Feeding intervention potentiates the effect of mechanical loading to induce new bone formation in mice

The benefits of increased human lifespan depend upon duration of healthy, independent living; the healthspan. Bone-wasting disorders contribute significantly to loss of independence, frailty, and morbidity in older people. Therefore, there is an unmet need globally for lifestyle interventions to reduce the likelihood of bone fractures with age. Although many mechanisms are involved in disorders of bone loss, there is no single regulatory pathway and, therefore, there is no single treatment available to prevent their occurrence. Our aim in these studies was to determine whether fasting/feeding interventions alter the effect of mechanical loading on bone anabolic activities and increase bone mass. In young 17-week-old mice, 16-hour fasting period followed by reintroduction of food for 2 hours increased markedly the potency of mechanical loading, that mimics the effect of exercise, to induce new cortical bone formation. Consistent with this finding, fasting and re-feeding increased the response of bone to a loading stimulus that, alone, does not stimulate new bone formation in ad-lib fed mice. Older mice (20 months) experienced no potentiation of loading-induced bone formation with the same timing of feeding interventions. Interestingly, the pre-, prandial, and postprandial endocrine responses in older mice were different from those in young animals. The hormones that change in response to timing of feeding have osteogenic effects that interact with loading-mediated effects. Our findings indicate associations between timing of food ingestion and bone adaptation to loading. If translated to humans, such non-pharmacological lifestyle interventions may benefit skeletal health of humans throughout life-course and in older age

Effect of maternal and post-weaning folate supply on gene-specific DNA methylation in the small intestine of weaning and adult apc +/min and wild type mice

Increasing evidence supports the developmental origins of adult health and disease hypothesis which argues for a causal relationship between adverse early life nutrition and increased disease risk in adulthood. Modulation of epigenetic marks, e.g., DNA methylation and consequential altered gene expression, has been proposed as a mechanism mediating these effects. Via its role as a methyl donor, dietary folate supply may influence DNA methylation. As aberrant methylation is an early event in colorectal cancer (CRC) pathogenesis, we hypothesized low maternal and/or post-weaning folate intake may influence methylation of genes involved in CRC development. We investigated the effects of maternal folate depletion during pregnancy and lactation on selected gene methylation in the small intestine of wild type (WT) and Apc(+/Min) mice at weaning and as adults. We also investigated the effects of folate depletion post-weaning on gene methylation in adult mice. Female C57Bl6/J mice were fed low or normal folate diets from mating with Apc(+/Min) males to the end of lactation. A sub-set of offspring were killed at weaning. Remaining offspring were weaned on to low or normal folate diets, resulting in four treatment groups of Apc(+/Min) and WT mice. p53 was more methylated in weaning and adult WT compared with Apc(+/Min) mice (p > 0.001). Igf2 and Apc were hypermethylated in adult Apc(+/Min) compared with WT mice (p = 0.004 and 0.012 respectively). Low maternal folate reduced p53 methylation in adults (p = 0.04). Low post-weaning folate increased Apc methylation in Apc(+/Min) mice only (p = 0.008 for interaction). These observations demonstrate that folate depletion in early life can alter epigenetic marks in a gene-specific manner. Also, the differential effects of altered folate supply on DNA methylation in WT and Apc(+/Min) mice suggest that genotype may modulate epigenetic responses to environmental cues and may have implications for the development of personalized nutrition

Towards a toolkit for the assessment and monitoring of musculoskeletal ageing

The complexities and heterogeneity of the ageing process have slowed the development of consensus on appropriate biomarkers of healthy ageing. The MRC-Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA) is a collaboration between researchers and clinicians at the Universities of Liverpool, Sheffield and Newcastle. One of CIMA's objectives is to 'Identify and share optimal techniques and approaches to monitor age-related changes in all musculoskeletal tissues, and to provide an integrated assessment of musculoskeletal function', i.e. to develop a toolkit for assessing musculoskeletal ageing. This toolkit is envisaged as an instrument that can be used to characterise and quantify musculoskeletal function during 'normal' ageing, lend itself to use in large-scale, internationally important cohorts, and provide a set of biomarker outcome measures for epidemiological and intervention studies designed to enhance healthy musculoskeletal ageing. Such potential biomarkers include: biochemical measurements in biofluids or tissue samples, in vivo measurements of body composition, imaging of structural and physical properties, and functional tests. The CIMA Toolkit Working Group assessed candidate biomarkers of musculoskeletal ageing under these four headings, detailed their biological bases, strengths and limitations, and made practical recommendations for their use. In addition, the CIMA Toolkit Working Group identified gaps in the evidence base and suggested priorities for further research on biomarkers of musculoskeletal ageing

