Alcohol Consumption and Measures of Sarcopenic Muscle Risk: Cross-Sectional and Prospective Associations Within the UK Biobank Study.

Alcohol intake is a major modifiable risk factor for many diseases. Alcohol can also damage skeletal muscle health during ageing which in turn increases risk of sarcopenia, frailty and falls but this relationship is understudied. The aim of this study was to model the relationship between a full range of alcohol consumption and components of sarcopenic risk, skeletal muscle mass and function, in middle-aged and younger older-aged men and women. A cross-sectional analyses was undertaken of 196,561 white participants from the UK Biobank with longitudinal analysis also in 12,298 of these participants, with outcome measures for the latter repeated after around four years. For the cross-sectional analysis fractional polynomial curves were fitted in models of measures of skeletal muscle mass, appendicular lean mass/body mass index (ALM/BMI), fat-free mass as a percentage of body weight (FFM%) and grip strength, all predicted from alcohol consumption with models fitted for men and women separately. Alcohol consumption at baseline was based on the mean of up to five dietary recalls, typically over 16 months. Linear regression was used for longitudinal analyses to model the effects of alcohol consumption groups on these measures. All models were adjusted for covariates. In the cross-sectional analysis, modelled values of the muscle mass measures all showed a peak at medium levels of alcohol consumption and a steep decline with increasing alcohol consumption. Modelled differences in muscle mass from zero consumption of alcohol to 160 g/d ranged from 3.6 to 4.9% for ALM/BMI for men and women, respectively, and 3.6 to 6.1% for FFM%. Grip strength consistently increased with alcohol consumption. No association between alcohol consumption and muscle measures were seen in the longitudinal results. Our results suggest that higher levels of alcohol consumption could have detrimental effects on muscle mass in middle- and older-aged men and women.

Higher dietary protein intake is associated with sarcopenia in older British twins.

BACKGROUND: Sarcopenia, characterised by an accelerated loss of skeletal muscle mass and function, is associated with negative outcomes. This study aimed to evaluate factors associated with skeletal muscle strength, mass and sarcopenia, particularly protein intake, and to assess whether shared twin characteristics are important. METHODS: This study utilised cross-sectional data from a study of community-dwelling twins aged ≥60 years. Multivariable logistic regression and between- and within-twin pair regression modelling were used. RESULTS: Participants (n = 3,302) were 89% female (n = 2,923), aged a mean of 72.1 (±7.3) years and composed of 858 (55%) monozygotic, 709 (45%) dizygotic twin pairs and 168 individual lone twins. Using optimal protein intake as the reference group (1.0-1.3 g/kg/day), there was no significant association between protein intake (neither high nor low) and low muscle strength, or between low protein intake and sarcopenia (odds ratio (OR) 0.7; 95% confidence interval (CI) 0.39-1.25; P = 0.229) in unadjusted models. High protein intake (>1.3 g/kg/day) was associated with low muscle mass (OR 1.76; 95% CI 1.39-2.24; P < 0.0001), while low protein intake was protective (OR 0.52; 95% CI 0.40-0.67; P < 0.0001). High protein intake was associated with sarcopenia (OR 2.04; 95% CI 1.21-3.44; P = 0.008), and this was robust to adjustment for demographic, anthropometric and dietary factors. The association between muscle strength and weight, body mass index, healthy eating index, protein intake and alpha diversity was not significantly influenced by shared twin factors, indicating greater amenability to interventions. CONCLUSIONS: High protein intake is associated with sarcopenia in a cohort of healthy older twins.

Coapplication of Magnesium Supplementation and Vibration Modulate Macrophage Polarization to Attenuate Sarcopenic Muscle Atrophy through PI3K/Akt/mTOR Signaling Pathway.

