or eating patterns with population health outcomes.

Design: Dietary exposure can be assessed by the measurement of food-derived chemicals in urine samples. We aimed to develop methodologies for urine collection that minimised impact on the day-to-day activities of participants but also yielded samples that were data-rich in terms of targeted biomarker measurements.

Setting: Urine collection methodologies were developed within home settings.

Participants: Different cohorts of free-living volunteers.

Results: Home collection of urine samples using vacuum transfer technology was deemed highly acceptable by volunteers. Statistical analysis of both metabolome and selected dietary exposure biomarkers in spot urine collected and stored using this method showed that they were compositionally similar to urine collected using a standard method with immediate sample freezing. Even without chemical preservatives, samples can be stored under different temperature regimes without any significant impact on the overall urine composition or concentration of forty-six exemplar dietary exposure biomarkers. Importantly, the samples could be posted directly to analytical facilities, without the need for refrigerated transport and involvement of clinical professionals.

Conclusions: This urine sampling methodology appears to be suitable for routine use and may provide a scalable, cost-effective means to collect urine samples and to assess diet in epidemiological studies.
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http://dx.doi.org/10.1017/S136898002000097XDOI Listing
December 2020

Protocol and recruitment results from a 13-week randomized controlled trial comparing the effects of different doses of nitrate-rich beetroot juice on cognition, cerebral blood flow and peripheral vascular function in overweight and obese older people.

Contemp Clin Trials Commun 2020 Jun 25;18:100571. Epub 2020 Apr 25.

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.

Background: Nitrate-rich food can increase NO production and may induce positive effects on brain function. This study examined the feasibility of a randomized clinical trial (RCT) testing the effects of prolonged consumption of incremental doses of dietary nitrate (NO) in overweight and obese older participants. Secondary aims tested dose-dependent changes in cognitive, vascular and pulmonary functions and cerebral blood flow (CBF).

Methods: This was a single blind, four-arm parallel RCT conducted in 60 overweight and obese older participants. Eligible participants were randomized to:1) high NO (140 ml of beetroot juice (BJ) per day, ~800 mg of NO/day), 2) moderate NO (70 ml of BJ per day, ~400 mg of NO/day), 3) low NO (70 ml on alternate days, ~400 mg of NO) or 4) NO depleted (70 ml on alternate days, ~0.001 mg of NO). Measurements of cognitive, vascular and pulmonary functions and CBF were conducted at baseline and 13-weeks NO intake was assessed by six 24-h recalls, and by measuring NO intake biomarkers. Feasibility was assessed by obtaining qualitative feedback and evaluating trial recruitment, retention, compliance with study visits and measurement protocols.

Results: Participant recruitment started in July 2018 and ended in April 2019. Of all the recruitment strategies that were used, advertisement of the study via Facebook generated the highest response rate. Sixty-two participants consented and were enrolled. Overall, characteristics of included participants matched our recruitment criteria.

Conclusion: The findings from this study provide evidence of the acceptability and feasibility of an intervention investigating the effects of incremental doses of high-nitrate BJ over a prolonged period.

Trial Registration: The intervention study was registered with clinical trial ISRCTN registry (ISRCTN14746723) on 27 December 2018.
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http://dx.doi.org/10.1016/j.conctc.2020.100571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212182PMC
June 2020

New developments in the .

Authors:
John C Mathers

Br J Nutr 2020 08 13;124(4):361-362. Epub 2020 May 13.

Editor-in-Chief, Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1017/S0007114520001452DOI Listing
August 2020

Resistant starch supplementation increases crypt cell proliferative state in the rectal mucosa of older healthy participants.

Br J Nutr 2020 08 13;124(4):374-385. Epub 2020 Apr 13.

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon TyneNE2 4HH, UK.

