Higher diet quality relates to decelerated epigenetic aging.

BACKGROUND: DNA methylation-based epigenetic age measures have been used as biological aging markers and are associated with a healthy lifespan. Few population-based studies have examined the relation between diet and epigenetic age acceleration. OBJECTIVES: We aimed to investigate the relation between diet quality and epigenetic age acceleration. METHODS: We analyzed data from 1995 participants (mean age, 67 years; 55% women) of the Framingham Heart Study Offspring Cohort. Cross-sectional associations between the Dietary Approaches to Stop Hypertension (DASH) score and 3 whole-blood DNA methylation-derived epigenetic age acceleration measures-Dunedin Pace of Aging Methylation (DunedinPoAm), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA)-were examined. A mediation analysis was conducted to assess the mediating role of epigenetic age acceleration in relation to DASH and all-cause mortality. RESULTS: A higher DASH score was associated with lower levels of DunedinPoAm (ß = -0.05; SE = 0.02; P = 0.007), GrimAA (ß = -0.09; SE = 0.02; P < 0.001), and PhenoAA (ß = -0.07; SE = 0.02; P = 0.001). All 3 epigenetic measures mediated the association between the DASH score and all-cause mortality, with mean proportions of 22.1% for DunedinPoAm (Pmediation = 0.04), 45.1% for GrimAA (Pmediation = 0.001), and 22.9% for PhenoAA (Pmediation = 0.03). An interaction was observed between the DASH score and smoking status in relation to the epigenetic aging markers. The association between the DASH score and epigenetic aging markers tended to be stronger in "ever-smokers" (former and current smokers) compared to "never-smokers." The proportions of mediation were 31.3% for DunedinPoAm, 46.8% for GrimAA, and 10.3% for PhenoAA in ever-smokers, whereas no significant mediation was observed in never-smokers. CONCLUSIONS: Higher diet quality is associated with slower epigenetic age acceleration, which partially explains the beneficial effect of diet quality on the lifespan. Our findings emphasize that adopting a healthy diet is crucial for maintaining healthy aging.

Genome-wide association study of breakfast skipping links clock regulation with food timing.

BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

Associations of Whole and Refined Grain Intakes with Adiposity-Related Cancer Risk in the Framingham Offspring Cohort (1991-2013).

Case-control studies suggest that higher whole grain and lower refined grain intakes are associated with reduced cancer risk, but longitudinal evidence is limited. The objective of this prospective cohort study is to evaluate associations between whole and refined grains and their food sources in relation to adiposity-related cancer risk. Participants were adults from the Framingham Offspring cohort (N = 3,184; ≥18 yr). Diet, measured using a food frequency questionnaire, medical and lifestyle data were collected at exam 5 (1991-95). Between 1991 and 2013, 565 adiposity-related cancers were ascertained using pathology reports. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals for associations of whole and refined grains with risk of adiposity-related cancers combined and with risk of breast and prostate cancers in exploratory site-specific analyses. Null associations between whole and refined grains and combined incidence of adiposity-related cancers were observed in multivariable-adjusted models (HR: 0.94; 95% CI: 0.71-1.23 and HR: 0.98; 95% CI: 0.70-1.38, respectively). In exploratory analyses, higher intakes of whole grains (oz eq/day) and whole grain food sources (servings/day) were associated with 39% and 47% lower breast cancer risk (HR: 0.61; 95% CI: 0.38-0.98 and HR: 0.53; 95% CI: 0.33-0.86, respectively). In conclusion, whole and refined grains were not associated with adiposity-related cancer risk. Whole grains may protect against breast cancer, but findings require confirmation within a larger sample and in other ethnic groups.

Magnesium Intake, Quality of Carbohydrates, and Risk of Type 2 Diabetes: Results From Three U.S. Cohorts.