Sarcopenia is an age-related geriatric syndrome characterized by the gradual loss of muscle mass and function. Low-magnitude high-frequency vibration (LMHFV) was shown to be beneficial to structural and functional outcomes of skeletal muscles, while magnesium (Mg) is a cofactor associated with better indices of skeletal muscle mass and strength. We hypothesized that LMHFV, Mg and their combinations could suppress inflammation and sarcopenic atrophy, promote myogenesis via PI3k/Akt/mTOR pathway in senescence-accelerated mouse P8 (SAMP8) mice and C2C12 myoblasts. Results showed that Mg treatment and LMHFV could significantly decrease inflammatory expression (C/EBPα and LYVE1) and modulate a CD206-positive M2 macrophage population at month four. Mg treatment also showed significant inhibitory effects on FOXO3, MuRF1 and MAFbx mRNA expression. Coapplication showed a synergistic effect on suppression of type I fiber atrophy, with significantly higher IGF-1, MyoD, MyoG mRNA (p < 0.05) and pAkt protein expression (p < 0.0001) during sarcopenia. In vitro inhibition of PI3K/Akt and mTOR abolished the enhancement effects on myotube formation and inhibited MRF mRNA and p85, Akt, pAkt and mTOR protein expressions. The present study demonstrated that the PI3K/Akt/mTOR pathway is the predominant regulatory mechanism through which LMHFV and Mg enhanced muscle regeneration and suppressed atrogene upregulation.

Nonsense-mediated mRNA decay efficiency varies in choroideremia providing a target to boost small molecule therapeutics.

Choroideremia (CHM) is an x-linked recessive chorioretinal dystrophy, with 30% caused by nonsense mutations in the CHM gene resulting in an in-frame premature termination codon (PTC). Nonsense-mediated mRNA decay (NMD) is the cell's natural surveillance mechanism that detects and destroys PTC-containing transcripts, with UPF1 being the central NMD modulator. NMD efficiency can be variable amongst individuals with some transcripts escaping destruction, leading to the production of a truncated non-functional or partially functional protein. Nonsense suppression drugs, such as ataluren, target these transcripts and read-through the PTC, leading to the production of a full length functional protein. Patients with higher transcript levels are considered to respond better to these drugs, as more substrate is available for read-through. Using Quantitative reverse transcription PCR (RT-qPCR), we show that CHM mRNA expression in blood from nonsense mutation CHM patients is 2.8-fold lower than controls, and varies widely amongst patients, with 40% variation between those carrying the same UGA mutation [c.715 C>T; p.(R239*)]. These results indicate that although NMD machinery is at work, efficiency is highly variable and not wholly dependent on mutation position. No significant difference in CHM mRNA levels was seen between two patients' fibroblasts and their induced pluripotent stem cell-derived retinal pigment epithelium. There was no correlation between CHM mRNA expression and genotype, phenotype or UPF1 transcript levels. NMD inhibition with caffeine was shown to restore CHM mRNA transcripts to near wild-type levels. Baseline mRNA levels may provide a prognostic indicator for response to nonsense suppression therapy, and caffeine may be a useful adjunct to enhance treatment efficacy where indicated.

Fracture Incidence and the Relevance of Dietary and Lifestyle Factors Differ in the United Kingdom and Hong Kong: An International Comparison of Longitudinal Cohort Study Data.

Geographic variation in fracture risk may be due to divergent profiles of dietary, lifestyle, and other risk factors between populations. We investigated differences in fracture rates between two older-population cohorts: the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk cohort (n = 7732) in the United Kingdom (UK), and the Mr and Ms Os cohort (n = 3956) in Hong Kong (HK). Data were collected by questionnaires, laboratory assessments, and hospital records. Incidence of hip, spine, and wrist fractures in the two cohorts was calculated and multivariable regression was used to explore variables important to fracture risk. Total hip, spine, and wrist fracture incidence was higher in the UK vs HK for women (13.70 vs 8.76 per 1000 person-years; p < 0.001), but not men (5.95 vs 5.37 per 1000 person-years; p = 0.337), and the proportions of different fractures also varied between cohorts (p < 0.001). Hip fracture was the most common UK fracture (accounting for 56.8% fractures in men and 52.6% in women), while wrist fracture was most common in HK (42.9% in men and 57.9% in women). The major contributor to total fracture risk in multivariable regression models of both cohorts and sexes, was age; with BMI also an important contributor to fracture risk HK men and UK women. The distribution of factors relevant to fracture risk, and the rates of different fractures, varied significantly between UK and HK cohorts. However, the importance of each factor in contributing to fracture risk was similar between the cohorts. The differences in fracture rates suggest targeted approaches may be required when developing interventions and public health recommendations to reduce the burden of osteoporosis in these two countries.