Dietary nitrate does not have an effect on physical activity outcomes in healthy older adults : a randomized, cross-over trial

Dietary nitrate (〖NO〗_3^-) ingestion appears to enhance exercise capacity and performance in young individuals whereas inconclusive findings have been reported in older people. We conducted a double-blind, cross-over randomized clinical trial in older normal weight and overweight healthy participants testing whether beetroot juice (a rich source of 〖NO〗_3^-) for one week may increase nitric oxide bioavailability via the non-enzymatic pathway and enhance 1) exercise capacity during an incremental exercise test, 2) physical capability and 3) free-living physical activity. Twenty non-smoking healthy participants aged 60-75y and BMI 20.0-29.9kg/m2 were included. Pre and post supplementation resting, sub-maximal, maximal and recovery gas exchanges were measured. Physical capability was measured by hand-grip strength (HGS), time-up-and-go (TUG), repeated-chair-rising-test (RCRT), and 10m walking speed (WLS). Free-living physical activity was assessed by triaxal accelerometry. Changes in urinary and plasma 〖NO〗_3^- concentrations were measured by gas chromatography mass spectrometry. Nineteen participants (M/F=9/10) completed the study. Beetroot juice increased significantly both plasma and urinary 〖NO〗_3^- concentrations (p<0.001) compared to placebo. Beetroot juice did not influence resting, sub-maximal and maximal oxygen consumption during the incremental exercise test. In addition, measures of physical capability and physical activity levels measured in free-living conditions were not modified by beetroot juice ingestion. The positive effects of beetroot juice ingestion on exercise performance seen in young individuals were not replicated in healthy, older adults. Whether aging represents a modifier of the effects of dietary 〖NO〗_3^- on muscular performance is not known and mechanistic studies and larger trials are needed to test this hypothesis. Keywords: inorganic nitrate, nitric oxide, exercise, oxygen consumption, agin

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

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

Long‐term selenium‐yeast supplementation does not affect bone turnover markers: a randomized placebo‐controlled trial

Higher selenium status has been associated with lower bone turnover markers (BTM) in epidemiological studies. However, the long-term impact of selenium supplementation on BTMs has not been studied. We investigated the effects of selenium supplementation on BTMs including osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), collagen type I cross-linked C-telopeptide (CTX), and bone alkaline phosphatase (BALP) in the short (6 months) and long term (5 years). A total of 481 Danish men and women (60–74 years) were randomized to receive placebo-yeast versus 100, 200, or 300 μg selenium as selenium-enriched yeast daily for 5 years. Plasma selenium concentration was measured using inductively coupled plasma mass spectrometry, and BTMs were measured in nonfasted samples at baseline, 6 months, and 5 years. Data were analyzed by ANCOVA to investigate the shape of the dose-response relationships. Covariates included age, body mass index, baseline selenium status, baseline BTM, smoking, alcohol, supplement use, and medication. Plasma selenium concentration (mean 86.5 μg/d at baseline) increased significantly with increasing selenium supplementation to 152.6, 209.1, and 253.7 μg/L after 6 months and remained elevated at 5 years (158.4, 222.4, and 275.9 μg/L for 100, 200, and 300 μg supplemental selenium/d, respectively (p < 0.001)). There was no change in plasma selenium concentration in the placebo-treated group. There was no significant effect of selenium supplementation on OC (6 months p = 0.37; 5 years p = 0.63), PINP (6 months p = 0.37; 5 years p = 0.79), CTX (6 months p = 0.91; 5 years p = 0.58) or BALP (6 months p = 0.17; 5 years p = 0.53). The relatively replete baseline selenium status in the study participants may explain this lack of effect. Testing in more deficient populations may provide further insights into the impact of selenium supplementation on bone health. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