OBJECTIVE: Magnesium intake is inversely associated with risk of type 2 diabetes in many observational studies, but few have assessed this association in the context of the carbohydrate quality of the diet. We hypothesized that higher magnesium intake is associated with lower risk of type 2 diabetes, especially in the context of a poor carbohydrate-quality diet characterized by low cereal fiber or high glycemic index (GI) or glycemic load (GL). RESEARCH DESIGN AND METHODS: In the Nurses' Health Study (NHS; 1984-2012, n = 69,176), NHS2 (1991-2013, n = 91,471), and the Health Professionals' Follow-Up Study (1986-2012, n = 42,096), dietary intake was assessed from food frequency questionnaires every 4 years. Type 2 diabetes was ascertained by biennial and supplementary questionnaires. We calculated multivariate hazard ratios (HRs) of magnesium intake and incident diabetes, adjusted for age, BMI, family history of diabetes, physical activity, smoking, hypertension, hypercholesterolemia, GL, energy intake, alcohol, cereal fiber, polyunsaturated fats, trans fatty acids, and processed meat, and we considered the joint associations of magnesium and carbohydrate quality on diabetes risk. RESULTS: We documented 17,130 incident cases of type 2 diabetes over 28 years of follow-up. In pooled analyses across the three cohorts, those with the highest magnesium intake had 15% lower risk of type 2 diabetes compared with those with the lowest intake (pooled multivariate HR in quintile 5 vs. 1: 0.85 [95% CI 0.80-0.91], P < 0.0001). Higher magnesium intake was more strongly associated with lower risk of type 2 diabetes among participants with high GI or low cereal fiber than among those with low GI or high cereal fiber (both P interaction <0.001). CONCLUSIONS: Higher magnesium intake is associated with lower risk of type 2 diabetes, especially in the context of lower carbohydrate-quality diets.

Phytochemical Pharmacokinetics and Bioactivity of Oat and Barley Flour: A Randomized Crossover Trial.

While dietary fiber plays an important role in the health benefits associated with whole grain consumption, other ingredients concentrated in the outer bran layer, including alkylresorcinols, lignans, phenolic acids, phytosterols, and tocols, may also contribute to these outcomes. To determine the acute bioavailability and pharmacokinetics of the major phytochemicals found in barley and oats, we conducted a randomized, three-way crossover trial in 13 healthy subjects, aged 40-70 years with a body mass index (BMI) of 27-35.9 kg/m². After a two-day run-in period following a diet low in phytochemicals, subjects were randomized to receive muffins made with either 48 g whole oat flour, whole barley flour, or refined wheat flour plus cellulose (control), with a one-week washout period between each intervention. At the same time, an oral glucose tolerance test was administered. In addition to plasma phytochemical concentrations, glucose and insulin responses, biomarkers of antioxidant activity, lipid peroxidation, inflammation, and vascular remodeling were determined over a 24-h period. There was no significant effect on acute bioavailability or pharmacokinetics of major phytochemicals. Administered concurrently with a glucose bolus, the source of whole grains did not attenuate the post-prandial response of markers of glucoregulation and insulin sensitivity, inflammation, nor vascular remodeling compared to the refined grain control. No significant differences were observed in the bioavailability or postprandial effects between whole-oat and whole-barley compared to a refined wheat control when administered with a glucose challenge. These null results may be due, in part, to the inclusion criteria for the subjects, dose of the whole grains, and concurrent acute administration of the whole grains with the glucose bolus.

Consumption of whole grains and cereal fiber in relation to cancer risk: a systematic review of longitudinal studies.

CONTEXT: Evidence from previous reviews is supportive of the hypothesis that whole grains may protect against various cancers. However, the reviews did not report risk estimates for both whole grains and cereal fiber and only case-control studies were evaluated. It is unclear whether longitudinal studies support this conclusion. OBJECTIVE: To evaluate associations between whole grains and cereal fiber in relation to risk of lifestyle-related cancers data from longitudinal studies was evaluated. DATA SOURCES: The following 3 databases were systematically searched: PubMed, EMBASE, and Cochrane CENTRAL. STUDY SELECTION: A total of 43 longitudinal studies conducted in Europe and North America that reported multivariable-adjusted risk estimates for whole grains (n = 14), cereal fiber (n = 23), or both (n = 6) in relation to lifestyle-related cancers were included. DATA EXTRACTION: Information on study location, cohort name, follow-up duration, sample characteristics, dietary assessment method, risk estimates, and confounders was extracted. DATA SYNTHESIS: Of 20 studies examining whole grains and cancer, 6 studies reported a statistically significant 6%-47% reduction in risk, but 14 studies showed no association. Of 29 studies examining cereal fiber intake in relation to cancer, 8 showed a statistically significant 6%-49% reduction in risk, whereas 21 studies reported no association. CONCLUSIONS: This systematic review concludes that most studies were suggestive of a null association. Whole grains and cereal fiber may protect against gastrointestinal cancers, but these findings require confirmation in additional studies.