Lower Dietary and Circulating Vitamin C in Middle- and Older-Aged Men and Women Are Associated with Lower Estimated Skeletal Muscle Mass.

BACKGROUND: Age-related loss of skeletal muscle mass contributes to poor outcomes including sarcopenia, physical disability, frailty, type 2 diabetes, and mortality. Vitamin C has physiological relevance to skeletal muscle and may protect it during aging, but few studies have investigated its importance in older populations. OBJECTIVES: We aimed to investigate cross-sectional associations of dietary and plasma vitamin C with proxy measures of skeletal muscle mass in a large cohort of middle- and older-aged individuals. METHODS: We analyzed data from >13,000 men and women in the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, aged 42-82 y. Fat-free mass (FFM), as a proxy for skeletal muscle mass, was estimated using bioelectrical impedance analysis and expressed as a percentage of total mass (FFM%) or standardized by BMI (FFMBMI). Dietary vitamin C intakes were calculated from 7-d food diary data, and plasma vitamin C was measured in peripheral blood. Multivariable regression models, including relevant lifestyle, dietary, and biological covariates, were used to determine associations between FFM measures and quintiles of dietary vitamin C or insufficient compared with sufficient plasma vitamin C (<50 µmol/L and ≥50 µmol/L). RESULTS: Positive trends were found across quintiles of dietary vitamin C and FFM measures for both sexes, with interquintile differences in FFM% and FFMBMI of 1.0% and 2.3% for men and 1.9% and 2.9% for women, respectively (all P < 0.001). Similarly, FFM% and FFMBMI measures were higher in participants with sufficient than with insufficient plasma vitamin C: by 1.6% and 2.0% in men, and 3.4% and 3.9% in women, respectively (all P < 0.001). Associations were also evident in analyses stratified into <65-y and ≥65-y age groups. CONCLUSIONS: Our findings of positive associations, of both dietary and circulating vitamin C with measures of skeletal muscle mass in middle- and older-aged men and women, suggest that dietary vitamin C intake may be useful for reducing age-related muscle loss.

The Relationship Between Omega-3, Omega-6 and Total Polyunsaturated Fat and Musculoskeletal Health and Functional Status in Adults: A Systematic Review and Meta-analysis of RCTs.

We conducted a systematic review and meta-analysis to assess the effects of increasing dietary omega-3, omega-6 and mixed polyunsaturated fatty acids (PUFA) on musculoskeletal health, functional status, sarcopenia and risk of fractures. We searched Medline, Embase, The Cochrane library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) databases for Randomised Controlled Trials (RCTs) of adults evaluating the effects of higher versus lower oral omega-3, omega-6 or mixed PUFA for ≥ 6 months on musculoskeletal and functional outcomes. We included 28 RCTs (7288 participants, 31 comparisons), 23 reported effects of omega-3, one of omega-6 and four of mixed total PUFA. Participants and doses were heterogeneous. Six omega-3 trials were judged at low summary risk of bias. We found low-quality evidence that increasing omega-3 increased lumbar spine BMD by 2.6% (0.03 g/cm2, 95% CI - 0.02 to 0.07, 463 participants). There was also the suggestion of an increase in femoral neck BMD (of 4.1%), but the evidence was of very low quality. There may be little or no effect of omega-3 on functional outcomes and bone mass; effects on other outcomes were unclear. Only one study reported on effects of omega-6 with very limited data. Increasing total PUFA had little or no effect on BMD or indices of fat-free (skeletal) muscle mass (low-quality evidence); no data were available on fractures, BMD or functional status and data on bone turnover markers were limited. Trials assessing effects of increasing omega-3, omega-6 and total PUFA on functional status, bone and skeletal muscle strength are limited with data lacking or of low quality. Whilst there is an indication that omega-3 may improve BMD, high-quality RCTs are needed to confirm this and effects on other musculoskeletal outcomes.