There is strong evidence that foods containing dietary fibre protect against colorectal cancer, resulting at least in part from its anti-proliferative properties. This study aimed to investigate the effects of supplementation with two non-digestible carbohydrates, resistant starch (RS) and polydextrose (PD), on crypt cell proliferative state (CCPS) in the macroscopically normal rectal mucosa of healthy individuals. We also investigated relationships between expression of regulators of apoptosis and of the cell cycle on markers of CCPS. Seventy-five healthy participants were supplemented with RS and/or PD or placebo for 50 d in a 2 × 2 factorial design in a randomised, double-blind, placebo-controlled trial (the Dietary Intervention, Stem cells and Colorectal Cancer (DISC) Study). CCPS was assessed, and the expression of regulators of the cell cycle and of apoptosis was measured by quantitative PCR in rectal mucosal biopsies. SCFA concentrations were quantified in faecal samples collected pre- and post-intervention. Supplementation with RS increased the total number of mitotic cells within the crypt by 60 % (P = 0·001) compared with placebo. This effect was limited to older participants (aged ≥50 years). No other differences were observed for the treatments with PD or RS as compared with their respective controls. PD did not influence any of the measured variables. RS, however, increased cell proliferation in the crypts of the macroscopically-normal rectum of older adults. Our findings suggest that the effects of RS on CCPS are not only dose, type of RS and health status-specific but are also influenced by age.
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http://dx.doi.org/10.1017/S0007114520001312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369377PMC
August 2020

Characteristics of participants who benefit most from personalised nutrition: findings from the pan-European Food4Me randomised controlled trial.

Br J Nutr 2020 Jun 27;123(12):1396-1405. Epub 2020 Feb 27.

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon TyneNE2 4HH, UK.

Little is known about who would benefit from Internet-based personalised nutrition (PN) interventions. This study aimed to evaluate the characteristics of participants who achieved greatest improvements (i.e. benefit) in diet, adiposity and biomarkers following an Internet-based PN intervention. Adults (n 1607) from seven European countries were recruited into a 6-month, randomised controlled trial (Food4Me) and randomised to receive conventional dietary advice (control) or PN advice. Information on dietary intake, adiposity, physical activity (PA), blood biomarkers and participant characteristics was collected at baseline and month 6. Benefit from the intervention was defined as ≥5 % change in the primary outcome (Healthy Eating Index) and secondary outcomes (waist circumference and BMI, PA, sedentary time and plasma concentrations of cholesterol, carotenoids and omega-3 index) at month 6. For our primary outcome, benefit from the intervention was greater in older participants, women and participants with lower HEI scores at baseline. Benefit was greater for individuals reporting greater self-efficacy for 'sticking to healthful foods' and who 'felt weird if [they] didn't eat healthily'. Participants benefited more if they reported wanting to improve their health and well-being. The characteristics of individuals benefiting did not differ by other demographic, health-related, anthropometric or genotypic characteristics. Findings were similar for secondary outcomes. These findings have implications for the design of more effective future PN intervention studies and for tailored nutritional advice in public health and clinical settings.
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http://dx.doi.org/10.1017/S0007114520000653DOI Listing
June 2020

Associations of fat and carbohydrate intake with cardiovascular disease and mortality: prospective cohort study of UK Biobank participants.

BMJ 2020 03 18;368:m688. Epub 2020 Mar 18.

Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK

Objective: To investigate the association of macronutrient intake with all cause mortality and cardiovascular disease (CVD), and the implications for dietary advice.

Design: Prospective population based study.

Setting: UK Biobank.

Participants: 195 658 of the 502 536 participants in UK Biobank completed at least one dietary questionnaire and were included in the analyses. Diet was assessed using Oxford WebQ, a web based 24 hour recall questionnaire, and nutrient intakes were estimated using standard methodology. Cox proportional models with penalised cubic splines were used to study non-linear associations.

Main Outcome Measures: All cause mortality and incidence of CVD.