Potential link between excess added sugar intake and ectopic fat: a systematic review of randomized controlled trials.

CONTEXT: The effect of added sugar intake on ectopic fat accumulation is a subject of debate. OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to examine the potential effect of added sugar intake on ectopic fat depots. DATA SOURCES: MEDLINE, CAB Abstracts, CAB Global Health, and EBM (Evidence-Based Medicine) Reviews - Cochrane Central Register of Controlled Trials databases were searched for studies published from 1973 to September 2014. DATA EXTRACTION: RCTs with a minimum of 6 days' duration of added sugar exposure in the intervention group were selected. The dosage of added sugar intake as a percentage of total energy was extracted or calculated. Means and standard deviations of pre- and post-test measurements or changes in ectopic fat depots were collected. DATA SYNTHESIS: Fourteen RCTs were included. Most of the studies had a medium to high risk of bias. Meta-analysis showed that, compared with eucaloric controls, subjects who consumed added sugar under hypercaloric conditions likely increased ectopic fat, particularly in the liver (pooled standardized mean difference = 0.9 [95%CI, 0.6-1.2], n = 6) and muscles (pooled SMD = 0.6 [95%CI, 0.2-1.0], n = 4). No significant difference was observed in liver fat, visceral adipose tissue, or muscle fat when isocaloric intakes of different sources of added sugars were compared. CONCLUSIONS: Data from a limited number of RCTs suggest that excess added sugar intake under hypercaloric diet conditions likely increases ectopic fat depots, particularly in the liver and in muscle fat. There are insufficient data to compare the effect of different sources of added sugars on ectopic fat deposition or to compare intake of added sugar with intakes of other macronutrients. Future well-designed RCTs with sufficient power and duration are needed to address the role of sugars on ectopic fat deposition.

Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease affects ∼30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. METHODS: Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda. RESULTS: After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend=0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend=0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. CONCLUSION: In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease.

Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study.

OBJECTIVES: The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC). BACKGROUND: Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying cardiovascular disease. Little is known about the association of magnesium intake and atherosclerotic calcification in humans. METHODS: We examined cross-sectional associations of self-reported total (dietary and supplemental) magnesium intake estimated by food frequency questionnaire with CAC and AAC in participants of the Framingham Heart Study who were free of cardiovascular disease and underwent Multi-Detector Computed Tomography (MDCT) of the heart and abdomen (n = 2,695; age: 53 ± 11 years), using multivariate-adjusted Tobit regression. CAC and AAC were quantified using modified Agatston scores (AS). Models were adjusted for age, sex, body mass index, smoking status, systolic blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy (women only), menopausal status (women only), treatment for hyperlipidemia, hypertension, cardiovascular disease prevention, or diabetes, as well as self-reported intake of calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy. Secondary analyses included logistic regressions of CAC and AAC outcomes as cut-points (AS >0 and AS ≥90th percentile for age and sex), as well as sex-stratified analyses. RESULTS: In fully adjusted models, a 50-mg/day increment in self-reported total magnesium intake was associated with 22% lower CAC (p < 0.001) and 12% lower AAC (p = 0.07). Consistent with these observations, the odds of having any CAC were 58% lower (p trend: <0.001) and any AAC were 34% lower (p trend: 0.01), in those with the highest compared to those with the lowest magnesium intake. Stronger inverse associations were observed in women than in men. CONCLUSIONS: In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium's protective associations in stroke and fatal coronary heart disease.

Whole- and refined-grain intakes are differentially associated with abdominal visceral and subcutaneous adiposity in healthy adults: the Framingham Heart Study.