Mediterranean Diet Reduces Risk of Incident Stroke in a Population With Varying Cardiovascular Disease Risk Profiles.

Background and Purpose­: Although some evidence has found that the Mediterranean diet (MD) is protective for stroke risk, few studies have investigated whether this relationship differs by sex or cardiovascular disease risk. Methods­: We investigated the relationship between adherence to the MD score, estimated using 7-day dietary diaries and risk of incident stroke in an observational prospective population-based cohort study of 23 232 men and women (54.5% women) aged 40 to 77 years who participated in the European Prospective Investigation into Cancer study in Norfolk, United Kingdom. Risk of incident stroke was calculated using multivariable Cox regression, in the whole population, and also stratified by sex and cardiovascular disease risk profile, using the Framingham risk score. Results­: During 17.0 years of follow-up (395 048 total person-years), 2009 incident strokes occurred. Risk of stroke was significantly reduced with greater adherence to the MD score (quartile 4 versus quartile 1 hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P-trend <0.01) in the whole population and in women (quartile 4 versus quartile 1 HR, 0.78; 95% CI, 0.65, 0.93; P-trend <0.01) but not in men (quartile 4 versus quartile 1 HR, 0.94; 95% CI, 0.79-1.12; P-trend =0.55). There was reduced risk of stroke in those at high risk of cardiovascular disease and across categories of the MD score (quartile 4 versus quartile 1 HR, 0.87; 95% CI, 0.76-0.99; P-trend =0.04). However, this was driven by the associations in women (quartile 4 versus quartile 1 HR, 0.80; 95% CI, 0.65-0.97; P-trend =0.02). Conclusions­: Greater adherence to the MD was associated with lower risk of stroke in a UK white population. For the first time in the literature, we also investigated the associations between the MD score in those at both low and high risk of cardiovascular disease. Although the findings in our study were driven by the associations in women, they have implications for the general public and clinicians for prevention of stroke.

Carotenoid dietary intakes and plasma concentrations are associated with heel bone ultrasound attenuation and osteoporotic fracture risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort.

Carotenoids are found in abundance in fruit and vegetables, and may be involved in the positive association of these foods with bone health. This study aimed to explore the associations of dietary carotenoid intakes and plasma concentrations with bone density status and osteoporotic fracture risk in a European population. Cross-sectional analyses (n 14 803) of bone density status, using calcaneal broadband ultrasound attenuation (BUA) and longitudinal analyses (n 25 439) of fracture cases were conducted on data from the prospective European Prospective Investigation into Cancer and Nutrition-Norfolk cohort of middle-aged and older men and women. Health and lifestyle questionnaires were completed, and dietary nutrient intakes were derived from 7-d food diaries. Multiple regression demonstrated significant positive trends in BUA for women across quintiles of dietary α-carotene intake (P=0·029), ß-carotene intake (P=0·003), ß-cryptoxanthin intake (P=0·031), combined lutein and zeaxanthin intake (P=0·010) and lycopene intake (P=0·005). No significant trends across plasma carotenoid concentration quintiles were apparent (n 4570). The Prentice-weighted Cox regression showed no trends in fracture risk across dietary carotenoid intake quintiles (mean follow-up time 12·5 years), except for a lower risk for wrist fracture in women with higher lutein and zeaxanthin intake (P=0·022); nevertheless, inter-quintile differences in fracture risk were found for both sexes. Analysis of plasma carotenoid data (mean follow-up time 11·9 years) showed lower hip fracture risk in men across higher plasma α-carotene (P=0·026) and ß-carotene (P=0·027) quintiles. This study provides novel evidence that dietary carotenoid intake is relevant to bone health in men and women, demonstrating that associations with bone density status and fracture risk exist for dietary intake of specific carotenoids and their plasma concentrations.