Selenium status and its determinants in very old adults: insights from the Newcastle 85+ Study

There is a dearth of data on Se status in very old adults. The aims of this study were to assess Se status and its determinants in 85-year-olds living in the Northeast of England by measuring serum Se and selenoprotein P (SELENOP) concentrations and glutathione peroxidase 3 (GPx3) activity. A secondary aim was to examine the interrelationships between each of the biomarkers. In total, 757 participants (463 women, 293 men) from the Newcastle 85+ Study were included. Biomarker concentrations were compared with selected cut-offs (serum Se: suboptimal 70 µg/l and deficient 45 µg/l; SELENOP: suboptimal 4·5 mg/l and deficient 2·6 mg/l). Determinants were assessed using linear regressions, and interrelationships were assessed using restricted cubic splines. Median (inter-quartile range) concentrations of serum Se, SELENOP and of GPx3 activity were 53·6 (23·6) µg/l, 2·9 (1·9) mg/l and 142·1 (50·7) U/l, respectively. Eighty-two percentage and 83 % of participants had suboptimal serum Se (< 70 µg/l) and SELENOP (< 4·5 mg/l), and 31 % and 40 % of participants had deficient serum Se (< 45 µg/l) and SELENOP (< 2·6 mg/l), respectively. Protein intake was a significant determinant of Se status. Additional determinants of serum Se were sex, waist:hip ratio, self-rated health and disease, while sex, BMI and physical activity were determinants of GPx3 activity. There was a linear association between serum Se and SELENOP, and nonlinear associations between serum Se and GPx3 activity and between SELENOP and GPx3 activity. These findings indicate that most participants had suboptimal Se status to saturate circulating SELENOP

Self-efficacy, habit strength, health locus of control and response to the personalised nutrition Food4Me intervention study

YesPurpose – Randomised controlled trials identify causal links between variables but not why an outcome has occurred. This analysis sought to determine how psychological factors assessed at baseline influenced response to personalised nutrition. Design/methodology/approach – Web-based, randomised, controlled trial (RCT) was conducted across seven European countries. Volunteers, both male and female, aged over 18 years were randomised to either a non-personalised (control) or a personalised (treatment) dietary advice condition. Linear mixed model analysis with fixed effects was used to compare associations between internal and external health locus of control (HLoC), nutrition self-efficacy (NS-E) and self-report habit index (S-RHI) at baseline (N 5 1444), with healthy eating index (HEI) and Mediterranean diet index (MDI) scores between conditions post-intervention (N 5 763). Findings – An increase in MDI scores was observed between baseline and six months in the treatment group which was associated with higher NS-E (pEU FP7 Project “Personalised nutrition: an integrated analysis of opportunities and challenges” (Contract No. KBBE. 2010.2.3–02, Project No. 265494

Association between diet-quality scores, adiposity, total cholesterol and markers of nutritional status in European adults: findings from the Food4Me study

Diet-quality scores (DQS), which are developed across the globe, are used to define adherence to specific eating patterns and have been associated with risk of coronary heart disease and type-II diabetes. We explored the association between five diet-quality scores (Healthy Eating Index, HEI; Alternate Healthy Eating Index, AHEI; MedDietScore, MDS; PREDIMED Mediterranean Diet Score, P-MDS; Dutch Healthy Diet-Index, DHDI) and markers of metabolic health (anthropometry, objective physical activity levels (PAL), and dried blood spot total cholesterol (TC), total carotenoids, and omega-3 index) in the Food4Me cohort, using regression analysis. Dietary intake was assessed using a validated Food Frequency Questionnaire. Participants (n = 1480) were adults recruited from seven European Union (EU) countries. Overall, women had higher HEI and AHEI than men (p < 0.05), and scores varied significantly between countries. For all DQS, higher scores were associated with lower body mass index, lower waist-to-height ratio and waist circumference, and higher total carotenoids and omega-3-index (p trends < 0.05). Higher HEI, AHEI, DHDI, and P-MDS scores were associated with increased daily PAL, moderate and vigorous activity, and reduced sedentary behaviour (p trend < 0.05). We observed no association between DQS and TC. To conclude, higher DQS, which reflect better dietary patterns, were associated with markers of better nutritional status and metabolic health