BACKGROUND: Observational studies have linked higher intakes of whole grains to lower abdominal adiposity; however, the association between whole- and refined-grain intake and body fat compartments has yet to be reported. OBJECTIVE: Different aspects of diet may be differentially related to body fat distribution. The purpose of this study was to assess associations between whole- and refined-grain intake and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). DESIGN: Cross-sectional associations between whole- and refined-grain intakes, waist circumference measures, and abdominal SAT and VAT volumes were examined in 2834 Framingham Heart Study participants (49.4% women; age range: 32-83 y). Dietary information was assessed with the use of a semiquantitative food-frequency questionnaire. RESULTS: Whole-grain intake was inversely associated with SAT (2895 compared with 2552 cm³ in the lowest compared with the highest quintile category, P for trend < 0.001) and VAT (1883 compared with 1563 cm³, P for trend < 0.001), after adjustment for age, sex, current smoking status, total energy, and alcohol intake. In contrast, refined-grain intake was positively associated with SAT (2748 compared with 2934 cm³, P for trend = 0.01) and VAT (1727 compared with 1928 cm³, P for trend < 0.001) in multivariable models. When SAT and VAT were evaluated jointly, the P value for SAT was attenuated (P = 0.28 for whole grains, P = 0.60 for refined grains), whereas VAT remained associated with both whole grains (P < 0.001) and refined grains (P < 0.001). CONCLUSIONS: Increasing whole-grain intake is associated with lower VAT in adults, whereas higher intakes of refined grains are associated with higher VAT. Further research is required to elicit the potential mechanisms whereby whole- and refined-grain foods may influence body fat distribution.

Predicted 25-hydroxyvitamin D score and incident type 2 diabetes in the Framingham Offspring Study.

BACKGROUND: Accumulating evidence suggests that vitamin D is involved in the development of type 2 diabetes (T2D). OBJECTIVE: Our objective was to examine the relation between vitamin D status and incidence of T2D. DESIGN: We used a subsample of 1972 Framingham Offspring Study participants to develop a regression model to predict plasma 25-hydroxyvitamin D [25(OH)D] concentrations from age, sex, body mass index, month of blood sampling, total vitamin D intake, smoking status, and total energy intake. Using this model, we calculated the predicted 25(OH)D score for each nondiabetic participant at the cohort's fifth examination to assess the association between the predicted 25(OH)D score and incidence of T2D by using Cox proportional hazards models. RESULTS: A total of 133 T2D cases were identified over a 7-y average follow-up. In comparison with individuals in the lowest tertile of the predicted 25(OH)D score at baseline, those in the highest tertile had a 40% lower incidence of T2D after adjustment for age, sex, waist circumference, parental history of T2D, hypertension, low HDL cholesterol, elevated triglycerides, impaired fasting glucose, and Dietary Guidelines for Americans Adherence Index score (hazard ratio: 0.60; 95% CI: 0.37, 0.97; P for trend = 0.03). CONCLUSIONS: Our findings suggest that higher vitamin D status is associated with decreased risk of T2D. Maintaining optimal 25(OH)D status may be a strategy to prevent the development of T2D.

Plasma 25-hydroxyvitamin d is associated with markers of the insulin resistant phenotype in nondiabetic adults.

We examined the cross-sectional association between plasma 25-hydroxyvitamin D [25(OH)D] and markers of the insulin resistant phenotype. Plasma 25(OH)D concentrations were measured in 808 nondiabetic participants of the Framingham Offspring Study. Outcome measures included fasting and 2-h post 75-g oral glucose tolerance test (OGTT) glucose and insulin; these were used to calculate the homeostatic model assessment-insulin resistance (HOMA-IR) and insulin sensitivity index (ISI(0,120)). We also measured plasma adiponectin, triacylglycerol, and HDL cholesterol concentrations as markers of the insulin-resistant phenotype. After adjusting for age, sex, BMI, waist circumference, and current smoking status, plasma 25(OH)D concentration was inversely associated with fasting plasma glucose and insulin concentrations, and HOMA-IR. Compared with the participants in the lowest tertile category of plasma 25(OH)D, those in the highest tertile category had a 1.6% lower concentration of fasting plasma glucose (P-trend = 0.007), 9.8% lower concentration of fasting plasma insulin (P-trend = 0.001), and 12.7% lower HOMA-IR score (P-trend < 0.001). After adjusting for age and sex, plasma 25(OH)D was positively associated with ISI(0,120), plasma adiponectin, and HDL cholesterol and inversely associated with plasma triacylglycerol, but these associations were no longer significant after further adjustment for BMI, waist circumference, and current smoking status. 25(OH)D and 2-h post-OGTT glucose were not associated. Among adults without diabetes, vitamin D status was inversely associated with surrogate fasting measures of insulin resistance. These results suggest that vitamin D status may be an important determinant for type 2 diabetes mellitus.