Amino Acid Intakes Are Inversely Associated with Arterial Stiffness and Central Blood Pressure in Women.

BACKGROUND: Although data suggest that intakes of total protein and specific amino acids (AAs) reduce blood pressure, data on other cardiovascular disease risk factors are limited. OBJECTIVE: We examined associations between intakes of AAs with known mechanistic links to cardiovascular health and direct measures of arterial stiffness, central blood pressure, and atherosclerosis. METHODS: In a cross-sectional study of 1898 female twins aged 18-75 y from the TwinsUK registry, intakes of 7 cardioprotective AAs (arginine, cysteine, glutamic acid, glycine, histidine, leucine, and tyrosine) were calculated from food-frequency questionnaires. Direct measures of arterial stiffness and atherosclerosis included central systolic blood pressure (cSBP), mean arterial pressure (MAP), augmentation index (AI), pulse wave velocity (PWV), and intima-media thickness (IMT). ANCOVA was used to assess the associations between endpoints of arterial stiffness and intake (per quintile), adjusting for potential confounders. RESULTS: In multivariable analyses, higher intakes of total protein and 7 potentially cardioprotective AAs were associated with lower cSBP, MAP, and PWV. Higher intakes of glutamic acid, leucine, and tyrosine were most strongly associated with PWV, with respective differences of -0.4 ± 0.2 m/s (P-trend = 0.02), -0.4 ± 0.2 m/s (P-trend = 0.03), and -0.4 ± 0.2 m/s (P-trend = 0.03), comparing extreme quintiles. There was a significant interaction between AA intakes and protein source, and higher intakes of AAs from vegetable sources were associated with lower central blood pressure and AI. Higher intakes of glutamic acid, leucine, and tyrosine from animal sources were associated with lower PWV. CONCLUSIONS: These data provide evidence to suggest that intakes of several AAs are associated with cardiovascular benefits beyond blood pressure reduction in healthy women. The magnitude of the observed associations was similar to those previously reported for other lifestyle factors. Increasing intakes of these AAs could be an important and readily achievable way to reduce cardiovascular disease risk.

Opposites don't attract: high spouse concordance for dietary supplement use in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) cohort study.

OBJECTIVE: Dietary supplements are commonly consumed but may not be beneficial for everyone. It is known that supplement users have healthy behaviour characteristics but until now concordance between spouses living in the same household has not been investigated and concordance may be an important behavioural determinant. DESIGN: Prospective cohort study, cross-sectional data analysis. SETTING: European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) in the UK, recruitment between 1993 and 1998. SUBJECTS: Married (or living as married) participants sharing a household, who attended a health examination and completed a 7 d diet diary were included in the analysis (n 11 060). The age range was 39-79 years. RESULTS: Nearly 75 % of the households in EPIC-Norfolk were concordant in their supplement use, with 46·7 % not using supplements and 27·0 % using supplements. Concordance increased with age; the percentage of concordant couples varied less by other sociodemographic characteristics. Participants who had a spouse who used a supplement were nearly nine times more likely to use a supplement (unadjusted). Depending on participants' sex and type of supplement used, odds ratios for 'supplement use by spouse' in the prediction of participants' supplement use varied between 6·2 and 11·7 adjusted for participants' age, smoking status, BMI, social class, education level and physical activity. CONCLUSIONS: 'Supplement use by spouse' is an independent and the strongest predictor of participants' supplement use. This phenomenon can be useful in the design of studies and health interventions; or when assessing risk of excessive intake from dietary supplements.

Intakes of anthocyanins and flavones are associated with biomarkers of insulin resistance and inflammation in women.