Results: 4780 (2.4%) participants died over a mean 10.6 (range 9.4-13.9) years of follow-up, and 948 (0.5%) and 9776 (5.0%) experienced fatal and non-fatal CVD events, respectively, over a mean 9.7 (range 8.5-13.0) years of follow-up. Non-linear associations were found for many macronutrients. Carbohydrate intake showed a non-linear association with mortality; no association at 20-50% of total energy intake but a positive association at 50-70% of energy intake (3.14 2.75 per 1000 person years, average hazard ratio 1.14, 95% confidence interval 1.03 to 1.28 (60-70% 50% of energy)). A similar pattern was observed for sugar but not for starch or fibre. A higher intake of monounsaturated fat (2.94 3.50 per 1000 person years, average hazard ratio 0.58, 0.51 to 0.66 (20-25% 5% of energy)) and lower intake of polyunsaturated fat (2.66 3.04 per 1000 person years, 0.78, 0.75 to 0.81 (5-7% 12% of energy)) and saturated fat (2.66 3.59 per 1000 person years, 0.67, 0.62 to 0.73 (5-10% 20% of energy)) were associated with a lower risk of mortality. A dietary risk matrix was developed to illustrate how dietary advice can be given based on current intake.

Conclusion: Many associations between macronutrient intake and health outcomes are non-linear. Thus dietary advice could be tailored to current intake. Dietary guidelines on macronutrients (eg, carbohydrate) should also take account of differential associations of its components (eg, sugar and starch).
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http://dx.doi.org/10.1136/bmj.m688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190059PMC
March 2020

Platelet mitochondrial DNA methylation predicts future cardiovascular outcome in adults with overweight and obesity.

Clin Epigenetics 2020 02 17;12(1):29. Epub 2020 Feb 17.

William Leech Building, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Background: The association between obesity and cardiovascular disease (CVD) is proven, but why some adults with obesity develop CVD while others remain disease-free is poorly understood. Here, we investigated whether mitochondrial DNA (mtDNA) methylation in platelets is altered prior to CVD development in a population of adults with overweight and obesity.

Methods: We devised a nested case-control study of 200 adults with overweight or obesity who were CVD-free at baseline, of whom 84 developed CVD within 5 years, while 116 remained CVD-free. Platelet mtDNA was isolated from plasma samples at baseline, and mtDNA methylation was quantified in mitochondrially encoded cytochrome-C-oxidase I (MT-CO1; nt6797 and nt6807), II (MT-CO2; nt8113 and nt8117), and III (MT-CO3; nt9444 and nt9449); tRNA leucine 1 (MT-TL1; nt3247 and nt3254); D-loop (nt16383); tRNA phenylalanine (MT-TF; nt624); and light-strand-origin-of-replication (MT-OLR; nt5737, nt5740, and nt5743) by bisulfite-pyrosequencing. Logistic regression was used to estimate the contribution of mtDNA methylation to future CVD risk. ROC curve analysis was used to identify the optimal mtDNA methylation threshold for future CVD risk prediction. A model was generated incorporating methylation at three loci (score 0, 1, or 2 according to 0, 1, or 2-3 hypermethylated loci, respectively), adjusted for potential confounders, such as diastolic and systolic blood pressure, fasting blood glucose, and cholesterol ratio. mtDNA methylation at MT-CO1 nt6807 (OR = 1.08, 95% CI 1.02-1.16; P = 0.014), MT-CO3 nt9444 (OR = 1.22, 95% CI 1.02-1.46, P = 0.042), and MT-TL1 nt3254 (OR = 1.30, 95% CI 1.05-1.61, P = 0.008) was higher at baseline in those who developed CVD by follow-up, compared with those who remained CVD-free. Combined use of the three loci significantly enhanced risk prediction, with hazard ratios of 1.38 (95% CI 0.68-2.78) and 2.68 (95% CI 1.41-5.08) for individuals with score 1 or 2, respectively (P = 0.003). Methylation at these sites was independent of conventional CVD risk factors, including inflammation markers, fasting blood glucose concentration, and blood pressure.