Dietary magnesium intake is related to metabolic syndrome in older Americans.

BACKGROUND: Magnesium (Mg) is an essential cofactor for enzymes involved in glucose and insulin metabolism. Low intakes of dietary magnesium may be linked to greater risk of metabolic syndrome (MS) in older adults. AIM OF THE STUDY: The objective of this study was to examine the cross-sectional relationship between dietary Mg intake, metabolic risk factors and MS in elderly adults. METHODS: This study was conducted in a sample of 535 (179 men and 356 women) community-living adults aged 60 years and in Boston Massachusetts between the years 1981 and 1984. Dietary Mg intake was assessed by a 3-day food record and categorized by quartiles of dietary intake. The MS was defined based on criteria set by the Third Report of the National Cholesterol Education Program except that body mass index was used in place of waist circumference. Logistic regression analysis was used to examine the association between quartile categories of Mg intake, prevalence of MS and components of the MS. Models were adjusted for age, gender, BMI, race, educational attainment, marital status, smoking status, alcohol intake, exercise, energy intake, percentage of calories from saturated fat, use of antihypertensive or lipid medication. RESULTS: Mg intake was inversely associated with the MS; those with the highest intake of Mg had significantly lower risk of having MS compared to the lowest quartile of intake (OR: 0.36, 95% CI 0.19-0.69, P for trend 0.002). Significant inverse relationships were observed between Mg intake and BMI (OR: 0.47, 95% CI: 0.22-1.00, P trend = 0.03), and fasting glucose (OR: 0.41, 95% CI 0.22-0.77, P trend = 0.005). CONCLUSION: Our study demonstrates that Mg intake is inversely associated with prevalence of the MS in older adults. Older adults should be encouraged to eat foods rich in Mg, such as green vegetables, legumes and whole-grains.

Dietary and nondietary determinants of vitamin K biochemical measures in men and women.

Few epidemiological studies that rely on the food frequency questionnaire (FFQ) for dietary assessment have measured biomarkers of vitamin K intake to independently confirm associations between self-reported dietary vitamin K intake and disease risk. Associations were examined between two sensitive biomarkers of vitamin K status, plasma phylloquinone and serum percent undercarboxylated osteocalcin (%ucOC), and self-reported usual phylloquinone intake as estimated from a FFQ. The influence of other dietary and nondietary factors on plasma phylloquinone concentrations was also examined. Dietary phylloquinone intake was estimated using a FFQ in 369 men and 468 women of the Framingham Offspring Study. The prevalence of high %ucOC concentrations (>/= 20%), suggestive of a low vitamin K status, was 44% in men and 54% in women, respectively. After multivariate adjustment, the odds of a high %ucOC was 2.5 greater for women (odds ratio: 2.5; 95% confidence interval [CI]: 1.2-5.1) and almost three times greater for men (odds ratio: 2.8; 95% CI: 1.3-5.9) in the lowest dietary phylloquinone intake quintile category compared to the highest quintile category. Fasting triglyceride concentrations, smoking status and season were associated with plasma phylloquinone concentrations, independent of dietary phylloquinone intake. Phylloquinone and green vegetable intake was linearly associated with plasma phylloquinone, after adjustment for potential confounding factors. There were limitations in the use of the FFQ to predict plasma phylloquinone, evident in an observed plateau effect and required nondietary adjustment factors. Despite these caveats, these findings support the use of a FFQ for a relative assessment of vitamin K status in population-based studies.