Although laboratory data suggest that several flavonoid subclasses are involved in glucose metabolism, limited clinical and epidemiologic data are available. The current study examined associations between habitual intake of flavonoid subclasses, insulin resistance, and related inflammatory biomarkers. In a cross-sectional study of 1997 females aged 18-76 y, intakes of total flavonoids and their subclasses (flavanones, anthocyanins, flavan-3-ols, polymeric flavonoids, flavonols, flavones) were calculated from food frequency questionnaires using an extended USDA database. Fasting serum glucose, insulin, high-sensitivity C-reactive protein (hs-CRP; n = 1432), plasminogen activator inhibitor-1 (n = 843), and adiponectin (n = 1452) concentrations were measured. In multivariable analyses, higher anthocyanin and flavone intake were associated with significantly lower peripheral insulin resistance [homeostasis model assessment of insulin resistance; quintile 5 (Q5) to Q1 = -0.1, P-trend = 0.04 for anthocyanins and flavones] as a result of a decrease in insulin concentrations (Q5-Q1 = -0.7 µU/mL, P-trend = 0.02 anthocyanins; Q5-Q1 = -0.5 µU/mL, P-trend = 0.02 flavones). Higher anthocyanin intake was also associated with lower hs-CRP concentrations (Q5-Q1 = -0.3 mg/L, P-trend = 0.04), whereas those in the highest quintile of flavone intake had improved adiponectin concentrations (Q5-Q1 = 0.7 µg/L, P-trend = 0.01). Anthocyanin-rich foods were also associated with lower insulin and inflammation levels. No significant associations were observed for total or other flavonoid subclasses. Higher intakes of both anthocyanins and flavones were associated with improvements in insulin resistance and hs-CRP. These associations were found with intakes readily achieved in the diet. The observed reduction in insulin concentrations was similar to that reported previously for other lifestyle factors. Dose-response trials are needed to ascertain optimal intakes for the potential reduction of type 2 diabetes risk.

Dietary fat and fatty acid profile are associated with indices of skeletal muscle mass in women aged 18-79 years.

Age-related loss of skeletal muscle mass results in a reduction in metabolically active tissue and has been related to the onset of obesity and sarcopenia. Although the causes of muscle loss are poorly understood, dietary fat has been postulated to have a role in determining protein turnover through an influence on both inflammation and insulin resistance. This study was designed to investigate the cross-sectional relation between dietary fat intake, as dietary percentage of fat energy (PFE) and fatty acid profile, with indices of skeletal muscle mass in the population setting. Body composition [fat-free mass (FFM; in kg)] and the fat-free mass index (FFMI; kg FFM/m(2)) was measured by using dual-energy X-ray absorptiometry in 2689 women aged 18-79 y from the TwinsUK Study and calculated according to quintile of dietary fat (by food-frequency questionnaire) after multivariate adjustment. Positive associations were found between the polyunsaturated-to-saturated fatty acid (SFA) ratio and indices of FFM, and inverse associations were found with PFE, SFAs, monounsaturated fatty acids (MUFAs), and trans fatty acids (TFAs) (all as % of energy). Extreme quintile dietary differences for PFE were -0.6 kg for FFM and -0.28 kg/m(2) for FFMI; for SFAs, MUFAs, and TFAs, these were -0.5 to -0.8 kg for FFM and -0.26 to -0.38 kg/m(2) for FFMI. These associations were of a similar magnitude to the expected decline in muscle mass that occurs over 10 y. To our knowledge, this is the first population-based study to demonstrate an association between a comprehensive range of dietary fat intake and FFM. These findings indicate that a dietary fat profile already associated with cardiovascular disease protection may also be beneficial for conservation of skeletal muscle mass.

Dietary intake measurement using 7 d diet diaries in British men and women in the European Prospective Investigation into Cancer-Norfolk study: a focus on methodological issues.