Conclusions: Methylations of MT-CO1, MT-CO3, and MT-TL1 are, together, strong predictors of future CVD incidence. Since methylation of these mtDNA domains was independent of conventional CVD risk factors, these markers may represent a novel intrinsic predictor of CVD risk in adults with overweight and obesity.
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http://dx.doi.org/10.1186/s13148-020-00825-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026975PMC
February 2020

Mediterranean Diet Increases Endothelial Function in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

J Nutr 2020 05;150(5):1151-1159

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, United Kingdom.

Background: The endothelium plays a key role in the maintenance of vascular health and represents a potential physiological target for dietary and other lifestyle interventions designed to reduce the risk of cardiovascular diseases (CVD) including stroke or coronary heart disease.

Objective: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the effects of the Mediterranean dietary pattern (MedDiet) on endothelial function.

Methods: Medline, Embase, and Scopus databases were searched from inception until January 2019 for studies that met the following criteria: 1) RCTs including adult participants, 2) interventions promoting the MedDiet, 3) inclusion of a control group, and 4) measurements of endothelial function. A random-effects meta-analysis was conducted. Metaregression and subgroup analyses were performed to identify whether effects were modified by health status (i.e., healthy participants versus participants with existing comorbidities), type of intervention (i.e., MedDiet alone or with a cointervention), study duration, study design (i.e., parallel or crossover), BMI, and age of participants.

Results: Fourteen articles reporting data for 1930 participants were included in the meta-analysis. Study duration ranged from 4 wk to 2.3 y. We observed a beneficial effect of the MedDiet on endothelial function [standardized mean difference (SMD): 0.35; 95% CI: 0.17, 0.53; P <0.001; I2 = 73.68%]. MedDiet interventions improved flow-mediated dilation (FMD)-the reference method for noninvasive, clinical measurement of endothelial function-by 1.66% (absolute change; 95% CI: 1.15, 2.17; P <0.001; I2 = 0%). Effects of the MedDiet on endothelial function were not modified by health status, type of intervention, study duration, study design, BMI, or age of participants (P >0.05).

Conclusions: MedDiet interventions improve endothelial function in adults, suggesting that the protective effects of the MedDiet are evident at early stages of the atherosclerotic process with important implications for the early prevention of CVD. This study has the PROSPERO registration number: CRD42018106188.
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http://dx.doi.org/10.1093/jn/nxaa002DOI Listing
May 2020

Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss.

Cell Metab 2020 02 19;31(2):233-249.e4. Epub 2019 Dec 19.

Magnetic Resonance Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. Electronic address:

The role of hepatic lipoprotein metabolism in diet-induced remission of type 2 diabetes is currently unclear. Here, we determined the contributions of hepatic VLDL1-triglyceride production rate and VLDL1-palmitic acid content to changes in intra-pancreatic fat and return of first phase insulin response in a subgroup of the Diabetes Remission Clinical Trial. Liver fat, VLDL1-triglyceride production, and intra-pancreatic fat decreased after weight loss and remained normalized after 24 months of remission. First-phase insulin response remained increased only in those maintaining diabetes remission. Compared with those in remission at 24 months, individuals who relapsed after initial remission had a greater rise in the content of VLDL1-triglyceride and VLDL1-palmitic acid, re-accumulated intra-pancreatic fat, and lost first-phase response by 24 months. Thus, we observed temporal relationships between VLDL1-triglyceride production, hepatic palmitic acid flux, intra-pancreatic fat, and β-cell function. Weight-related disordered fat metabolism appears to drive development and reversal of type 2 diabetes.
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http://dx.doi.org/10.1016/j.cmet.2019.11.018DOI Listing
February 2020

Effects of bariatric surgery on DNA methylation in adults: a systematic review and meta-analysis.