The aim of the present study was to describe the energy, nutrient and crude v. disaggregated food intake measured using 7 d diet diaries (7dDD) for the full baseline Norfolk cohort recruited for the European Prospective Investigation into Cancer (EPIC-Norfolk) study, with emphasis on methodological issues. The first data collection took place between 1993 and 1998 in Norfolk, East Anglia (UK). Of the 30,445 men and women, aged 40-79 years, registered with a general practitioner invited to participate in the study, 25,639 came for a health examination and were asked to complete a 7dDD. Data from diaries with data recorded for at least 1 d were obtained for 99% members of the cohort; 10,354 (89·8%) of the men and 12,779 (91·5%) of the women completed the diet diaries for all 7 d. Mean energy intake (EI) was 9·44 (SD 2·22) MJ/d and 7·15 (SD 1·66) MJ/d, respectively. EI remained approximately stable across the days, but there was apparent under-reporting among the participants, especially among those with BMI >25 kg/m². Micronutrient density was higher among women than among men. In conclusion, under-reporting is an issue, but not more so than that found in national surveys. How foods were grouped (crude or disaggregated) made a difference to the estimates obtained, and comparison of intakes showed wide limits of agreement. The choice of variables influences estimates obtained from the food group data; while this may not alter the ranking of individuals within studies, this issue may be relevant when comparing absolute food intakes between studies.

The effects of flavonoids on bone.

Osteoporosis and fragility fractures are a growing problem for our aging population with around 1 in 2 women and 1 in 5 men suffering from an osteoporotic fracture during their lifetime. Although there are established factors that can reduce the risk of fracture such as maintaining physical activity, ceasing smoking, and adequate vitamin D status, and intakes of calcium; dietary mechanisms are less well established. The relevance of the flavonoid group of bioactive compounds found in fruits and vegetables has been less investigated. Two human epidemiologic studies in women found positive associations between total dietary flavonoid intake and bone mineral density. Flavonoids may protect against bone loss by upregulating signaling pathways that promote osteoblast function, by reducing the effects of oxidative stress or chronic low-grade inflammation. The limitations of the existing research are explored in the manuscript and it is concluded that further research is needed, in this promising area.

Is there a role for vitamin C in preventing osteoporosis and fractures? A review of the potential underlying mechanisms and current epidemiological evidence.

Osteoporosis and related fractures are a major global health issue, but there are few preventative strategies. Previously reported associations between higher intakes of fruits and vegetables and skeletal health have been suggested to be partly attributable to vitamin C. To date, there is some evidence for a potential role of vitamin C in osteoporosis and fracture prevention but an overall consensus of published studies has not yet been drawn. The present review aims to provide a summary of the proposed underlying mechanisms of vitamin C on bone and reviews the current evidence in the literature, examining a potential link between vitamin C intake and status with osteoporosis and fractures. The Bradford Hill criteria were used to assess reported associations. Recent animal studies have provided insights into the involvement of vitamin C in osteoclastogenesis and osteoblastogenesis, and its role as a mediator of bone matrix deposition, affecting both the quantity and quality of bone collagen. Observational studies have provided some evidence for this in the general population, showing positive associations between dietary vitamin C intake and supplements and higher bone mineral density or reduced fracture risk. However, previous intervention studies were not sufficiently well designed to evaluate these associations. Epidemiological data are particularly limited for vitamin C status and for fracture risk and good-quality randomised controlled trials are needed to confirm previous epidemiological findings. The present review also highlights that associations between vitamin C and bone health may be non-linear and further research is needed to ascertain optimal intakes for osteoporosis and fracture prevention.

Dietary antioxidants and the aetiology of pancreatic cancer: a cohort study using data from food diaries and biomarkers.

OBJECTIVE: To investigate whether the dietary antioxidants vitamins C and E, selenium and zinc decrease the risk of developing pancreatic cancer, for the first time using 7-day food diaries, the most accurate dietary methodology in prospective work. DESIGN: 23,658 participants, aged 40-74 years, recruited into the EPIC-Norfolk Study completed 7-day food diaries which recorded foods, brands and portion sizes. Nutrient intakes were calculated in those later diagnosed with pancreatic cancer and in 3970 controls, using a computer program with information on 11,000 foods. Vitamin C was measured in serum samples. The HRs of developing pancreatic cancer were estimated across quartiles of intake and thresholds of the lowest quartile (Q1) against a summation of the three highest (Q2-4). RESULTS: Within 10 years, 49 participants (55% men), developed pancreatic cancer. Those eating a combination of the highest three quartiles of all of vitamins C and E and selenium had a decreased risk (HR=0.33, 95% CI 0.13 to 0.84, p<0.05). There were threshold effects (Q2-4 vs Q1) for selenium (HR=0.49, 95% CI 0.26 to 0.93, p<0.05) and vitamin E (HR=0.57, 95% CI 0.29 to 1.09, p<0.10). The HRs of quartiles for antioxidants, apart from zinc, were <1, but not statistically significant. For vitamin C, there was an inverse association with serum measurements (HR trend=0.67, 95% CI 0.49 to 0.91, p=0.01), but the threshold effect from diaries was not significant (HR=0.68, 95% CI 0.37 to 1.26). CONCLUSION: The results support measuring antioxidants in studies investigating the aetiology of pancreatic cancer. If the association is causal, 1 in 12 cancers might be prevented by avoiding the lowest intakes.

The Dietary Inflammatory Index and Its Associations with Biomarkers of Nutrients with Antioxidant Potential, a Biomarker of Inflammation and Multiple Long-Term Conditions.

We aimed to validate the Dietary Inflammatory Index (DII®) and assess the cross-sectional associations between the DII® and multiple long-term conditions (MLTCs) and biomarker concentrations and MLTCs using data from the European Prospective Investigation into Cancer (EPIC-Norfolk) study (11,113 men and 13,408 women). The development of MLTCs is associated with low-grade chronic inflammation, and ten self-reported conditions were selected for our MLTC score. Data from a validated FFQ were used to calculate energy-adjusted DII® scores. High-sensitivity C-reactive protein (hs-CRP) and circulating vitamins A, C, E, ß-carotene and magnesium were available. Micronutrient biomarker concentrations were significantly lower as the diet became more pro-inflammatory (p-trend < 0.001), and hs-CRP concentrations were significantly higher in men (p-trend = 0.006). A lower DII® (anti-inflammatory) score was associated with 12-40% higher odds of MLTCs. Lower concentrations of vitamin C and higher concentrations of hs-CRP were associated with higher odds of MLTCs. The majority of the associations in our study between MLTCs, nutritional biomarkers, hs-CRP and the DII® were as expected, indicating that the DII® score has criterion validity. Despite this, a more anti-inflammatory diet was associated with higher odds of MLTCs, which was unexpected. Future studies are required to better understand the associations between MLTCs and the DII®.

Effect of gut microbiome modulation on muscle function and cognition: the PROMOTe randomised controlled trial.

Studies suggest that inducing gut microbiota changes may alter both muscle physiology and cognitive behaviour. Gut microbiota may play a role in both anabolic resistance of older muscle, and cognition. In this placebo controlled double blinded randomised controlled trial of 36 twin pairs (72 individuals), aged ≥60, each twin pair are block randomised to receive either placebo or prebiotic daily for 12 weeks. Resistance exercise and branched chain amino acid (BCAA) supplementation is prescribed to all participants. Outcomes are physical function and cognition. The trial is carried out remotely using video visits, online questionnaires and cognitive testing, and posting of equipment and biological samples. The prebiotic supplement is well tolerated and results in a changed gut microbiome [e.g., increased relative Bifidobacterium abundance]. There is no significant difference between prebiotic and placebo for the primary outcome of chair rise time (ß = 0.579; 95% CI -1.080-2.239 p = 0.494). The prebiotic improves cognition (factor score versus placebo (ß = -0.482; 95% CI,-0.813, -0.141; p = 0.014)). Our results demonstrate that cheap and readily available gut microbiome interventions may improve cognition in our ageing population. We illustrate the feasibility of remotely delivered trials for older people, which could reduce under-representation of older people in clinical trials. ClinicalTrials.gov registration: NCT04309292.