Surg Obes Relat Dis 2020 Jan 11;16(1):128-136. Epub 2019 Oct 11.

Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Background: DNA methylation is an epigenetic mechanism through which environmental factors, including obesity, influence health. Obesity is a major modifiable risk factor for many common diseases, including cardiovascular diseases and cancer. Obesity-induced metabolic stress and inflammation are key mechanisms that affect disease risk and that may result from changes in methylation of metabolic and inflammatory genes.

Objectives: This review aims to report the effects of weight loss induced by bariatric surgery (BS) on DNA methylation in adults with obesity focusing on changes in metabolic and inflammatory genes.

Methods: A systematic review was performed using MEDLINE, EMBASE, and Scopus, to identify studies in adult humans that reported DNA methylation after BS.

Results: Of 15,996 screened titles, 15 intervention studies were identified, all of which reported significantly lower body mass index postsurgery. DNA methylation was assessed in 5 different tissues (blood = 7 studies, adipose tissues = 4, skeletal muscle = 2, liver, and spermatozoa). Twelve studies reported significant changes in DNA methylation after BS. Meta-analysis showed that BS increased methylation of PDK4 loci in skeletal muscle and blood in 2 studies, while the effects of BS on IL6 methylation levels in blood were inconsistent. BS had no overall effect on LINE1 or PPARGC1 methylation.

Conclusion: The current evidence supports the reversibility of DNA methylation at specific loci in response to BS-induced weight loss. These changes are consistent with improved metabolic and inflammatory profiles of patients after BS. However, the evidence regarding the effects of BS on DNA methylation in humans is limited and inconsistent, which makes it difficult to combine and compare data across studies.
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http://dx.doi.org/10.1016/j.soard.2019.09.075DOI Listing
January 2020

Knowledge and beliefs about dietary inorganic nitrate among UK-based nutrition professionals: Development and application of the KINDS online questionnaire

BMJ Open 2019 10 31;9(10):e030719. Epub 2019 Oct 31.

Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

Objectives: To examine knowledge and beliefs about the biological roles of dietary inorganic nitrate in UK-based nutrition professionals, and to explore potential differences by participants' education level.

Setting: An online questionnaire was administered to UK-based nutrition professionals, exploring knowledge and/or beliefs across five areas: (1) health and performance effects of nitrate; (2) current and recommended intake values for nitrate; (3) dietary sources of nitrate; (4) methods of evaluating nitrate intake and (5) nitrate metabolism.

Participants: One hundred and twenty-five nutrition professionals.

Primary Outcome: Knowledge and beliefs about inorganic nitrate.

Results: Most nutrition professionals taking part in the survey had previously heard of inorganic nitrate (71%) and perceived it to be primarily beneficial (51%). The majority believed that nitrate consumption can improve sports performance (59%) and reduce blood pressure (54%), but were unsure about effects on cognitive function (71%), kidney function (80%) and cancer risk (70%). Knowledge of dietary sources of nitrate and factors affecting its content in food were generally good (41%-79% of participants providing correct answers). However, most participants were unsure of the average population intake (65%) and the acceptable daily intake (64%) of nitrate. Most participants (65%) recognised at least one compound (ie, nitric oxide or nitrosamines) that is derived from dietary nitrate in the body. Knowledge of nitrate, quantified by a 23-point index created by summing correct responses, was greater in individuals with a PhD (p=0.01; median (IQR)=13 (9-17)) and tended to be better in respondents with a masters degree (p=0.054; 13 (8-15)) compared with undergraduate-level qualifications (10 (2-14)).

Conclusions: UK-based nutrition professionals demonstrated mixed knowledge about the physiology of dietary nitrate, which was better in participants with higher education. More efficient dissemination of current knowledge about inorganic nitrate and its effects on health to nutrition professionals will support them to make more informed recommendations about consumption of this compound.
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http://dx.doi.org/10.1136/bmjopen-2019-030719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830619PMC
October 2019